Concerns about HAART
(Highly Active Anti-Retroviral Therapy)

HAART is the therapy, composed of multiple anti-HIV drugs, that is prescribed to many HIV-positive people, even before they develop symptoms of AIDS (and without considering that many will never develop these symptoms). The therapy usually includes one nucleoside analog (DNA chain terminator), one protease inhibitor and either a second nucleoside analog (“nuke”) or a non-nucleoside reverse transcription inhibitor (NNRTI).

 

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Adverse Effects, in General

The list of side effects of HAART (Highly Active Antiretroviral Therapy) is so long, that it is impossible to categorize all of them. Further, some papers document side effects in a number of categories. The quotes below illustrate this.

“Between December 1996 and December 2001, 2947 patients with a diagnosis of HIV infection were enrolled into 1 of 5 CPCRA [Terry Beim Community Programs for Clinical Research on AIDS] clinical trials…for this analysis…All patients in this cohort were prescribed ART following enrollment. At 12 months of follow-up, 1951/2120 (92%) were [still] prescribed ART with 1475/2120 (70%) on protease inhibitor –based regimens, 421/2120 (20%) on nonnucleoside reverse transcription inhibitor–based regimens (no protease inhibitor), and 55/2120 (3%) solely on nucleoside reverse transcription inhibitors. Median follow-up was 20.7 months, a total of 5940 person-years…675 patients experienced a grade 4 event [serious or life threatening]; 332 developed an AIDS event; and 272 died (4.6 per 100 person-years)…The cumulative percentage of patients with a grade 4 event after 12, 24, and 36 months are, respectively, 15.6%, 23.7%, and 30.8%. Corresponding percentages for AIDS are, respectively, 7.3%, 10.8%, and 16.5% and corresponding percentages for death are, respectively, 3.9%, 7.9%, and 13.1%. The most common grade 4 events were: liver related (148 patients; rate = 2.6 per 100 person-years); neutropenia (89; 1.5/100 person-year); anemia (64; 1.1/100 person-year); cardiovascular (51; 0.89/100 person-year); pancreatitis (50; 0.85/100 person-year); psychiatric (44; 0.75/100 personyear); kidney-related (34; 0.58/100 person-year); thrombocytopenia (32; 0.54/100 person-year); and hemorrhage (25; 0.42/100 person-year) [these are much more likely to be therapy-related than HIV-related]…the rate of grade 4 events is greater than the rate of AIDS events, and the risk of death associated with these grade 4 events was very high for many events. ”

“Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear…The A/S/D [Abacavir/Stavudine/Didanosine] arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms…The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.”

“A daily dose of [Protease Inhibitors] includes about 1 gram of one or more DNA chain-terminators [AZT, 3TC etc.] per clinically ill person and 0.5 grams per asymptomatic HIV positive [person] per day, which is the equivalent of 1.5-3 million molecules of DNA chain terminators per body cell! ”

“Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxic effects resulting in multiple organ disorders. Liver involvement has been associated mainly with severe lactic acidosis and massive steatosis [fatty degeneration]…13 patients with HIV infection treated with NRTI-based regimens had low-grade abnormal liver test results associated with digestive and nonspecific general symptoms. Histologic examination of liver samples showed diffuse steatosis in only 6 cases and mild steatosis in the remaining cases…In all cases, ultrastructural study disclosed mitochondrial abnormalities. Our work demonstrates that NRTI-induced toxic effects in the liver may occur as indolent [without symptoms] nonspecific disease [but probably not forever, as the side effects worsen]”

“A total of 1064 treatment-emergent events were reported by 70 of the ITT patient set (100.0%), the majority of which (925 events; 86.9%) were grade 2 or less in severity. Just under 50% of patients experienced diarrhea and 44% reported experiencing nausea. Hyperlipidemia and neuropathy were reported in 25% and 10% of patients, respectively. Approximately 19% of patients developed rash and approximately 7% reported a general allergic reaction. No rash or allergic reaction was defined by an investigator [!] as a hypersensitivity reaction. In total, 266 events (25%) were considered by [!] the study investigator to be treatment related. The most common treatment-related adverse events were associated with the injection of enfuvirtide, with 52 patients (74.3%) experiencing at least one injection site-related adverse event…Treatment-related diarrhea was experienced by 8 patients (11.4%), and nausea and asthenia by 6 patients each (8.6%)…Of the 266 treatment-related adverse events, most (236, 88.7%) were classified as grade 1 or grade 2. Such events were reported by 58 (82.9%) and 26 patients (37.1%), respectively. Injection site reaction was the most common treatment-related grade 1 event reported (31 patients, 44.3%). Grade 1 injection site mass was reported by 21 patients (30.0%). Grade 1 injection site pain and injection site inflammation were reported by 16 (22.9%) and 11 patients (15.7%), respectively. Grade 2 asthenia, injection site pain, diarrhea and insomnia were each reported by three patients (4.3%)…44 serious adverse events were reported and 10 of these, reported by 7 patients (10.0%), were considered in the opinion of the investigator [!] to be potentially related to enfuvirtide…There were five deaths during the study, all of which were related to the progression of HIV disease and were not considered to be [!] attributable to enfuvirtide administration. ”

“We tested the long-term mitochondrial toxicity of NRTI [Nucleoside Reverse Transcriptase Inhibitors] with respect to mtDNA [Mitochondrial DNA], mtDNA-encoded respiratory chain protein and cell function (lactate production, intracellular lipids and cell proliferation) and confirm previous findings that NRTI are able to mediate a rapid decline of mtDNA [Mitochondria are the energy regulating organelles in every living cell]…We observed increased toxicity in some NRTI combinations, namely ddC–d4T and ZDV[AZT]–3TC, whereas the d4T–ddI combination did not result in increased toxicity…The fact that some NRTI at clinically relevant concentrations were able to decrease mtDNA beyond 25 days of exposure, suggests that studies on mitochondrial toxicity must be long-term investigations [not even a hint that people should stop taking these drugs, even though damaging mitochondria has extremely serious long-term health consequences, eventually fatal]”

“Our study shows that significant mitochondrial damage [mitochondria are the energy regulating units in every living cell] is present in HIV-infected patients with severe adverse effects after long-term antiretroviral treatment…Several lines of evidence support the clinical relevance of the mitochondrial damage…The level of lactate in CSF [Cerebro-Spinal Fluid] was correlated to the clinical severity…[Secondly, ] biochemical analyses of the respiratory chain…confirm the ubiquitous tissue dysfunction indicated by the clinical sympmtoms…[Thirdly ] the activities of respiratory chain in muscle and liver were significantly low both in individual patients and in the patient group taken as a whole…1 HIV patient without long-term antiretroviral therapy…[but with] chronic myalgias [muscle pain] for more than 10 years…had completely normal muscle mitochondrial function”

“the HIV protease inhibitor ritonavir at concentrations near clinical plasma levels is able to directly cause endothelial [blood vessel lining] mitochondrial DNA damage and cell death…This study suggests that HIV protease inhibitor-mediated endothelial injury may contribute to its cardiovascular complications.”

“In a short period of time we have observed three patients taking indinavir/ritonavir combined therapy who developed striking alopecia [hair loss] a few weeks after beginning treatment. In two of these patients the alopecia was severe, affecting the scalp, eyelids, eyebrows, beard, axilar [armpit] and pubic areas, and body hair. In all the patients alopecia was rapidly reversible after withdrawing drugs.”

“The toxicity and tolerability of HAART…are increasingly important factors in the decision to prescribe one of the more than 3000 potential regimens, because side-effects are frequent (74% of adults in the largest survey) and because long-term benefits depend on near perfect (>95%) and life-long adherence, which in turn are affected by tolerability (and human factors)…In view of the effect of adverse events on successful HAART, the fact that their study, analysis, and reporting by academia, industry, regulators, conference presenters, report writers, and journal editors has been poor, although not unique to HIV-1, is disappointing…The only adverse events that have to be studied to gain regulatory approval relate to essential (central nervous system, cardiovascular, and respiratory) organs. Blood, liver, and kidneys are invariably studied, although usually only by chemical analysis rather than by clinical assessment. However, many organs relevant to HAART toxicity were rarely studied in HAART trials…Adequate safety data for accelerated regulatory approval are thought to be generated from 400 to 500 patients who receive treatment for 6 months in controlled, blinded trials, and from about 100 patients treated for 12 months (500 for traditional approval--ie, 48-week, randomised data, usually with clinical endpoints), but not necessarily in randomised studies. The pooled data identify adverse events with 1% and 3% incidence with 3 months' and 12 months' therapy, respectively. The 23 HAART trials assessed [in this study] had a median of only 81 patients per group, and so individually had less power to detect adverse events (those with about 15% incidence)…Despite the many long-term adverse effects associated with HAART, phase 3 antiretroviral studies are often shorter than they used to be before HAART became available because of accelerated licensing and because of the emphasis placed on 24-week virological data as a marker of clinical benefit. Only half of 60 antiretroviral therapy trials done before 1997 and three of the 23 HAART trials reported post-week 48 data [yet people are expected to take these drug regimens for life]…Chronic, low-grade events, which are often not reported by patients and do not lead to immediate change in therapy, rather than acute, severe events, which are well reported and lead to early change in therapy, affect adherence to treatment in cohort studies. It is disappointing, therefore, that only two HAART studies reported adherence, and that no HAART study reported what adverse events resulted in poor adherence…Patients prevented from dying or developing AIDS by HAART can be thought of as having an increased quality of life. The same cannot be said, however, for asymptomatic patients at low risk of AIDS. And yet, as with adherence, quality of life was reported in only two of the 23 HAART studies…Additional weaknesses with respect to the study of adverse events include the absence of any systematic approach for identification of cause, prevention, and management of many adverse reactions, especially if unexpected…The number of individuals treated after approval of a drug is generally more than 1000 times that exposed before approval.2 An adverse reaction with a one in 1000 incidence has about a 50% chance of arising once before approval, but will arise in hundreds of patients after licensing…Additionally, any incidence often triples after licensing (and includes more severe events) because patients excluded from studies for various reasons are treated but studied less intensively…The aim of post-marketing surveillance, therefore, is to assess real-world safety, but passive surveillance is spontaneous and voluntary, with only occasional detailed, long-term monitoring. Passive surveillance is judged "the most cost-effective approach" (although this assertion has not been tested), but cannot reliably ascertain prevalence or risk factors, or compare drugs…The effect of post-marketing surveillance is further limited in that, for adverse events identified after approval of a drug, there is no standardised approach for the study of the association between the implicated drug or drug class and such adverse events…To account for individuals who withdraw from a study or who stop taking the study drug, plasma HIV-1 RNA is analysed by intention-to-treat, and missing values classified as virological failures (ITTM=F). Many HAART studies did not state, however, whether patients with undetectable HIV-1 RNA at study conclusion and who switched study drug during the trial were classified as virological failures. ITTM=F overestimates tolerability and adherence if it does not account for backbone antiretroviral drug switching for toxicity or if study drug continues only because another drug is initiated to control toxicity. Results of one study showed that 10% of patients ceased one backbone drug but continued to participate in the study with undetectable viral load at week 52. No study reported what proportion of patients required concomitant therapy to continue HAART…There are clear guidelines with respect to analysis and reporting of adverse events for regulatory submissions…Most reports do not, however, provide these data.”

“The two matched groups consisted of 283 treated [voluntarily with HAART] and 283 untreated patients [voluntarily untreated, matched for various characteristics]…The first AIDS-defining diseases consisted of 1 versus 3 esophageal candidiasis, 1 versus 1 Pneumocystis carinii pneumonia, 0 versus 2 cases of tuberculosis, 0 versus 1 recurrent bacterial pneumonia, 1 versus 3 Kaposi’s sarcoma, 2 versus 1 non-Hodgkin’s lymphoma, 0 versus 3 AIDS dementia, and 0 versus 2 others…Patients with the transmission category of IDU [Intravenous Drug User] had higher progression rates, but the groups also differed when only patients without IDU were considered…3 versus 8 (2.8%) deaths occurred in the treated and untreated group, respectively…Only 64 (25%) patients remained on the same, initial, unchanged regimen, whereas 12 (4.7%) patients added one or more drugs, and 181 (70%) patients replaced, interrupted, or stopped one or more drugs of their initial HAART regimen…The entire antiretroviral regimen was interrupted at least once by 117 (46%) patients, and 61 (24%) of 252 patients who were alive and did not participate in the trial of structured treatment interruptions had no anti- HIV treatment anymore at the end of follow-up. Reasons for stopping all antiretroviral drugs was virologic failure in 2 patients, intolerance/adverse events in 16, patient’s wish in 26, physician’s recommendation in 13, and other in 4.”

“Bacillary splenitis occurred during immune restoration induced by highly active antiretroviral therapy (HAART) [by this theory, the problem with pathogens is the inflammatory reaction that they cause, something that is suppressed by HIV]…We report a case of B. henselae infection contracted during the phase of immune restoration by HAART in a young HIV-positive woman, with an unusual evolution…The excised spleen weighed 339 g and bore multiple nodules and abscesses.”

“In a warning letter to physicians Bristol-Myers Squibb has reported 22 cases (including 7 deaths) worldwide of a stavudine-associated rapidly ascending neuromuscular weakness and respiratory failure mimicking Guillain–Barré syndrome (GBS)...All 22 cases occurred in the context of hyperlactatemia, a recognized stavudine effect. Preliminary analysis of 15 of the cases showed symptom onset 12 months on average (range 4–30 months) after the start of treatment and that most of the patients had only modestly elevated lactate levels...Stavudine (d4T), a thymidine analogue and nucleoside analogue reverse transcriptase inhibitor (NRTI), is often used in combination with other HIV drugs. A known side effect of the drug is a peripheral neuropathy (numbness, tingling or pain in the hands or feet). Stavudine is also associated with a spectrum of lactic acid abnormalities, from asymptomatic, mild hyperlactatemia to a potentially fatal lactic acidosis syndrome (LAS). NRTI-related lactic acidosis can be associated with myopathy (causing muscle wasting, myalgia, fatigue, weakness and elevated creatinine kinase levels), lipoatrophy, hepatic steatosis [loss of fatty tissue in the liver], liver dysfunction and possible fulminant liver failure, and pancreatitis. The toxic effects appear to result from mitochondria damage as a result of DNA polymerase gamma inhibition, but it is unknown whether the new GBS-like symptoms are mediated similarly.

Hyperlactatemia (and LAS) is often associated with symptoms of generalized fatigue, nausea, vomiting, sudden weight loss, abdominal pain and distension. Tachypnea and dyspnea are not reliable early signs of LAS and may signal a preterminal state. Similarly, although serum transaminase levels can eventually rise in patients with LAS, they are often normal at presentation.4 An elevated plasma lactate level is diagnostic of hyperlactatemia (mild 2–5 mmol/L, severe > 5 mmol/L),7 and patients with LAS often have an additional anion gap metabolic acidosis.

The prevalence of moderate or severe hyperlactatemia (plasma lactate level > 2.2 times the normal limit) was determined to be 1% (9 of 880 patients) in a cross-sectional study of HIV-infected patients, with stavudine predisposing to high lactate levels more than other drugs.5 The incidence of hyperlactatemia in stavudine-treated patients has been estimated to be 1.2% per year.6 In most patients in whom lactate levels rise, the levels tend to remain only slightly elevated; however, LAS can develop in these patients, and sudden onset is possible in those with initially normal lactate levels.7,8 Obesity, prolonged drug exposure, and female sex and pregnancy may be risk factors for hyperlactatemia.3 The role of riboflavin and other agents in treating hyperlactatemia7 is evolving.

What to do: Patients should be warned of stavudine-associated LAS and the possibility of potentially lethal neuromuscular failure. If severe hyperlactatemia or motor weakness develops, the drug should be stopped immediately and appropriate supportive care (e.g., ventilation) introduced as needed. Physicians should consider monitoring the lactate levels of patients taking stavudine (recognizing that asymptomatic, mild hyperlactatemia poorly predicts progression to LAS) particularly if symptoms such as fatigue, weight loss, abdominal pain, nausea, vomiting or dyspnea develop.
”

“[Chapters in this guide are entitled Introduction, Appetite loss, Body distortions (lipodystrophy), Bone death and destruction, Cardiac concerns, Diarrhea, Fatigue, Gas and bloating, Hair loss, Headaches, Insulin resistance and diabetes, Kidney stones, Liver toxicity, Muscle aches and pains, Nausea and vomiting, Nightmares, daymares and sleeping difficulties, Pancreatitis, Peripheral neuropathy, Skin problems, Sexual difficulties, The end]”

“Unfortunately, complications of HAART and complications of HIV infection, particularly in patients with advanced disease and AIDS, overlap significantly”

“The 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24%, mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch”

“[the purpose of this study was to] evaluate the impact of official recommendations for non-occupational HIV post-exposure prophylaxis (PEP), issued in France in 1998, on physicians' prescriptions and attitudes and the occurrence of severe PEP side-effects...Nationally, from 1997 to 1999, PEP requests and prescriptions increased sevenfold and ninefold, respectively. Most requests followed sexual exposure (71% in 1997 and 86% in 1999; P = 10(-6)). The proportion of prescriptions for exposure to a known HIV-infected person decreased from 78% in 1997 to 41% in 1999 (P = 10(-6)). Three-drug combination therapies increased from 46% in 1997 to 83% in 1999 (P = 10(-6)). In 1999, 13 (0.9%; 95% confidence interval, 0.5-1.5%) severe reversible adverse events occurred [were reported] among patients on a three-drug regimen. Prescription attitudes based mainly on risk assessment in 1997 (64% versus 33% in 1999) were based mainly on the request of the patient in 1999 (41% versus 11% in 1997)...Recommendations were followed by an increase of PEP, particularly after less risky exposures, and a substantial risk of severe side-effects. PEP should be restricted to well-documented exposures for which the risk of transmission outweighs the risk of severe side-effects. Drug regimens should be revised.”

“The clinical paradigm of treating HIV disease from the onset of infection, for life, is now under intense scrutiny...HIV...is unlikely to be eradicated even with decades of therapy. HIV therapy itself has produced an entirely new set of serious complications for HIV-infected patients including body deformities, insulin resistance, lactic acidosis, osteoporosis, neuropathy, osteonecrosis, lipid abnormalities, and cardiovascular disease. Most disconcerting is the fact that both the mechanisms of these toxicities as well as the long term consequences are unknown...Interventions may harm the host more than the virus before progression to AIDS...Are we outsmarting the virus, or once again, will the follies of our thinking be exposed?”

“[In this study, patients in the HAART era (1997 through 2000) were significantly healthier than patients seen in the pre-HAART era (1993 through 1995) BEFORE therapy -- higher CD4 cell counts (155 vs 71), less likelihood of prior PCP (30% versus 74%) and prior cytomegalovirus (7% versus 43%), however]...HAART was protective against PCP [pneumonia] only when CD4 cell count was not included in the regression model. HAART was associated with [greater than two times] increased risk of developing bacterial pneumonia and [a 15-fold increase in the likelihood of developing] NHL [Non-Hodgkins Lymphoma]...Perhaps the development of lymphoma is somehow triggered by the therapy itself”

“during 1995-2000, we identified an increasing number of cases of the symptomatic lactic acidosis syndrome [elevated lactic acid levels, first presenting as nausea, vomiting or abdominal pain, and sometimes leading to liver or pancreas failure] in patients infected with HIV who had been treated with antiretrovirals, which suggests enhanced physician recognition and/or cumulative toxicities. We found concurrent chemical pancreatitis [pancreas inflammation] in 6 patients and identified a clinical syndrome similar to lipoatrophy [fat wasting] that occurred as an early component of symptomatic hyperlactatemia…Early recognition and discontinuation of antiretroviral therapies are probably essential to recovery.”

“the treatment [HAART; Highly Active Antiretroviral Therapy] often has significant adverse effects. This is the case with virtually all drugs in the various classes of antiretroviral compounds...Because of the increasingly reported serious adverse effects of the diverse drug constituents of HAART, studies were conducted to attempt to determine the time at which initiation of ART [anti-retroviral therapy] was most efficacious...most patients could be monitored closely [for declines in CD4 cell counts, not declines in observable health] rather than immediately beginning therapy with drugs that have potential significant adverse effects over several years of therapy (e.g. lipodystrophy [fat redistribution], mitochondrial toxicity [damage to the energy regulating mechanisms within every living cell], lipid abnormalities [potentially fatal metabolic abnormalities], osteopenia [loss of bone mass] and lactic acidosis [buildup of lactic acid]).”

“Around 40% of the patients in our analysis experienced some change in their antiretroviral therapy during the first 40 weeks... It previously has been shown that most early changes are due to toxicity.”

“side effects [of Kaletra, a combination of the protease inhibitors Lopinavir and Ritonavir] include diarrhea, abnormal stools, abdominal pain, nausea, vomiting, and asthenia [loss of strength]. A number of patients experienced grade 3-4 laboratory abnormalities in liver function tests, cholesterol, and triglycerides while receiving this drug combination”

“47% (545 of 1160) of patients presented with clinical and 27% (194 of 712) with laboratory adverse events probably or definitely attributed to antiretroviral treatment. Among these, 9% (47 of 545) and 16% (30 of 194), respectively, were graded as serious or severe...Compared with single-PI treatment [drug combination including one type of protease inhibitor], use of dual-PI-antiretroviral treatment and three-class-antiretroviral treatment was associated with higher prevalence of adverse events (odds ratio [OR] 2.0, and 3.9, respectively). Compound specific associations were identified for zidovudine, lamivudine, stavudine, didanosine, abacavir, ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, and nevirapine.”

“7 HIV patients presenting LD [Lipodystrophy, all taking antiretroviral therapy] and 5 HIV non-LD controls participated in the study…Structural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. The mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy. ”

“The US National Clinicians’ Post-Exposure Prophylaxis Hotline has received more than 19,000 calls. We recommend nevirapine for post-exposure prophylaxis only under extraordinary circumstances…If these criteria are met, the risks and benefits of nevirapine…should be explained to HCWs [health care workers]…The HCW should be monitored carefully for toxic effects; nevirapine should be stopped if adverse events develop or are suspected.”

“The authors studied the occurrence of IRV [Immune Recovery Vitritis], defined as symptomatic (vision decrease and/or floaters) vitritis of 1+ or greater severity associated with inactive CMV retinitis. ...19 (63%) of 30 HAART responders [improvements in CD4 cell counts] developed IRV (26 eyes). The clinical spectrum of inflammation included vitritis, papillitis, macular edema, and epiretinal membranes. Eyes with CMV surface area >30% of the retina were at the highest risk (relative risk = 4.5) of developing IRV”

“A decrease in mtDNA [DNA of the mitochondria; the autonomous energy regulating entities within every cell] content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts...Lipodystrophy with peripheral fat wasting following treatment with NRTI[Nucleoside Reverse Transcriptase Inhibitor]-containing HAART is associated with a decrease in subcutaneous adipose [under the skin fat] tissue”

“Between May 1997 and November 1999, a diagnosis of SJS [Stevens-Johnson syndrome] or TEN [toxic epidermal necrolysis] was established in 246 patients [both are severe skin disorders characterized by acute skin blisters and mucous membrane erosions. SJS is generally diagnosed if skin detachment is <10% and TEN if it is >30%]. Eighteen [of these patients] were known to be infected by HIV-1 (7.3%), 15 out of these 18 had been exposed to nevirapine. The reaction began 10-240 days after the introduction of nevirapine (median, 12 days) and all patients had received escalating doses. In 10 patients the reaction occurred with the initial dosage. All but one patients received simultaneously a variety of other antiretroviral agents but no specific drug combination emerged, and nevirapine was the only drug significantly associated with an increased risk of SJS or TEN in HIV-infected persons...In European countries the risk of SJS or TEN in the context of HIV infection appears to be associated with nevirapine. The respect of a lead-in period does not appear to prevent SJS or TEN. Because of the severity of these reactions and the long elimination half-life of nevirapine, we suggest discontinuation of the drug as soon as any skin eruption occurs.”

“The cases of 2 patients with nevirapine-associated hepatotoxicity [liver damage] in conjunction with rash and eosinophilia [increase in eosinophil blood cells, common in allergic reactions] are reported here. Both patients' conditions improved following withdrawal of nevirapine. Previous case reports have described a variety of interventions other than drug withdrawal that might have contributed to resolution of drug-induced hepatitis. Until a better understanding of the clinical spectrum and pathophysiology of nevirapine-associated hepatotoxicity is realized, treatment will remain largely empiric [translation: we are not too sure what we are doing, but we never like to take a drug away from a patient]”

“ANTHONY FAUCI [US Government AIDS researchers]: Well, I think a lot of what we've discussed tonight-- clearly therapies make a difference in a positive way for people who have advanced disease...MARTIN DELANEY [AIDS treatment activist]: Well, and I think the dilemma here is we've got to learn from what has happened here in the last 18 years and try not to repeat it, as we move into--into Africa and Asia and India. I can't overstate...how severe the problems are with the current therapies. Clearly they have helped people in all the ways that we've heard but they've also hurt people. People are dying from the effects of the therapies themselves in some cases...People are suffering from severe life-threatening complications of drugs. And a lot of them get to the point where they simply can't use them anymore. So as we talk about bringing therapy to Africa, even if we can solve the problem and cost and infrastructure and delivery...are we doing the right thing with these drugs? Or are we unleashing another kind of epidemic over there of drug side effects as well?”

“There was...a striking increase in [oral] warts: threefold for patients on antiretroviral therapy and six-fold for those on HAART (p = 0.01). This pattern of oral disease in a referral clinic suggests that an increase in oral warts could be occurring as a complication of HAART.”

“We report two patients with a history of remote sarcoidosis who later in life contracted HIV infection and developed recurrent, progressive pulmonary sarcoidosis while receiving highly active antiretroviral therapy (HAART)”

“Adverse events were evaluated using the Division of AIDS Table for grading severity of adult adverse experiences. Adjudication of safety and adverse event data were performed by study investigators blinded to patient treatment assignment, except in cases of medical emergencies…4 deaths were reported during the study [out of 562 patients who received any medications, although only 316 completed the 48-week trial]. In the abacavir-lamivudine-zidovudine group, 1 death was attributed to hypersensitivity reaction that occurred following rechallenge with abacavir approximately 3 weeks after initiating study treatment, and 2 were attributed to cardiac arryhthmia and myocardial infarction occurring 30 to 35 weeks after initial study treatment.”

“Altering a long-held policy, federal health officials are now recommending that treatment for the AIDS virus be delayed as long as possible for people without symptoms because of increased concerns over toxic effects of the therapies. . . . More recently, concern has grown over nerve damage, weakened bones, unusual accumulations of fat in the neck and abdomen, diabetes and a number of other serious side effects of therapy. Many people have developed dangerously high levels of cholesterol and other lipids in the blood, raising concern that H.I.V.-infected people might face another epidemic–of heart disease. . . . Dr Fauci, who is co-chairman of the panel, said in an interview, ‘We are adopting a significantly more conservative recommendation profile’”. (According to the panel), “Much remains to be learned about how best to treat H.I.V.-infected individuals. ”

“In two of 15 patients coinfected with HIV and hepatitis C virus who received interferon- plus ribavirin in addition to HAART, we observed multiorgan dysfunction and lactic acidaemia. As ribavirin is a nucleoside analogue, an increased risk of mitochondrial toxicity can be induced in HIV-infected patients already treated with nucleoside analogues, leading to clinical deterioration in some cases.”

“The effect of highly active antiretroviral therapy (HAART) in the treatment of HIV infection is usually measured by survival, CD4 lymphocyte counts, HIV-1 RNA viral load testing, and the occurrence of opportunistic infections. This pilot study sought to measure the impact of HAART treatments on a wide range of clinical outcomes and psychological variables...The only psychosocial measure that improved significantly with treatment was depression. Ratings of pain intensity, physical and psychological symptom distress, and overall quality of life did not change. Of the 70 patients studied, 84% were still alive after the 3-month study period...17 surviving patients (24%) had HAART regimens discontinued due to drug intolerance and 11 (16%) expired [died] during the study period...During the 3-month period [the following illnesses arose - ] wasting syndrome (4), AIDS dementia (1), resistant esophageal candidiasis [fungal throat infection] (1) and acute herpes zoster (1). In addition, there were a number of other infectious medical events that occurred...The causes of death were progressive wasting (5), bacterial pneumonia (3), disseminated Kaposi sarcoma (1), non-Hodgkin lymphoma (1) and end-stage renal disease (1)”

“FDA received reports of 22 cases of serious adverse events related to NVP [Nevirapine/Viramune] taken for PEP [post-exposure prophylaxis] from March 1997 through September 2000. These 22 events included hepatotoxicity (12), skin reaction (14), and rhabdomyolysis (one); four cases involved both hepatotoxicity and skin reaction, and one case involved both rhabdomyolysis and skin reaction.”

“1 patient [out of a grand total of 10 in this 72 week clinical trial of combination therapy with nucleoside analogs (zidovudine-AZT, lamivudine-3TC and didanosine-ddI), Protease Inhibitors (saquinavir and ritonavir) as well as interleukin-2] suffered from severe anemia resulting from ZDV [AZT] therapy and was switched to d4T [another nucleoside analog] at week 20...8 patients had minor gastrointestinal side effects on initiation of HAART. All patients presented with either fatigue low grade fever, or pruritus [itching] at the injection site during IL-2 administration”

“Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic [creates kidney stones]...At 78 weeks 43.2% of patients had stones...The clinical prevalence of indinavir nephrolithiasis [kidney stone formation] is much greater than initially reported”

“A severe hypersensitivity reaction is a known complication of nevirapine and can present as a fulminant hepatitis or as a systemic syndrome with predominant cutaneous manifestations referred to as hypersensitivity syndrome (HSS) or drug rash with eosinophilia and systemic symptoms. We report a case of a severe systemic reaction with rash in a health care worker shortly after administration of a nevirapine-containing PEP [post-exposure prophylaxis] regimen...In light of the increased reports of severe hypersensitivity reactions to nevirapine, we suggest that this agent not be used for PEP until the incidence and full spectrum of nevirapine toxicity is clear, particularly if the risk of HIV seroconversion following a needlestick (0.3%) is equal to or less than the risk of this life-threatening complication. ”

“the severity of the HIV epidemic led to accelerated licensing of many antiretroviral agents, often with very little known about long-term safety...drug-related toxicity is being increasingly recognised because of the declining incidence of HIV-1-associated opportunistic disease...the number of possible HAART combinations is huge. Choosing between many of these combinations is, therefore, increasingly dependent upon knowledge of antiretroviral toxicities...[which includes] myopathy (zidovudine), neuropathy (stavudine, didanosine, zalcitabine; hepatic steatosis and lactic acidaemia (didanosine, stavudine, zidovudine); and possible also peripheral lipoatrophy and pancreatitis (didanosine)...drug hypersensitivity...[which] is about 100 times more common [in HIV infected people] than in the general population...a syndrome (or syndromes) of lipodystrophy...[including] peripheral fat loss (Presumed lipoatrophy in the face, limbs and buttocks) and central fat accumulation (within the abdomen, breasts and over the dorsocervical spine [so-called buffalo hump]...[and prevalent in] about 50% [of patients] after 12-18 months of therapy...Metabolic features significantly associated with lipodystrophy and protease-inhibitor therapy include hypertriglyceridaemia, hypercholesterolaemia, insulin resistance...and type 2 ...diabetes mellitus. Dyslipidaemia at concentrations associated with increased cardiovascular disease occurs in about 70% of patients. These metabolic abnormalities are more profound in those receiving protease inhibitors...Most cases of diabetes have been identified in recipients of protease inhibitors, but a causal relation has not been established...Anemia and granulocytopenia affect about 5-10% of patients who receive zidovudine...Virtually all antiretroviral medications can cause nausea, vomiting, or diarrhoea early in therapy, but these are often transient...Diarrhoea is probably most common with protease inhibitors...Most antiretroviral agents have been associated with hepatic [liver] toxicity...Most protease inhibitors seem to result in increased rates of spontaneous bleeding (bruising, haemarthrosis, and rarely intracranial haemorrhage) in haemophiliacs...Combination therapy for about 4 weeks after high-risk exposure to HIV-1 [e.g. needle-stick injury] is recommended...but 25-35% of patients cannot tolerate [Zidovudine monotherapy] or triple combination therapy for 4 weeks...antiviral potency should not be sacrificed at the expense of tolerability if possible.”

“Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts [normally considered signs of success of therapy]”

“The incidence of MI [Myocardial Infarction (heart attack)] in HIV infected patients increased in our cohort after the introduction of HAART”

“Previously published data on CD4 cell count changes during therapy interruptions have mainly consisted of reports on very small numbers, but there has been a tendency to observe a distinct fall in numbers. The relatively rapid early fall in CD4 cell count after interrupting therapy may correspond to the relatively rapid increase in CD4 cell count after initiating therapy, which has been ascribed to the redistribution of cells from the lymphoid tissue”

“Since the introduction of HAART there has been a dramatic decrease in HIV-related mortality. For example, at the University Hospitals of Cleveland John Carey Special Immunology Unit, the annual observed number of deaths decreased by approximately 80% between 1995 and 1998 [but later in this paper it is revealed that deaths increased from 20 in 1998 to 32 in 1999!]...There is reason to be concerned that the spectrum of morbidity and mortality in HIV disease is changing rapidly to include metabolic complications of therapies and infectious complications, such as hepatitis C. Of recent HIV-related deaths occurring in the John Carey Special Immunology Unit of University Hospitals of Cleveland (number of deaths ranging from 20 in 1998 to 32 in 1999), although OIs [Opportunistic Infections] constituted less than 25% of deaths in 1999, end-organ failures [which could well be caused by medication] constituted nearly half. Importantly, the median CD4 cell count among the patients who died in our clinic has risen, from 0/L in 1995 to 75 million/L in 1999, and about 20% of recent deaths have occurred among patients with plasma HIV RNA levels below the limit of detection.”

“We report 2 cases of neutrophil-rich ALCL [Anaplastic Large Cell Lymphoma] of T-cell lineage involving the scalp of HIV-positive men. Despite chemotherapy, both patients died within 6 months of infectious complications...Both patients were being treated with antiretroviral therapy (stavudine and lamivudine) [prior to admittance for cancer]”

“I just had a dental checkup yesterday. Damn depressing.... The dentist told me all my teeth's enamel had been eaten up by the drugs; that I had so many cavities he was wondering how I could manage to eat and sleep; and that it was beyond his capacity to do anything. When I got out I was crying like a baby. We looked at the x-rays. I got cavities directly in the bones. He's flabbergasted by the unexpected side effects. Has anyone heard of this shit with crix [Crixivan, a protease inhibitor], 3TC [a nucleoside analog] and d4t [a second nucleoside analog] combo?”

“NRTIs [Nucleoside Reverse Transcriptase Inhibitors] do inhibit mitochondrial DNA synthesis but many also interfere with mitochondrial RNA formation. Although base excision repair operates in mitochondrial DNA, no repair mechanisms have been established for mitochondrial RNA. [Note that mitochondria are the energy producers present in all living human cells]”

“One of the major barriers to effectively treating HIV is that most people do not feel sick at the time that they are offered anti-HIV medications. In fact, it is only after starting the medications that they begin to feel sick...Side effects, onset of new diseases caused by the treatment for HIV and the immense pill burden are new problems that many individuals with HIV must adapt to. The lives of many patients have become governed by their drug ‘cocktails’, which for some patients involves as many as 40 pills a day.”

“HAART use had an independent effect on REE [Resting Energy Expenditure]...Compared with the subjects who were not on HAART, the adjusted REE was 339 kJ/day higher in the patients receiving HAART.”

“The incidence of diarrhea was 14.2 per 100 person-years (95% confidence interval, 13.0-15.4). Among patients with CD4 cell counts below 0.05 x 10**9/L, the probability to develop diarrhea within 1, 2, and 3 years was 48.5%, 74.3%, and 95.6%, respectively. The risk to develop diarrhea was increased among patients with severe immunodeficiency, homosexual men, and patients taking antiretroviral therapy...Diarrhea was an independent negative predictor of survival.”

“...we examined 304 anti-retroviral-experienced patients who were placed on HAART for a period of 18 months. The baseline CD4 count was 385x10(6)/1 and HIV RNA level was 3.2 log[10] copies/ml. At baseline, 39% were classified as asymptomatic, 33% were symptomatic, and 28% had an AIDS defining illness. The HAART regimens included 3-5 anti-retroviral agents at least one of which was a protease inhibitor...After 18 months, 14% of the population remained asymptomatic, 10% of which had an undetectable viral load. 39% were symptomatic and 47% of the population had an AIDS defining illness. The average CD4 count after 18 months on HAART was 301.79x10(6)/1 and HIV RNA level of 3.2 log[10] copies/ml. [i.e. HAART did not prevent progression, reduced CD4 counts and did not affect HIV RNA levels]”

“This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to HAART. We followed 30 HAART-responders with CD4 cell counts of >=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients”

“We report on the occurrence of autoimmune hyperthyroidism in three patients with AIDS after 16-22 months of taking highly active antiretroviral therapy (HAART). A woman aged 41 years with AIDS presented with progressive weight loss, asthenia [loss of strength], tachycardia [abnormally rapid heartbeat], tremor and swollen eyelids. She had been taking indinavir, stavudine and lamivudine for 19 months...A male aged 42 years with AIDS presented with progressive weight loss, tremor,, and tachycardia....The patient had been on indinavir, stavudine, and lamivudine for 16 months...A man aged 36 years with AIDS was started on ritonavir, stavudine and lamivudine in April, 1996. In February, 1998, he presented with progressive weight loss, tremor, and hypertension...Although the number is small and the onset of hyperthyroidism could be coincidental to AIDS, autoimmunity probably relates to incomplete or unbalanced immune restoration under HAART [or direct toxic effects of these medications?]”

“The use of antiretrovirals and PCP prophylaxis before AIDS were associated with a significantly poorer survival after AIDS [median of 16 months before death with antiretrovirals, 25 months without].”

“Of 5,574 SCKP members identified with HIV infection, 429 (7.7%) were diagnosed with a malignancy between 1991 and 1995, of which 57 (13.3%) were non AIDS defining (NAD). Although cohort member census declined slightly in successive study years, the number of NAD malignancies diagnosed tended to increase over time, with six, eight, 13, 15, and 15 such neoplasms occurring in 1991-1995, respectively. The most frequent NAD cancers included anorectal (14); Hodgkin's disease (9); lung/intrathoracic cancer (9); and melanoma (8). Less frequently seen malignancies included leukemias (2); testicular seminoma (2); prostate cancer (2); urinary tract cancer (ureters) (1); vaginal cancer (1); multiple myeloma (1); and "other and unspecified" malignancies (3). [the possibility that non-AIDS cancers are caused by the therapy was apparently not considered by the authors]”

“The overall rate of adverse events was 37A%, 32%, and 60%, respectively, for the nucleoside, 1-mIU interforn, and 6-mIU interferon combination groups. 26 patients (43%) had a serious treatment-related toxicity”

“The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection. [apparently the possibility that drug treatments could be causing this was not considered.]”

“Overall rates [of adverse drug reactions] ranged from 16.2 to 37.0 events for 100 person-years of follow-up on [Zidovudine, Didanosine, Zalcitabine, Cotrimoxazole, Dapsone]. For all of these drugs except dapsone, there was an increasing risk of adverse events as the CD4+ count declines.”

“The precise duration of HIV suppression [low viral load] necessary to result in measurable clinical benefit still needs to be clearly defined [and there is no guarantee that people taking these drugs can withstand the toxic side effects long enough for the clinical benefits to materialize]”

“41 patients were enrolled into the study [with 5 different treatment arms and with about half of the patients having previously taken AZT]…5 patients had 7 reported episodes of severe adverse events during the study period, including 1 episode each of grade 3 nausea, fever, abnormal liver function tests, and 4 episodes of neutropenia [deficiency in neutrophil blood cells] in 2 patients. Only the episodes of neutropenia were attributed by the investigators to study medications…During the maintenance phase after completion of the study, 2 additional patients showed signs of severe hematologic toxicity, and one patient had severe myopathy. These toxicities were attributed to ZDV [AZT]. Other adverse events reported frequently during the study period included fatigue (39.0%), fever (22.0%), headache (46.3%), anorexia (24.4%), stomatitis [mouth inflammation] (22.0%), diarrhea (26.8%), oral leukoplakia [thickened white patches in mouth], nausea (31.7%), oral candidiasis (22.0%), anemia (12.2%), myalgias [muscle pain] (12.2%), parasthesias [hallucinations] (14.6%), decreased reflexes (12.2%), cough (34.1%), pharyngitis (24.4%), sinusitits (24.4%), acne (12.2%), rash (26.8%), pruritus [itching] (19.5%), and dysgeusia (12.2%)…Concurrent administration of rCD4-IgG and ZDV was well tolerated in this study[!]. No unusual toxicities were observed with the combination.”

“An undesirable effect associated with the chronic use of [nucleoside analog] drugs is toxicity to normal tissues or cells limiting the dosage or length of time with which the therapeutic [drug] can be used”

Adverse Effects with Nucleoside Analogs ("Nukes")

Also see information specifically related to AZT in <a href="http://www.aras.ab.ca/azt.html">azt.html</a>.

“this rare but often life-threatening syndrom, now named ‘severe nucleoside-associated lactic acidosis’ (NALA) has been reported increasingly often. Hepatic steatosis [loss of fat in liver] and lactic acidosis are thought to be caused by nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial toxicity…Low levels of hyperlactatemia have been reported in 21% of NRTI-treated patients, although the majority of these patients are asymptomatic…From 1997 through 2000, we identified 12 HIV-infected patients treated with NRTIs who developed unexplained metabolic acidosis…A total of 5400 patients treated with NRTIs were observed in these [Spanish] hospitals during the study period. In all cases, known causes of lactici acidosis other than antiretroviral therapy were ruled out…Cases of NALA have been reported as soon as 1 month and as late as 20 months after the start of antiretroviral treatment…NALA can develop at any stage of HIV disease…The mortality rate among patients with lactic acidosis is very high: 33% for our series of patients and 57% for the patients described in the literature.”

“Bristol Myers Squibb (BMS) has chosen to inform doctors of rapidly ascending muscular weakness as new symptom of nucleoside-related lactic acidosis and hyperlactataemia...A review by the EMEA of nucleoside analogue-related LA [lactic acidosis] and HL [hyperlactataemia] has highlighted seven cases of rapidly ascending muscular weakness, similar to that symptoms seen with Guillain-Barré Syndrome, and a further seven cases of muscular weakness or pain which preceded the development of LA and HL...Early symptoms of LA and HL include nausea, vomiting, diarrhoea, rapid and deep breathing, stomach cramp, myalgia [muscle pain] and paresthesia [numbness]. Ascending neuromuscular weakness should now be added to this list. Severe complications which currently include pancreatitis [pancreas failure] and liver failure should now be broadened to include motor paralysis...All nucleoside analogues have been associated with symptoms of LA and HA...Severe lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, renal failure, or motor paralysis.”

“Pancreatitis occurs with a frequency of 1 to 7% with the currently recommended doses of didanosine...Our analysis demonstrated that the use of hydroxyurea was associated with an adjusted fourfold increase in the risk of pancreatitis compared with patients on didanosine alone...There was one fatal case in a patient on didanosine + stavudine + hydroxyurea”

“FDA and Bristol Myers Squibb are warning health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed the combination of the HIV drugs stavudine (Zerit) and didanosine (Videx or Videx EC) with other antiretroviral agents.

Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs such as the liver or pancreas may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues. Pancreatitis is also a well-described complication of Videx and Zerit.

This new warning follows three reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking Zerit and Videx in combination with other drugs used to treat HIV.”

“Fourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia [elevated lactic acid levels that can result in fatal lactic acidosis] during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered. Clinical symptoms included abnormal fatigue, tachycardia [abnormally rapid heart beat], abdominal pain, weight loss, peripheral neuropathy [surface nerve damage], and more specifically exercise-induced dyspnoea [shortness of breath] occurring despite effective antiretroviral treatment [note: effectiveness is defined by elevated CD4 cell counts/reduced viral load not improved health]. FRT [functional respiratory tests] showed a metabolic deviation towards anaerobiosis with a high lactate/ pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction...One patient developed severe lactic acidosis...and died. Another was lost to follow-up. Among the remaining 12 patients, nucleoside analogue therapy was stopped in 10, as clinical improvement was combined with a decrease in lactate levels...The improvements observed in the next few weeks after drug withdrawal or modification suggest that antiretroviral drugs are responsible for the occurrence of symptomatic hyperlactataemia. Furthermore, symptomatic hyperlactataemia has never been diagnosed in naive untreated HIV-infected subjects followed up in our unit...Stavudine [d4T/Zerit] was strikingly involved in treating all these hyperlactataemic patients.”

“Glaxo Wellcome on Sunday played down renewed fears about its Ziagen [Abacavir, a nucleoside analog] HIV treatment and said it planned to proceed with this year's European launch of Trizivir, its new Aids drug, which contains Ziagen...Glaxo...yesterday confirmed patients had died as a result of "hypersensitive" reactions since Ziagen was launched in the US and Europe last year. There are as yet no reliable figures on the number of fatalities from the treatment but Glaxo admitted that about 4 per cent of patients had displayed symptoms such as fever and vomiting. It put the negative response to the drug at about two people in every 10,000 patients, which is 10 times higher than the figures for other drugs generally. The company said: "This is a very potent drug and clinical trials have indeed shown that it has a potential for side effects and patients have died from using it."”

“An uncommon but life-threatening syndrome of severe hepatic steatosis and lactic acidosis among patients infected with HIV-1 was first described in the early 1990s. By early 1994, at least 40 such cases had been reported to regulatory authorities, and an association with use of zidovudine and didanosine was established. An underlying mechanism involving impaired replication of mitochondrial DNA was proposed. Although stavudine (Zerit, Bristol-Myers Squibb, Princeton, New Jersey) is the second most widely prescribed antiretroviral nucleoside analogue, it has rarely been associated with the syndrome of severe hepatic steatosis and lactic acidosis. We report on four patients who developed this syndrome while receiving an antiretroviral regimen containing stavudine.”

“Bristol-Myers Squibb Co., the No. 1 maker of cancer drugs, has strengthened the warning on its HIV drug Videx after four patients, who were taking Videx and another top-selling AIDS drug, died of pancreatitis.”

“The antiretroviral drugs currently licensed in the United Kingdom [June 1996] are zidovudine (azidothymidine [AZT]), zalcitabine (ddC) and didanosine (ddI). All three are nucleoside analogues...All are very toxic. Suppression of bone marrow elements can occur with any of the three, as can peripheral neuropathy [nerve damage].”

Adverse Effects with Other Anti-HIV Drugs

AIDS patients are not just exposed to antiretroviral drugs, but also to many other drugs, such as potent antibiotics, or experimental therapies outside the normal classes of AIDS drugs. These have their own significant side effects.

“The protease inhibitor class of antiretroviral agents is associated with the unwanted side effect of hypertriglyceridemia, which is usually treated with either…statins…or fibrates. However, since statin therapy is intrinsically immunomodulatory, we questioned whether the T-cell response of patients who received PI-based therapy plus statin differed from the response of patients on PI therapy alone or on PI therapy with a fibrate…35 patients who had received ritonavir/saquinavir-based antiretroviral therapy for 5 or more years were evaluated and stratified into four treatment groups…T-cell responses were similar in all four groups before they were exposed to lipid-lowering agents. After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in [the other three] groups, when measured after 6, 12, and 18 months of treatment.”

“myelosuppression [deficiency of white blood cell production] and neutropenia [deficiency of one type of white blood cells responsible for clearing bacteria and cellular debris] may result from any one of several medications commonly used in HIV-infected patients [including nucleoside analogs AZT, 3TC, ddI, ddC and d4T as well as anti-PCP therapies Trimethoprim, Pyrimethamine and Pentamidine]”

“In January 1998 a 26 year old man who was HIV positive started taking stavudine..., didanosine..., and nevirapine...because of a falling CD4 count (250x10^6/l), high viral load (81,747 copies/ml), and symptoms related to HIV. He was receiving no other treatment. He had no additional risk factors for pancreatitis. Response to treatment was good: the viral load decreased to undetectable levels, the CD4 count increased to 470x10^6/l, and the symptoms improved, enabling the patient to resume full time employment. In June 1999 the viral load increased to 1390 copies/ml despite the patient's adherence to treatment, so treatment was intensified with hydroxyurea 500 mg twice daily (Hydrea, Bristol-Myers Squibb). The viral load decreased to 237 copies/ml. The patient began to experience malaise and pain in the upper abdomen. This was attributed to the hydroxyurea, which was stopped after 42 days. The symptoms worsened, and three weeks later he was admitted to hospital with severe pain, vomiting, fever, tenderness of the upper abdomen, and guarding...Computed tomography showed changes consistent with pancreatitis. All drugs were stopped. The patient made an uneventful recovery with conservative treatment. He is no longer taking antiretroviral drugs”

“We report a case of sarcoidosis beginning after 2 months of interleukin-2 (IL-2) therapy in a patient with HIV who had undetectable plasmatic viral load under HAART and we discuss possible mechanisms...IL-2 [Interleukin-2] plays a pivotal role in the pathology of sarcoidosis [formation of nodules in the lungs, liver, lymph nodes and salivary glands].”

“RhuIL-10 [Recombinant Inter-Leukin 10] was generally well tolerated. [Out of 39 HIV-positive subjects] 2…required discontinuation due to thrombocytopenia [deficiency of platelets]. 1 patient…who had chronic hepatitis B and C infections discontinued drug because of elevated liver function tests…Fatigue, headache, nausea and dizziness occurred moer frequently in subjects receiving rhuIL-10 than…placebo (8/29 vs. 1/10, 8/29 vs. 2/10, 6/29 vs. 1/10 and 4/29 vs. 0/10 for each adverse event, respectively).”

“the potential benefit gained from an increase in the number of CD4 cells needs to be balanced against the toxic effects of the treatment. In the study by Davey et al, 54% of the patients receiving IL-2 [Interleukin-2] with HAART had serious adverse effects compared with 16% of patients receiving HAART alone. Studies demonstrating a clinical benefit from IL-2 therapy are needed before it is adopted as a complementary option in conjunction with antiretroviral therapy.”

“IL-2 [Interleukin-2] recipients experienced more adverse events than recipients of ART [standard antiretroviral therapy, not including IL-2] alone. The most common toxic effects experienced by IL-2-treated patients were constitutional symptoms of fever, fatigue, and myalgias of varying severity. Per protocol-defined guidelines, mild-to-moderate symptoms were managed by scheduled administration of alternating acetaminophen and ibuprofen, oral hydration, oral narcotics to control rigors, and rest. More serious or sustained symptoms were managed by omitting a scheduled dose, dosage reduction, or both, as required. Despite these measures, serious (at least grade 3) adverse events occurred in 20 (54%) of 37 evaluable IL-2 recipients and 7 (16%) of 43 ART recipients.”

“Physicians describe in [Clin Infect Dis 1999;29:692-693] two cases of myelosuppression that occurred in HIV-infected patients while on hydroxyurea. Both cases required prolonged platelet or red blood cell transfusions after hydroxyurea was discontinued…Although data on hydroxyurea for HIV therapy are incomplete, the use of this drug is on the rise…”

“Among severely ill patients, mortality was 3-fold higher when corticosteroids were given according to CDC guidelines. Our findings suggest that that the utility of adjunctive corticosteroids in severe PCP needs to be revisited.”

“The present study reveals a relationship between the occurrence of adverse reactions to TMP-SMZ [strong antibiotics often given to HIV-positive people to prevent pneumocystis carinii pneumonia] and the course of HIV infection. Adverse reactions to TMP-SMZ were associated with a more rapid progression to AIDS and death and with a more rapid decline in CD4+ cell counts...A low CD4+ cell count, repeated CD4+ cell counts below 200/mm3, T cell reactivity at baseline, and...the use of antiretroviral agents before the start of prophylaxis were also statistically associated with a more rapid progression to AIDS and death”

“the use of systemic corticosteroids in immunocompromised patients is generally to be avoided. Patient 3…did not demonstrate any contraindications to corticosteriod therapy. Unfortunately, it appears his disease was exacerbated [resulting in retinal detachment and complete blindness in both eyes] by the corticosteroid use”

“Drug reactions are common in patients infected with human immunodeficiency virus (HIV). Administration of trimethoprim-sulfamethoxazole (TMP-SMZ) is associated with adverse reactions in 40% to 80% of HIV-infected patients. However, pulmonary reactions have been rare...We report a patient who developed two episodes of acute pulmonary edema [fluid on the lungs] after administration of ibuprofen [although perhaps TMP-SMZ was involved]”

“a 23-year-old homosexual man with human immunodeficiency virus infection developed progressive exertional dyspnea [difficulty in breathing]...[after diagnosing pneumocystis carinii pneumonia] the patient was started on oral TMP/SMX [sulfa antibiotics]...after 7 days he developed patchy erethema and hives over his trunk and arms. These resolved after one day off medication. He did well until dyspnea recurred...and in response took another dose of his prescribed TMP/SMX. He quickly became flushed, diaphoretic, more dyspneic, nauseated and experienced vomiting and diarrhea. A bifrontal headache developed [which resolved after TMP/SMX was withdrawn again]...Re-exposure to TMP/SMX can indeed mimic progression of the underlying pulmonary infection”

Adverse Effects with Protease Inhibitors

Protease Inhibitors were described as miracle drugs when they first were made available in late 1995. However, the miracle turned out to be a mirage, as a whole range of new side effects, particularly metabolic abnormalities, were discovered. As with all AIDS drugs, this should not have been a surprise, because they are tested for only a short time, in order to rush them to market.

“We report the cases of a young woman who received post-exposure prophylaxis (PEP) with two protease inhibitors, prescribed sequentially, and developed a generalized allergic skin rash to both…These rashes, as well as producing patient discomfort, caused significant anxiety in the patient and the managing clinicians. They were severe enough to require several days on leave. There was concern that the rashes may represent acute HIV seroconversion illness, and an HIV proviral DNA test was ordered and was negative. ”

“Our results show that a single oral dose of the HIV PI [Protease Inhibitor] indinavir induced insulin resistance [precursor to diabetes] in healthy HIV negative volunteers. The onset of insulin resistance was rapid and occurred at plasma concentrations of indinavir approximating steady-state levels observed in HIV-infected patients maintained on standard clinical doses.”

“Participants who initiated therapy with a protease inhibitor were 2.02 times more likely to die than those who did not start therapy with this class of drug”

“[In this study on 55 healthy, uninfected, volunteers taking various combinations of the Protease Inhibitors Amprenavir (AVP) and Ritonavir (RTV) for 2 weeks]...the most common drug-related adverse events...were diarrhea, nausea, and oral paresthesia [prickling or tingling sensations in the mouth] in [treatment group 1]; nausea/vomiting, headache and dizziness in [treatment group 2] and diarrhea, nausea/vomiting, headache, and oral paresthesia in [treatment group 3, with double the dose of AVP]. In [treatment group 1] 1 individual withdrew from the study with rash...in [treatment group 2] 2 participants withdrew from the study, 1 due to rash...and 1 due to rash and pruritis...in [treatment group 3] 3 participants [16%] withdrew from the study, 1 due to nausea after the first dose of APV, one due to oral/perioral numbness, rash, edema of the face, ocular swelling and pruritis [itching] during APV/RTV, and 1 due to lightheadedness after RTV alone followed by vomiting and oral lesions. [Note that people diagnosed with AIDS have to take similar drugs for a lifetime, not 2 weeks, and usually in common with nucleoside analogs that are at least as toxic as protease inhibitors]”

“A decrease in sexual interest was significantly more frequently reported by subjects (men and women) using HAART containing protease inhibitors (PI), compared with PI-naive patients”

“Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones...Our cohort study of the prevalence of indinavir nephrolitihiasis [kidney stone formation] included 155 patients with HIV for 5,732 patient-weeks...At 78 weeks 43.2% of patients had stones...The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported.”

“This study demonstrates a higher than expected prevalence of premature carotid vessel lesions in the patient group treated with PI [Protease Inhibitors] for at least 12 months with respect to a patient cohort previously untreated with these drugs, thus confirming preliminary observations...The overwhelming difference between the percentage of acquired lesions reported for healthy individuals (6.7%) and our two seropositive groups including the PI-naive (14.9%) and PI-experienced (52.7%) patients indicates that HIV-1-positive patients have a much higher risk of endothelial damage which becomes quite remarkable in the case of the patients treated with PI-containing regimens for prolonged periods of time…drug abuse was not related to an increased risk of vascular lesions, nor was the viral load.”

“It has previously been suggested that the metabolic and fat distribution abnormalities are a result of chronic HIV infection itself. Our results support those of others who have suggested that hyperlipidemia in the setting of HAART is a drug effect that reverses with drug withdrawal”

“Osteopenia and osteoporosis [bone weakening disorders] are unique metabolic complications associated with protease inhibitor[PI]-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution…Prior to the availability of PIs, low BMD [bone mineral density] was rarely observed in HIV-infected individuals”

“Use of HIV-1 protease inhibitors is associated with endothelial dysfunction. The metabolic and phenotypic changes observed with these medications may predispose to atherosclerosis and increased vascular risk.”

“Dr. Klein and her colleagues at the University of Wisconsin Medical School in Madison are conducting an ongoing pilot study with 21 HIV-infected patients who have received protease inhibitor therapy for more than 6 months and 7 HIV-infected controls...Flow-mediated vasodilation was impaired in all of the patients receiving protease inhibitors, but in none of the controls...These preliminary observations suggest that protease inhibitor use is associated with endothelial dysfunction, which may ...predispose to atherosclerosis and increased vascular risk.”

“Higher plasma levels of ritonavir are significantly associated with an increased risk of neurological or gastrointestinal side effects, Italian investigators report in [AIDS 1999; 13:2083-9]” “We describe four men with HIV infection who sustained myocardial infarction (two of which were fatal) after 24 to 29 months of protease inhibitor therapy...Thus, AIDS, a fatal illness that is routinely and effectively managed with protease inhibitors, now seems to be presenting with potentially serious new risks associated with that therapy.” “British investigators have added two new cases to the growing list of reports of disfiguring striae [stretch-marks] in HIV-infected patients using protease inhibitors. "In both cases, the appearance of striae occurred within 3 months after the patient began treatment with the protease inhibitor indinavir," Dr. Amrit Darvay, now at St. Thomas’ Hospital in London, UK, and colleagues at Ealing Hospital report in the September issue of the Journal of the American Academy of Dermatology.” “Adverse reactions to protease inhibitors occurred in 29% of the cohort...patients taking ritonavir were at increased risk for adverse drug reactions [particularly gastrointestinal disturbances]” “Hyperlipidaemia at degrees associated with cardiovascular morbidity occurred in 74% of protease-inhibitor recipients. Our cut-offs may be conservative because cholesterol concentrations above 5.0 mmol/L and triglyceride concentrations above 1.6 mmol/L have been identified as clinically significant.” “71% of the protease inhibitor-treated patients had hyperlipidemia compared with only 24% of the protease inhibitor-naive patients. Among the protease inhibitor-treated patients, 44% had isolated hypertriglyceridemia, 7% had type V hyperlipidemia, 37% had type IV hyperlipidemia, 36% had type IIb hyperlipidemia, and 18% had isolated hypercholesterolemia.” “Despite biological plausibility, studies of protease inhibitors which evaluate survival benefit have not yet been carried out. The post-1996 AIDS conference hype that 'combination therapy including a protease inhibitor will make HIV a chronic, manageable disease just like diabetes' came back to haunt us.” “Protease inhibitors can be associated with a non-ketosis-prone hyperglycaemia that occurs 1-7 months after starting treatment”

Bone Disease

HAART can have debilitating effects on the bones of people that take these drugs.

“Bone disorders in HIV-1 patients treated with highly active antiretroviral therapy (HAART) are an emerging issue…After approximately 27 months of treatment with indinavir (800 mg three times a day), zidovudine [AZT] and lamivudine [3TC], a 56-year-old HIV-1-infected bisexual man noticed thickenings on almost all fingers of his hands. He also noted several small protrusions at the costosternal [breastbone] junctions…After the introduction of indinavir [a protease inhibitor] in June 1998, the patient experienced myalgia [muscle pain], arthralgia [joint pain], dry skin, body hair loss, and ingrown toenails developed. The patient has also been taking trimethoprim–sulfamethoxazole…On examination in November 2000, a hand X-ray revealed periostal [near the bone] reactions in the diaphyseal [shaft] regions of all proximal phalanges, the middle phalanges [finger bones] of both index fingers, and navicular bones. Osteosclerosis [bone thinning] was present throughout the spine, this was now also apparent in the lumbar region. Radiographic evidence of osteosclerosis [bone thinning] was also observed in the skull, and a marked periostal reaction was present in the middle part of both radial bones…In December 2000, indinavir was replaced with nelfinavir, nucleoside analogues were not changed, but the patient refused to stop taking multivitamins [which he had been taking for 20 years]. Four months after indinavir therapy was discontinued, an X-ray showed a strikingly reduced periostal reaction on the patient's fingers…We have presented the first patient with osteosclerosis and new bone formation during indinavir therapy…The concomitant long-term use of indinavir with vitamin A, even at the recommended daily dietary allowance, should be discouraged [note that the doctors have no evidence that stopping Vitamin A would have reduced this problem]”

“Bone mineral density (BMD) of total body and lumbar spine (L2-L4) was assessed by dual-energy X-ray absorptiometry in 40 children vertically infected with HIV: 35 taking HAART and 5 naive to any antiretroviral treatment (untreated). 6 HAART-treated children showed clinical evidence of lipodystrophy [abnormal fat redistribution]...HAART-treated children showed lower spine BMD values than untreated (P = 0.045) and healthy (P = 0.004) children and lower total body BMD values than untreated (P = 0.012) and healthy (P < 0.0001) children. Spine and total body BMD were similar between untreated and healthy children.” “Bone density...was reduced significantly in the HIV+ lipodystrophy versus HIV- control groups...and HIV+ non-lipodystrophy groups...PI [Protease Inhibitor] and NRTI [Nucleoside Analog] use were more prevalent among those diagnosed with lipodystrophy [Table 1 shows that, comparing HIV+ with lipodystrophy against HIV+ without, current NRTI use/duration of use was 100%/67 months vs. 60%/26 months and PI use/duration of use was 90%/35 months vs. 45%/11 months]” “Prior to the introduction of long-term highly active antiretroviral therapy, healthy HIV-infected adults generally had normal bone mineral density that was stable over time...The present study has confirmed previous studies that found osteopenia [loss of bone mass] to be common in HIV-infected adult males receiving antiretroviral therapy even after adjustment for age. This osteopenia may result from mitochondrial toxicity of nucleoside analogues [which also may be the cause of excessive, sometimes fatal, levels of lactic acid]” “We describe 5 patients whose symptoms of osteonecrosis [bone disintegration] developed with viral suppression and improvement in CD4 lymphocyte counts as a result of antiretroviral therapy. In addition, we review previously reported cases...We conclude that osteonecrosis is an emerging manifestation of HIV infection and that it may be either a consequence of immunologic and virologic improvement resulting from antiretroviral therapy or a complication caused by the drugs themselves.” “We report on six patients (out of a cohort of 508 HIV-infected patients, including 280 on triple antiretroviral treatment) who were diagnosed with bilateral avascular necrosis of the femoral head, all between 1998 and January 2000...Four of the six patients had to undergo hip replacement surgery (bilateral in three cases). Of note was the fact that no case of osteonecrosis had been diagnosed in our cohort between 1992 and 1998. As shown in Table 1, all six patients had long exposure to antiretroviral treatments, including protease inhibitors; five out of six had signs of fat redistribution. When on therapy including a protease inhibitor, all patients had an elevated level of plasma triglycerides or cholesterol, and three had developed diabetes linked to insulin resistance...osteonecrosis may be more frequent in HIV-infected individuals, and two cases have already been reported in patients on highly active antiretroviral therapy In our cohort, osteonecrosis involved 2% of all treated patients and approximately 10% of patients had clinical features of lipodystrophy.” “Osteopenia and osteoporosis [bone weakening disorders] are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution…HIV-infected individuals receiving PI-based HAART are more likely to have significant bone demineralization…which may increase the risk of fracture”

AIDS Drugs cause Heart Disease

HAART therapy has been associated with an increase in heart disease (no pun intended). This is apparently related to the mechanism that also causes fat redistribution and other problems.

“Our results point to a duration-related effect relationship [more drugs, more disease] between PI [Protease Inhibitor] and MI [Myocardial infarction; heart attack], with a higher MI incidence rate among men exposed to PI for 18 months or more. ”

“Taken in aggregate, the weight of the evidence suggests that HIV-infected patients treated with combination antiretroviral regimens are at increased risk for the development of premature atherosclerotic complications [heart disease, potentially fatal]. ”

“we conducted a collaborative, observational study of 11 previously established cohorts comprising 23,468 HIV-1–infected patients followed at 188 clinics in 21 countries in Europe, the United States, and Australia…A total of 126 patients had a myocardial infarction during follow-up (incidence, 3.5 events per 1000 person-years).…36 of the events (29%) were fatal…The incidence of myocardial infarction increased with increasing exposure to combination antiretroviral therapy. The patients with no exposure to therapy had a lower incidence of myocardial infarction than for any of the treated groups…the relative rate was 1.22 per additional year of exposure to combination antiretroviral therapy; it was 1.26 after adjustment for demographic risk factors, including age, which increased with increasing duration of therapy [i.e. every year of therapy with protease inhibitors increased the risk of a heart attack another 22% (26% after adjustment for confounding factors)]…None of the markers of HIV-1 disease were associated with myocardial infarction in the adjusted model. Including these variables in the model did not modify the association between duration of exposure to combination antiretroviral therapy and myocardial infarction. ”

“Of the 5082 individuals who have ever received ART [anti-retroviral therapy], 63 (< 1%) were captured in the Cardiac Registry. There were 97 events: 70 (72%) since 1999. The age-adjusted [cardiac] event rate per 1000 HIV-positive individuals on ART increased significantly over time whereas that for the general BC [British Columbia, Canada] population did not increase over time. In multivariate analysis, age at baseline per 10 year increase, and months on ART remained significant. ”

“Simon Mallal, MBBS, of Royal Perth Hospital in Perth, Australia, proposed an interesting hypothesis: that HIV infection yields protective benefits against cardiovascular disease (CVD) which HAART effectively abrogates. Following this line of reasoning, any strategy that limits total exposure to HAART (eg, delayed therapy) would be beneficial in terms of cardiovascular outcomes [conveniently for drug proponents, this would mean that HAART drugs aren’t bad for your heart, they just erase the goodness that HIV does for you!]”

“We describe a case of severe and premature vascular disease, occurring in a young [37 year old] female patient, multiexperienced for HAART [having taken several different AIDS drugs], who is part of a cohort of patients followed for drug-induced toxicity. After 6 years of treatment she suffered a bilateral carotid stenosis [narrowing of one of the carotid arteries]; the only [other] risk factors were cigarette smoking and hypercholesterolemia…[The woman] was started on antiretroviral therapy with nucleoside reverse transcriptase inhibitors in 1993. Since 1998 the therapy was enhanced first with non-nucleoside reverse transcriptase inhibitors and then with protease inhibitors. In June 1999, as a result of unsatisfactory immunovirological control, a mega-HAART regimen with stavudine, abacavir, lamivudine, ritonavir and indinavir was introduced [resulting in a number of serious side effects, and eventually] a total obstruction of the right carotid artery, as well as the presence of soft lipidic plaque causing stenosis of the left carotid bifurcation…We must therefore consider the possibility that antiretroviral treatment may have contributed to the occurrence of vascular pathology.”

“The use of PIs [Protease Inhibitors] is associated with coronary artery calcification, atherogenic lipid changes [clogged arteries], and increased erythrocyte volume [larger red blood cells] in individuals infected with HIV-1.”

“Dr. Egger estimates that the more severe forms of lipodystrophy that develop as a result of highly active antiretroviral therapy (HAART) can increase the risk of coronary artery disease by three to four times.”

“A significant number of the HAART patients had very high levels of Lp(a) and various combinations of increased lipid values associated with considerably increased risk for CHD [coronary heart disease]. The elevation of Lp(a) did not relate to any other clinical or laboratory parameter than to LDL-cholesterol.”

“highly active antiretroviral therapy [HAART], which includes two nucleoside reverse-transcriptase inhibitors and a protease inhibitor, has been associated with an increased risk of potential cardiovascular complications that was related to the length of protease-inhibitor treatment and the type of protease inhibitor used. In approximately 60% of patients who were treated with this type of therapy, complications such as lipodystrophy, insulin resistance, and high cholesterol and triglyceride levels developed. In 10% to 20% of patients these complications were severe. There is also anecdotal information suggesting that the risk of angina and myocardial infarction is increased with high active antiretroviral therapy.”

Ineffectiveness or Lack of Proof of Effectiveness, often Combined with Toxicity

HAART is still often described as having miraculous effects. Not surprisingly, proponents of these drugs are less anxious to discuss the times when the drugs simply don’t seem to do what they are supposed to.

“It is more and more difficult to imagine anti-HIV treatments as life-long prescriptions, given the side effects described in the long terms, such as lipodystrophy (found [in this study of 41 patients] in nearly 60% of patients), metabolic disturbances, a possibly increased cardiovascular risk, mitochondrial toxicity and altered quality of life. In other words, the inconvenience of a very-long-term treatment may outweigh the benefit of maintaining the CD4 cell count at a high level, considering that treatment beyond 2 to 4 years will not result in a significant reduction of the HIV-1 DNA load…In summary, the data presented here show that HIV-1 DNA does not seem influenced by HAART after the third year and confirm that the CD4 cell count gain is less apparent after 18 months on treatment. Based on these observations, we question the benefits of a life-long treatment for HIV infection ”

“Extending the model to include current antiretroviral status suggested that use of combination therapy [rather than no therapy or monotherapy] was associated with high [!] rates of disease progression (hazard ratios compared with treatment naive: 1.54 for AIDS, 1.14 for death), confirming the presence of treatment indication bias [i.e. sicker people are treated] [but, hold on, this data is also compatible with the therapy causing AIDS and death!]”

“For pre-treated patients [those who were taking anti-retroviral therapy for more than a year before the study] the risk of progression to AIDS was 1.91 times larger than for patients who had no or less than 1 year of previous treatment [and the risk of death was 2.18 times larger]…Non-HIV-related mortality was 2 to 3 times higher than in the general population. Part of this excess can be explained by the 7 proven and approximately 25 possibly-related causes of death”

“The incidence of OI [opportunistic infections (e.g. AIDS-defining conditions)] after the initiation of HAART in advanced AIDS patients with very low CD4 cell counts is high. Tuberculosis is the most common OI in an area with a high prevalence of tuberculosis”

“By contrast with the pre-HAART era, when most deaths were associated with recent AIDS-defining events, the situation has become more complex in the era of HAART. The current definition of AIDS is no longer a near-complete marker for overall progression. Infectious complications such as sepsis, pneumonia, or meningitis, and cancers such as Hodgkin’s disease are not included in the definition of AIDS. Unfortunately, these conditions and adverse events associated with antiretroviral therapy are not recorded in a standardised fashion. There is a need for complete and standardised information on all events that affect patients infected with HIV-1, and on causes of death, whether or not they are directly related to HIV-1 infection [or, presumably, to the therapy] ”

“Baseline CD4 count was the strongest predictor of subsequent clinical progression [i.e. a woman’s immune status is more important than taking drugs]…By the end of the study, only 52% of the participants were on highly active antiretroviral therapy (HAART)…Despite underutilization of HAART in this multicenter cohort of urban women, opportunistic infections were uncommon, despite CD4 declines…As with changes in CD4, treatment effect was more pronounced for those with lower baseline CD4 counts. For those with baseline CD4 counts between 200-500 cells/cubic-mm, the OR associated with ART versus no therapy was 0.66, a 34% reduction in odds of progression; for HAART, the OR was 0.42, a 58% reduction [but the authors omit to quote the data (shown in Table 6 of the paper) for those with baseline CD4 over 500. This shows a 1.84 times greater risk of progression to AIDS with ART and a 1.58 times greater risk with HAART]…Women who were on ART at the start of this study had increased rates of disease progression, which may reflect confounding by indication; i.e., anti-HIV medication was prescribed because the women were ill [or perhaps the use of ART really did make the women sicker, not healthier]”

“The WHO [World Health Organization] and the [Durban] Declaration [a catechism signed by 5,000 scientists] report in 2000 34.3 million ‘living with HIV’, and the WHO reports 471,451 AIDS cases for 2000 (obtained by subtracting the WHO’s cumulative total of 1999 from that of 2000. Thus, even if we assume that all AIDS cases were fatal in 2000, the resulting global mortality rate of HIV-positives would only be 1.4% - and thus 4 to 6 times lower than the 6.7%-8.8% mortality rate of HIV-positives treated with anti-HIV drugs in the US and Canada. Therefore the claims that anti-HIV drugs reduce the mortality of, and delay progression to AIDS are at odds with the AIDS facts reported by the Durban Declaration and the WHO. ”

“During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI [body mass index], CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change [but, these last two measurements should have improved if the therapy was being effective].”

“[The objective of this study was to] determine the incidence of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) in the UK haemophilia population during the 22 year period 1978-1999…89 cases of lymphoma were identified. 72 cases (81%) occurred in HIV-positive patients (67 NHL, 5 HD), and 17 cases (19%) in HIV-negative patients (9 NHL, 8 HD). The incidence of NHL in the HIV-positive cohort was significantly increased [by a factor of 84 over the general population] in the period 1985-1996. The ratio reduced to 42.15 during the period 1997-1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART) [the authors do not consider the possibility that nucleoside analogs are the cause, and that HAART merely reduced the amount of these drugs and their side effects, in favour of more Protease Inhibitors and their different side effects, such as lipodystrophy, heart disease etc.]”

“Detection of HIV infection occurred in 19 newborns, 9 (1.4%) of 631 deliveries in the nevirapine arm and 10 (1.6%) of 617 deliveries in the placebo arm [Nevirapine is supposed to prevent HIV transmission]”

“The paradoxical worsening of TB is not a new entity, but since the introduction of HAART it has turned into a common clinical problem. It is defined as the development of new signs or symptoms of TB or the exacerbation of current manifestations of TB in patients receiving appropriate treatment. The incidence seems to be higher among patients receiving both HAART and TB treatment…As HAART is often quite difficult for patients on TB treatment, it is essential to ask whether it is really appropriate to use both treatments simultaneously as current guidelines recommend, or it is a more practical approach to defer HAART for 6 months until TB is cured. Before HAART was available, patients with AIDS were usually cured with TB treatment, even in the face of severe immunocompromise.”

“We found (see Table 3 and Fig. 2) that interruptions of HAART did not significantly increase the risk of HIV-associated morbidity and mortality, except for a statistically marginally increased risk for a CDC stage C event after the first interruption.”

“We found that in vitro treatment of PBMC [peripheral blood mononuclear cells] from healthy donors with either IDV [Protease inhibitor Indinavir] or SQV [Protease inhibitor Saquinavir] is associated with a loss in mitochondrial membrane potential. However, the mechanisms by which SQV and IDV induced mitochondrial damage remain to be clarified. We also noted that in vitro treatment of healthy donor PBMC with the combination of IDV (5 mcM; cell death, 15.7%) and SQV (5 mcM; cell death, 13.9%) is additive and induced cell death in 36.8% of the cells, which was similar to that observed with 10 mcM drugs used individually. Thus, the concentrations used in vitro to assess toxicity in this study reflect pharmacologic concentrations [in other words, at realistic concentrations, protease inhibitors can kill the cells that HIV supposedly targets]”

“HIV-1 DNA [HIV ‘integrated’ into cell nuclei] in peripheral blood mononuclear cells (PBMC) was quantified in 31 children who received efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors for 2 years and in whom undetectable plasma HIV-1 RNA [believed to be the genetic material found in HIV particles outside cells] levels (<50 copies/mL) were sustained…despite prolonged maintenance of undetectable levels of plasma HIV-1 RNA, HIV-1 DNA remains detectable in PBMC of children”

“a subset of non-T cells with NK [Natural Killer] markers are persistently infected [even after 1-2 years of HAART]”

“where highly active antiretroviral therapy is available its combination with the treatment of active tuberculosis is difficult for several reasons: overlapping toxicity profiles of some antituberculosis and antiretroviral drugs, drug interactions, and non-adherence to complicated [as well as painful and debilitating, if not fatal] treatment regimens. An important problem is the possibility of paradoxical reactions. Such reactions include the transient worsening or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis within days to weeks after starting antiretroviral treatment. These reactions may be particularly severe when highly active antiretroviral therapy is started soon after the start of treatment for active tuberculosis. The explanation for these reactions is probably the restoration of the immunity towards mycobacterial antigens [in other words, we only get sick because we have an immune system]. Even in patients with low CD4+ lymphocyte counts, it is recommended to delay highly active antiretroviral therapy until the first two months of treatment for tuberculosis have been completed.”

“These results indicate that HAART has little effect on ASIL [Anal Squamous Intraepithelial Lesions] or HPV [Human Papillomavirus] in the first 6 months after HAART initiation”

“Conclusions: The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease [but, is this strong conclusion warranted?]…The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus non-leukoreduced red blood cell transfusion in HIV-infected patients [note that this was not a trial of HAART versus placebo] who required a first transfusion for anemia [quite possibly due as a side effect of prior use of AZT and similar agents]…patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively [i.e. the study was turned into a HAART versus non-HAART study after the fact, and the actual use of HAART drugs was not monitored]…The proportion of patients receiving HAART changed significantly over the course of VATS…In January 1996, only 1% of 83 active patients were taking HAART. This proportion increased to 52% on 1 January 1997, 69% on 1 January 1998, and 79% on 1 January 1999. At the time of enrollment, 31% of patients were taking no antiretroviral medication, 44% were taking antiretroviral medication other than HAART, and 24% were taking HAART. Most of the HAART regimens contained an HIV protease inhibitor…There were 110 deaths during 466.2 post-HAART person-years (mortality rate, 0.24 case/person-year) and 179 deaths during 202.4 pre-HAART person-years (mortality rate, 0.88 case/person-year), for a crude mortality rate ratio of 0.26 [0.30 after adjustments]”

“The drugs are imperfect: Experts say they only extend life, on average, 1.8 years for people with AIDS, and have many severe side effects. Some people live longer, others shorter, on the drugs. About 10 percent of AIDS deaths now are due to protease inhibitor-induced heart disease...Half the people who try the medications do not respond to them and the side effects, such increased cholesterol levels and diabetes, may be so severe that the risk of taking the drug outweighs their benefits.”

“in 28 patients treated for up to 2-1/2 years with indinavir, zidovudine [AZT], and lamivudine...HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF [cerebrospinal fluid] samples after 2 years of treatment”

“Of some concern, however, is the observation that despite increased pharmaceutical usage, the total mortality has not decreased since the first quarter of FY1997. Furthermore, we found an upward tendency of per-patient costs over the last 12 months of this study...The virological failure of up to 60% of treatment-experienced patients and the increased recognition of the toxicities of antiretroviral therapy suggests that substantial additional medical costs may eventually accrue in the care of these patients”

“One of the first studies to look at the success of HIV treatment in inner-city patients from the time of diagnosis reveals a dire situation, a doctor working in Atlanta, Georgia, said here on Tuesday at the 8th Conference on Retroviruses and Opportunistic Infections. His study found that only 1 in 10 patients newly diagnosed with HIV achieved a reduction in virus in blood to ''undetectable'' levels--a major goal of treatment...One year after being diagnosed, 24 patients (18%) had died, del Rio reported. Of the 103 eligible to attend an outpatient clinic, the majority discontinued treatment after a few months. Only 55 patients (53%) ever went to the outpatient clinic and 40% of these dropped out within 1 year. Of the 55 patients seen at the outpatient clinic, 30 were prescribed antiretroviral therapy. One year from diagnosis, only 23 were still on therapy and 12 (of the original 135 patients) had undetectable levels of virus in their blood.”

“Five patients with plasma HIV-1-RNA levels of less than 500 copies/ml for at least 3 months and less than 50 copies/ml at the time of sampling were initially selected, followed by an additional five patients with viral loads of less than 50 copies/ml for 3 months or more...Virus was recovered from monocytes of five patients. Sequencing of the recovered viruses did not reveal multiple drug resistance, and was consistent with a non-syncytium-inducing/CCR5 phenotype. Proviral DNA was detectable in monocytes from all subjects, and unintegrated HIV-1 DNA and MS RNA was found in four out of five populations examined.” “Clinicians are now realizing that the existing therapies are no longer long-term therapies, they start to give out sometimes within two years. In addition, the drugs are having severe side effects, including osteoporosis and cardiac problems.” “All AIDS diagnoses from 1992-1998 notified to the Victorian State [Australia] AIDS Registry were included. Subjects were grouped as individuals diagnosed with AIDS within 8 weeks of a first positive HIV test (late presenters), or individuals for whom there was more than 8 weeks between AIDS diagnosis and first positive HIV test (non-late presenters) [this group is more likely to have taken anti-HIV drugs]. Of 1021 AIDS diagnoses notified, 24% were late presenters...Late presenters survived longer following AIDS diagnosis (P <0.0001).” “There's no hope for a cure for AIDS with current drugs, the head of the National Institute of Allergy and Infectious Diseases (NIAID) said at the 13th International AIDS Conference. ''Eradication is not possible,'' Anthony Fauci said.” “If therapy is started too early, cumulative side-effects of the drugs used and the development of multidrug resistance may outweigh the net benefits of the lengthening of life. If therapy is started too late, increases in disease progression and mortality outweigh the risk of adverse events.” “This study provides evidence that triple-drug antiretroviral therapy (IDV [protease inhibitor Indinavir] plus 3TC [nucleoside analog] plus ZDV [Zidovudine, another nucleoside analog]) fails to produce a sustained increase in anti-HIV-1 CD8+ T-cell functions in HIV-1-infected patients with advanced immunodeficiency” “our data demonstrated that...HIV PIs [protease inhibitors], which are major components of HAART regimens, can be partially inhibitory on Pneumocystis carinii [cause of PCP, a type of serious pneumonia and one of the first diseases defined as ‘AIDS’], at clinically achievable drug concentrations [meaning that the short-term benefits derived from these drugs in some cases may be due to this, and not anti-HIV activity at all]” “We studied the HIV aspartyl PIs [Protease Inhibitors] indinavir, ritonavir, nelfinavir and saquinavir, at clinically achievable concentrations, for their ability to inhibit P. carinii [causative factor of AIDS-defining pneumonia PCP]...We found a partial, dose-dependent antipneumocystis effect [i.e. perhaps the benefits of this therapy that are sometimes found are because they directly target PCP, and not HIV]” “Amanda Mocroft (Royal Free Centre for HIV Medicine, London, UK) reported that rates of treatment failure in the EuroSIDA cohort were 50%, 70%, and 80% after first, second, and third courses, respectively. Results from several trials confirmed the poor response (about 30%) to salvage regimens in patients who had already taken a protease inhibitor. Previous use of non-nucleoside reverse-transcriptase inhibitors lowered the response rate further (to about 15%)...Over the past year, the development of several promising drugs has been put on hold or stopped because of toxicity, unfavourable pharmacokinetics, and inadequate potency” “current potent regimens do not completely inhibit HIV replication in most patients...resistance develops during ongoing HIV replication in the presence of anti-HIV drugs...in most patients...Although it may seem reasonable to believe that use of potent therapy could delay or prevent the evolution of more virulent strains of the virus, few data support that argument...cure with current potent therapy may be possible after 10 years of therapy, 60 to 115 years of therapy, or never [depending on the research cited]...it is safe to conclude that a cure is extremely unlikely with the current approach to treatment...There is growing concern about the long-term toxicity and adverse effects of therapy, including liver damage and mitochondrial toxicity caused by nucleosides, the most studied anti-HIV drugs. After drugs are approved, fewer organized efforts are made to monitor them for long-term toxicities...the quest for HIV treatment is fueled by the expensive, technologically oriented approach used in wealthy countries. Current research is not directed toward simple long-term survival...The fastest-growing treatment category in my clinic [Regions Hospital, Minnesota] is no treatment or delayed treatment.” “The existence of a reservoir of resting CD4+ T cells harboring latent replication-competent HIV has been demonstrated in patients on prolonged highly active antiretroviral therapy (HAART). Latently infected tissue macrophages may constitute a second HIV reservoir...These results demonstrate the long-term persistence of infectious virus in cells of the monocyte-macrophage lineage in patients receiving HAART.” “Our results show that immune responses are potent in antiretroviral-naive [i.e. not taking antiretroviral therapy] but significantly reduced in HAART-treated patients with undetectable viraemia (< 500 copies/ml)...T-cell proliferation to HIV-specific and HIV-unrelated antigens is potent in antiretroviral-naive but suppressed in HAART-treated individuals...because of the side effects associated with HAART and of the known compliance problems of the therapeutic regimens, initiation of therapy might be delayed in those cases where a powerful immune response is detected.” “These data suggest that a large pool of infectious virus is established soon after infection [as early as 2-4 days] and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network...The FDC pool of virus is established by the time symptoms associated with primary HIV infection are recognized, based on these data. We observed 7-8 log10 copies of HIV-1 RNA/g of LT sampled within a few days of symptom onset [mostly mild symptoms and, in 6 patients, no symptoms were observed, so HIV antibodies were declared to by a ‘symptom’], similar to levels associated with late-stage disease. The fact that this tissue was both axillary and from patients with rectal exposure illustrates the speed at which systemic dissemination occurs after mucosal transmission...This finding was a surprise to us, because it has been reported that accumulation of virus into this pool is gradual...Collectively, these findings on the early accumulation of virus into the FDC pool make it unlikely that antiretroviral therapy initiated as soon as symptoms are recognized will necessarily prevent deposition of large enough quantities of virus in the FDC pool or the FDC network.” “This study shows that virologic failure [rises in ‘viral load’] during the Trilege trial maintenance phase was not associated with key zidovudine or indinavir resistance mutations. No such mutations were found at viral rebound or baseline, consistent with the patients’ antiretroviral naive status.” “HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression.” “Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy.” “"This virus is a really smart actor," said Dr. Ann Collier, director of the AIDS Clinical Trial Unit at Harborview's Madison Clinic. Collier said about one-third of patients are resistant to the drugs within six months of starting treatment, and the proportion increases over time. Patients are often switched to new combinations of drugs, but their conditions often gradually deteriorate, she said.” “in a cohort of patients with undetectable viral RNA for between 5 months and several years while taking HAART and with fewer than 50 copies/mL of viral RNA in peripheral blood plasma at the time of these analyses, all subjects had low but detectable levels of HIV-1 RNA in blood plasma. This was surprising in that these data demonstrated that viral expression could not only be shown by viral replication in selected cell types within patients taking suppressive HAART but by actual virion production within blood plasma...Our study...demonstrates that some cell-free virion production may be quite common in patients taking suppressive HAART [although it is not clear how viruses can possibly replicate outside a cell]” “A dormant reservoir of HIV is established early on during primary infection which consists of latently infected, resting CD4+ T cells carrying replication competent HIV. This pool can persist even in individuals who are receiving HAART. Here we show that this pool rapidly re-emerges within weeks of discontinuing HAART in two patients” “our data demonstrate that indinavir and ritonavir [both protease inhibitors (PI)], two major components of HAART regimens, have direct anticandidal effects in vitro and in vivo...Thus, we are tempted to speculate that this novel effect of PI on Candida virulence might concur with and possibly also favor immunoreconstitution in explaining the unprecedented beneficial activity of HAART on candidiasis in persons with AIDS [i.e. these drugs may have beneficial effects due to their activity on this fungal infection, and not from their activity against HIV]” “the proportion of patients who experience virologic suppression during HAART in the clinic setting was substantially lower than that in clinical trials...only 23% experienced viral suppression in all three time periods” “According to the study, [published in 7/20/99 Annals of Internal Medicine] 37 percent of the Johns Hopkins patients getting the cocktail treatment had undetectable HIV levels one year after starting therapy. Only 23 percent suppressed the virus in all three time periods studied - 1-90 days, 3-7 months and 7-14 months. Clinical trials using similar drugs show suppression rates twice as high as those numbers.” “our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir” “As the ADARC group suggested, immediate attention should focus on the reasons why three- and four-drug potent anti-retroviral therapy does not completely suppress virus replication. Based on their data, it is unlikely that anatomical sanctuaries are protecting cells from drugs; instead, the positive cells seem to be readily circulating through the body, as suggested by the presence of many of the HIV-expressing cells in lymphoid sinuses.” “the ultimate therapeutic goal of virus eradication does not seem to be achievable in a period of time compatible with the management of problems such as complexity, toxicity and costs.” “The current study demonstrates that, in a cohort of patients with undetectable viral RNA for between 5 months and several years while taking HAART and with fewer than 50 copies/mL of viral RNA in peripheral blood plasma at the time of the analyses, all subjects had low but detectable levels of HIV-1 RNA in blood plasma.” “The researchers concluded that, while combination antiretroviral therapies effectively suppress HIV-1 replication in some patients, the benefit to others may not be as great. Considering the half-life of latently infected CD4 lymphocytes, researchers conclude that efficacious antiretroviral therapy may take years to eliminate such sources of HIV-1...The continued replication of HIV-1 in two patients seems to be due to the presence of drug-sensitive viruses within lymphoid tissues. We are unable, however, to explain why drug-sensitive HIV-1 is capable of replicating at low levels during treatment with three or four drugs. But it is essential to the therapeutic effort that the answer, be it pharmacokinetic or cellular in nature, be obtained promptly.” “Potent antiretroviral therapy seems unable to eradicate latent HIV-1 reservoirs in CD4+ T cells.” “The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status.” “As the evanescent blush of success with so-called highly active antiretroviral therapy (HAART) regimens begins to recede into the darkness, we have increasingly come to appreciate the importance of the host immune response. As with pharmacotherapy of other infectious diseases, the drugs are not very effective without substantial help from the immune system. [note that AZT, by damaging or destroying bone marrow, damages the immune system]” “In 3 of the 5 patients, the percentage of productively infected cells increased while on therapy” “The main kinetic difference in the HAART [ritonavir/saquinavir plus one or more nucleoside analogs] group was therefore higher production rates of circulating T cells and shorter (not longer) half lives…This analysis confirms that the rate of removal of CD4+ T cells is indeed elevated and the half-life is indeed shortened in the HAART group” “We collected peripheral-blood and semen samples from 7 men with HIV-1 infections who were receiving highly active antiretroviral therapy [HAART] and who had no detectable viral RNA (fewer than 50 copies per milliliter) in plasma and analyzed the samples for cell-associated proviral DNA…Despite the long-term suppression of HIV-1 RNA in the plasma of the 7 men, proviral DNA was detected in seminal cells in 4. Replication-competent viruses were recovered from peripheral-blood cells in 3 men and from the seminal cells in 2 of these 3 men.” “Disease progressed faster in participants who sought medical care for their acute seroconversion syndrome (P=0.01)” “The antiviral effect ot adding interferon-alpha was initially more pronounced with teh 6-mIU interferon combination group. However, this effect was lost by 24 weeks of therapy, such that the 1-mIU interferon combination group and the nucleoside combination group experienced a more durable suppression of plasma HIV-1 RNA. The lack of any durable antiviral response for the higher dose of interferon-alpha may be related to the higher toxicity rate in the 6-mIU interferon combination group…No increased in CD4 cell conts were noted with the addition of either dose of interferon-alpha [there was no control group in this study]” “our analysis shows that San Francisco would have experienced a significant decline in AIDS cases, due to the decrease in HIV seroconversions, even if combination antiretroviral therapy had not been developed...the treatment [AZT] benefit is temporary and confers no long-term survival advantage” “Decreases in concentrations of and detection of seminal HIV in men taking zidovudine or newer antiretroviral drugs have been observed in some [2 referenced], but not all studies [4 referenced]. Antiretroviral therapy apparently does not affect the detection of HIV in cervicovaginal specimens” “The median prolongation of survival associated with changing therapy was, at best, 3 to 6 months...Mortality within [3.5-4.9 years, depending on starting CD4 cell counts] was 100%, regardless of treatment group or landmark...Overall long-term survival [in a study comparing AZT monotherapy with various combination therapies] was grim, even among patients who changed therapy; this finding indicates the continued need for newer, more active antiretroviral regimens. The small effect of changing ther” “The survival of patients in group B [symptomatic at time of HIV diagnosis] after the onset of AIDS was significantly longer than that of patients in group A [asymptomatic at the time of diagnosis] as determined by Kaplan-Meier log rank analysis (P = 0.0026) [i.e. does exposure to antiviral therapy earlier make AIDS worse?] ” “Almost complete replacement of wild-type virus in plasma by drug-resistant variants occurs after fourteen days” “a 77-year-old woman [received a femoral head bone from an HIV-positive donor] during a knee-replacement procedure in December 1985. She…tested positive for HIV-1 antibody in 1987. Her CD4+ count was 0.316 billion cells per liter in September 1989, after which she was treated intermittently with zidovudine and didannosine. In December 1990, her CD4+ count was 0.024 billion cells per liter [more than 10 times lower after taking drugs supposed to kill the virus that kills the CD4 cells!], and orpharyneal candidiasis developed. The patient died in August 1991 of aspiration pneumonia.”

Liver Damage

HAART therapy can cause serious or even fatal liver damage.

“Women with CD4+ counts >250 cells/mm3, including pregnant
women receiving chronic treatment for HIV infection, are at
considerably higher risk (12 fold) of hepatotoxicity [liver damage]. Some of these
events have been fatal…The greatest risk of severe and potentially fatal hepatic events (often
associated with rash) occurs in the first 6 weeks of VIRAMUNE [nevirapine]
treatment. However, the risk continues after this time and patients
should be monitored closely for the first 18 weeks of treatment with
VIRAMUNE…In some cases hepatic injury progresses despite discontinuation of
treatment. [Boehringer Ingelheim is the manufacturer of Nevirapine]”

“30 non-HIV-infected individuals developed hepatotoxicity [liver toxicity] after 8 to 35 days of single-agent nevirapine (8 people) or a nevirapine-containing PEP regimen (22). Findings included ECOG grade 3 or 4 hepatotoxicity (n = 14), fevers (n = 11), skin rashes (n = 8), eosinophilia (n = 6), and fulminant hepatic necrosis requiring an orthotopic liver transplant (n = 1). Rates of severe hepatotoxicity (grade 3 or 4) in non-HIV-infected individuals ranged from 10% (4/41) to 62% (5/8). Liver biopsy material from 2 individuals was consistent with a hypersensitivity syndrome.” “In multivariate analysis [of 692 Thai HIV patients], predictors of severe hepatotoxicity [liver toxicity] were HBV [Hepatitis B virus] or HCV [Hepatitis C virus] coinfection, and NNRTI[Non-Nucleoside Reverse Transcriptase Inhibitor]-containing therapy. Incidence of severe hepatotoxicity was particularly high among patients receiving nevirapine and nevirapine/efavirenz” “306 patients started a nevirapine-containing regimen, of whom 8 developed an acute hepatitis (2.6%) in a median of 24 days. Transaminases peaked at 28 days. Injury pattern was in general mixed-hepatocellular. Withdrawal of the antiretroviral agent led to rapid restoration of transaminase levels and resolution of clinical symptoms.” “In 655 individuals receiving HIV postexposure prophylaxis (PEP), drug-induced aminotransferase alterations were frequent and severe in the nevirapine-including regimen, rare and mild-to-moderate in other combinations, and always reversible. Grade 3–4 incidence in protease inhibitor or nevirapine PEP was 0.5 and 25.0 per 100 person-months, respectively. Apart from nevirapine, continuing PEP appears to be safe [but without long-term follow-up this claim is a bit shaky] even in the case of aminotransferase alterations. The usefulness of routine monitoring of liver function during PEP could be re-considered. ” “755 HIV-seropositive patients consecutively prescribed new [i.e. changed, not necessarily the first] ART [anti-retroviral therapy] were selected…26 cases of SH [severe hepatotoxicity] were observed with an incidence of 4.2% person-years. Liver failure (LF) was rarely seen (1.1 per 100 person-years)…Death occurred during follow-up in 7 of 26 (27%) patients, all of whom showed LF and baseline CD4 count less than 200 cells/mm. Relapse of SH was observed after ART was recommenced in 7 of 17 (41%) patients. [Note that Severe Hepatotoxicity was also somewhat associated with IV drug abus and alcohol abuse, which may have been contributing factors]” “the liver-related mortality rate was…twice as high after 1996, when highly active antiretroviral therapy (HAART) was introduced.” “Whether by HAART, viral hepatitis, or alcohol, transaminitis (elevated ALT and AST [liver enzyme levels]) is common among those with HIV infection... In unadjusted analyses, CD4 [immune cell counts], VL [viral load], and AST were significant predictors of survival in both cohorts (p<0.001). ALT was significant only in CHORUS [one cohort]…Transaminitis is a major determinant of survival and should be carefully considered in all phases of HIV therapy [note that the cumulative length of treatment with antiretroviral drugs, which are known to be toxic to the liver, was not considered]” “The occurrence of a severe elevation of [the liver enzymes] transaminases was associated with poorer survival, although HCV [Hepatitis C Virus] was not. If liver toxicity may be treatment induced, plasma drug concentrations could guide dosage adjustments ofantiretroviral treatments currently prescribed to optimize their use.” “Current highly active antiretroviral therapy (HAART) is based on combination regimens with substances from three different classes: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI)…HAART-associated toxicity has evolved as the main reason to discontinue or modify antiretroviral therapy. Hepatotoxicity [liver damage] appears to be of particular importance in this context as it can occur with any antiretroviral regimen currently in use. Most remarkably, longitudinal surveys have not only reported an increased incidence of hepatic injury in HAART-treated patients but also identified life-threatening hepatotoxic events and end-stage liver disease in patients on antiretroviral treatment. Since rational alternatives to HAART [i.e. not taking HAART is not rational] are currently not available to control HIV infection, understanding the pathophysiology as well as a profound knowledge of how to prevent and to treat HAART-related liver damage will be a continuous challenge [and source of income] for the present and future generations of hepatologists. ” “In a case-control study, 70 patients taking nevirapine (200 mg twice a day) triple combinations were chosen and classified into two groups, one including subjects who developed any grade of hepatotoxicity [liver disease], and a control group including subjects without transaminase elevations. The use of nucleoside analogs was comparable in both groups...The peak in transaminase levels [surrogate marker for liver toxicity] among the 33 subjects of the first group occurred at a median time of 6.1 months after beginning nevirapine-based therapy...our preliminary findings support the theory that nevirapine-associated liver toxicity occurring after several months on therapy is not part of a systemic hypersensitivity reaction, and seems to be correlated with higher plasma drug concentrations involving a dose-dependent mechanism” “In conclusion, we believe that our patient developed liver failure and portal hypertension in the absence of cirrhosis because of long-term nucleoside-analogue therapy without development of symptomatic lactic acidaemia. Gliclazide and metformin are not related to hepatocellular damage; however, tuberculostatic drugs used might have accelerated this process. This case suggests that even mild hyperlactaemia, which occurs in 15-35% of nucleoside-analogue-treated patients, can be associated with progressive liver damage” “We describe four instances of reversible hepatocellular [liver] damage associated with the use of nevirapine in patients with HIV infection...Evidence of malaise, skin rash, and icteric hepatitis [jaundice] with pruritis [skin rash] occurred 4-6 weeks after the beginning of nevirapine therapy...In all cases, liver test results declined to normal or near normal levels, and pruritus disappeared 4-6 weeks after discontinuation of the medication. No patient was rechallenged with the drug.” “A comprehensive retrospective review of more than 10,000 adult AIDS patients participating in 21 different AIDS Clinical Trials Group (ACTG) studies [confirms]... that antiretroviral therapy is associated with a high rate of severe hepatotoxicity [liver damage], regardless of drug class or combination. Dr. Chung of Massachusetts General Hospital in Boston presented the findings to the Digestive Disease Week annual meeting...The researchers evaluated data for AIDS patients, enrolled in ACTG studies between 1991 and 2000. The subjects were taking a variety of drug combinations including one or more nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)...Overall, 10% of patients developed grade 3 and 4 hepatotoxicity and 23% of them had to discontinue therapy permanently. According to the data, 2.5% of all deaths in the study period were liver related. NNRTI[non-nucleoside reverse-transcriptase inhibitors]-containing regimens, especially those including nevirapine and efavirenz, were particularly hard on the liver, with high rates of discontinuation.” “Acute hepatitis with lactic acidosis is a life-threatening but [sometimes] reversible toxic effect on mitochondria of HIV-1 nucleoside-analogue treatment [later this letter notes that 80% of patients with lactate greater than 10 mmol/L die]. We report fatal portal hypertension, liver failure, and persistent mitochondrial dysfunction in a man aged 65 years with HIV-1 infection who had recovered from nucleoside-analogue-induced acute hepatitis and lactic acidaemia more than 18 months previously. We believe that symptom-free patients who receive nucleoside-analogue therapy should have hepatic [liver] function constantly monitored, especially those with past or present lactic acidaemia.” “The antiretroviral drugs used to fight HIV, particularly the protease inhibitors, place a great strain on the liver, the organ whose function it is to metabolize them...When Brian Klein of San Francisco found out that he was HIV-positive in 1996, he immediately started on a three-drug regimen that included a protease inhibitor. "Within two weeks I got extremely sick," he recalled. "I became jaundiced. I lost 15 pounds. They did some tests, and, lo and behold, I had hepatitis C [or liver damage from the protease inhibitors generated auto-antibodies misidentified as from Hepatitis C]. They pulled me off the medications because this was all new at the time and they didn't know what to do.” “In 1998-1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996 (P = .003). In 1998-1999, 55% of patients had nondetectable plasma HIV RNA levels and/or CD4 cell counts of >200 cells/mm3 within the year before death. Most of the patients that were tested had detectable antibodies to hepatitis C virus (75% of patients who died in 1991, 57.7% who died in 1996, and 93.8% who died in 1998-1999; P = NS). In 1998-1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.” “We retrospectively examined
the causes of death of HIV-seropositive patients at our institution in 1991, 1996, and 1998–1999. In
1998–1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991
and 5 (13.9%) of 36 in 1996…In 1998–1999, 7 patients (31.8%) discontinued antiretroviral
therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is
now the leading cause of death in our hospitalized HIV-seropositive population.” “In a cohort of 1,047 human immunodeficiency virus type 1-infected patients started on protease inhibitors (PIs), the incidence of severe hepatic [liver] cytolysis (alanine aminotransferase concentration five times or more above the upper limit of the normal level>=5N) was 5% patient-years after a mean follow-up of 5 months...At the onset of severe cytolysis, 2 patients were receiving Saquinavir (SQV), 5...Ritonavir (RTV), 7...Indinavir (IDV), 5...Nelfinavir (NFV), 1...SQV and RTV, 1...IDV and NFV, and 1...RTV and NFV” “treatment with certain PIs [Protease Inhibitors] is associated with fat redistribution, hyperlipidemia (high fat levels in the blood), or both...we examined the effects of PIs on lipid synthesis in cultured hepatocytes [liver cells] and AKR/J mice. The results showed that NFV [nelfinavir] and RTV [ritonavir] increased serum TG [triglyceride] levels in mice...ABT-378, NFV, RTV, and SQV [saquinavir], but not APV [amprenavir] or IDV [indinavir], increased TG synthesis and RTV increased CH [cholesterol] synthesis in HepG2 [liver] cells...select PIs affect multiple, distinct metabolic pathways, perhaps accounting for the different side effects observed for each PI” “While the risk of transmission of HIV via a needlestick is approximately 0.3%, the risk of serious adverse effects of these preventive strategies remains undefined. We report a case of a health care worker who experienced serious morbidity from PEP [post-exposure prophylaxis]...A 43-year-old female, African American phlebotomist sustained a needlestick injury after drawing blood from an HIV- and hepatitis C virus (HCV) infected patient. She received PEP with zidovudine, lamivudine, and nevirapine. Triple therapy including nevirapine was selected based on the source patient's advanced disease, antiretroviral treatment history, and severity of the exposure...The patient required an orthotopic liver transplant 35 days following initiation of PEP. Pathology of the native liver showed confluent hepatic necrosis...We think that this patient had a severe hypersensitivity reaction to nevirapine that resulted in hepatic failure...This case raises the question of whether the safety profile of nevirapine warrants its use as a prophylactic medication in health care workers who are exposed to HIV when the risk of transmission is low.” “The existing sections [of the product label for Nevirapine/Viramune] have been updated to provide additional warning information about the risk of severe, life-threatening and in some cases, fatal hepatotoxicity [liver damage] that have been reported in patients treated with Viramune. Although clinical presentation varied among patients, frequently occurring features included non-specific prodromal [early] signs and symptoms of fatigue, malaise, anorexia and nausea, with or without abnormal serum transaminase levels. In these reports, symptoms progressed to jaundice, hepatomegaly [enlarged liver], elevation of transaminase levels and hepatic [liver] failure over several days.” “Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients...Risk of severe hepatoxicity was 5-fold higher for patients taking [the protease inhibitor] ritonavir, which accounted for half of all cases...Likewise, more than half of cases of severe hyperbilirubinemia [excess of bilirubin] were associated with indinavir use” “Liver disease has become the leading cause of death among HIV patients at a Massachusetts hospital, a report issued on Friday...[by] Dr. Barbara McGovern, a professor at Tufts University School of Medicine and a member of staff at Lemuel Shattuck Hospital in Jamaica Plains, Mass. The findings were reported on Friday at the annual meeting of the Infectious Diseases Society of America in Philadelphia. McGovern said HIV patients who take a powerful combination of AIDS drugs called highly active antiretroviral therapy (HAART) were at particular risk because of the drug's potential toxicity to the liver. One-third of HIV patients with underlying liver disease at Lemuel Shattuck have had to stop taking HAART.” “hepatotoxicity is frequently seen in patients under HAART, and can force the withdrawal of antiviral treatment in a significant proportion of patients, occasionally resulting in fatal outcome”

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

These drugs supposedly also inhibit the reverse transcriptase enzyme, but without emulating a nucleoside (DNA building block). They also have severe toxicity. Nevirapine is the most famous of these drugs, and is also prescribed to pregnant women and children, like AZT. Another commonly prescribed NNRTI is Efavirenz.

“HIV clinicians are well aware of the potential toxicities associated with nevirapine (NVP) therapy, including rash and hepatic injury, both of which appear in the FDA-mandated NVP black box warning. [2] In the vast majority of patients in whom they develop, these complications are mild to moderate; however, in some patients, they can be severe and life-threatening…there is a significant risk of NVP-associated hepatotoxicity in pregnant women, especially those with high CD4 +cell counts, and that the progression to severe hepatotoxicity may be explosive in nature and not predicted by the patient's liver enzyme level determinations obtained before and during NVP therapy”

Health Without Toxic Therapies

A few people have questioned whether people who are HIV-positive need AIDS drugs at all, particularly when they have no current AIDS-defining ilnesses.

“Vitamin B12 treatment led to an increase in the number of lymphocytes, including CD8+ cells, not only in [Vit. B12 deficient] patients but also in control subjects, and to a significant increase of NK cell activity in patients”

“we estimate that between 21 and 40% (95% confidence interval) [of healthy, HIV+ people not using antiretroviral drugs] will be free from clinical AIDS 12 years from seroconversion and between 10 and 17%…20 years from seroconversion.” “LTNPs [Long-term non-progressors] were defined as having documented HIV-1 infection for >7 years, CD4 cell counts of >600 cells/cubic mm, and no symptoms related to HIV-1 infection. With the exception of [two of nineteen] patients, no patients had ever received antiretroviral therapy.” “During follow-up of subjects with transfusion-acquired HIV-1 infection in New South Wales, Australia, we identified a group of 6 subjects who had been infected through a single common donor…Throughout follow-up (range 6.8-10.1 years after infection, 5 of the recipients and the donor (last follow-up 10.2 years after infection of the first recipient) remained clinically free of symptoms, with normal CD4 cell counts and no p24 antigenaemia [i.e. undetectable p24 antigen]…1 infected recipient (who had received extensive immunsuppressive treatment for systemic lupus erthematosus) developed Pneumocystis carinii pneumonia and died…The donor…has never received antiretroviral therapy, nor any prophylactic treatment for Pneumocystis carinii pneumonia…Recipients A-E had no signs or symptoms of HIV-1 disease during follow-up of 6.8 to 10.1 years…No recipient has been given antiretroviral therapy or prophylaxis against P carinii pneumonia.” “we have three reasons to question the administration of combination therapy (also known as highly activated antiviral therapy, or HAART: -- The drugs do not eliminate virus-infected cells and thus cannot "cure." -- Long-term use of antiviral therapy, which can be toxic, may also lead to the emergence of resistant viruses. -- There is no evidence that early treatment has made a difference in overall disease progression.”

Adverse Effects, Mothers & Children

Many women are encouraged to take antiviral drugs to prevent transmission of HIV to their infants, and their babies are often prescribed AIDS drugs as well. There is evidence that should give us pause to think whether giving cell-killing drugs to the rapidly growing fetus or baby is really a sane course of action.

“A rash occurred in 20% of patients (15/74), and was severe (grade 3–4) requiring the cessation of treatment in four children (5%). In the other 11 children, the rash was managed with antihistamines. The rash developed after a median of 9 days (1–44) of treatment, and lasted a median of 10 days (1–60)…One child had elevated hepatic transaminases and discontinued nevirapine, but she also had hepatitis C infection. 5 children experienced grade 3 neutropenia that may have been attributable to concomitant medication. No other grade 3 or 4 adverse events were documented. Grade 1 and 2 adverse events related or possibly related to nevirapine, but possibly attributable to concomitant medication, included: vomiting (n=8); diarrhoea (n=7); unexplained fever (n=8); headache (n=3); dizziness (n=2); paraesthesia [hallucination] (n=3); alopecia [hair loss] (n=3); nail dystrophia (n=2); hepatomegaly [swollen liver] (n=1); muscle pain (n=1); gall bladder sludge (n=1); elevated cholesterol and triglyceride levels associated with pancreatitis (n=1); neutropenia (n=15); anaemia (n=3); leucopenia (n=6); abnormal liver functions: raised alanine aminotransferase (n=7), raised bilirubin (n=2) and raised gamma-glutamyl transferase (n=3). ”

“30 PI[Protease Inhibitor]-treated and 20 PI-naive [untreated] children were evaluated (76% prepubertal). PI-treated children had significantly higher total cholesterol, LDL-cholesterol and triglycerides…Clinical and immunological HIV categories,
viral load, CD4 cell count…were not significantly
associated with serum lipids, insulin resistance or abdominal adipose tissue distribution [indicating that it is the therapy, not HIV, that is the cause of this metabolic abnormality]” “During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI, CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change.” “Although all children in group 1 [with persistent metabolic acidosis] received ART [antiretroviral therapy] (versus
146/167 in group 2) a univariate comparison for this
variable was not [statistically] significant [due to the small number of children in the study not taking ART, however the risk was 4.75 times higher among those taking ART]” “There were no serious adverse effects in the mothers [but double the rate of anemia at delivery (the end of the course of therapy), and also more mothers with elevated levels of aspartate aminotransferase, blood urea nitrogen and creatinine]. Adverse events noted in neonates were anemia (in 6 neonates), elevated transaminase levels (in 1), and thrombocytopenia (in 3) [but the authors forgot to mention, in the abstract, that 15 were later hospitalized for a variety of conditions, some quite likely therapy related]…Short-course therapy with zidovudine plus lamivudine appeared to be safe and effective for prevention of perinatal transmission of HIV-1 [but this trial did not have a placebo, so this statement is purely hypothetical]” “Drugs typically administered to prevent the transmission of human immunodeficiency virus (HIV) accounted for 25% of all the reported adverse events through maternal exposure [in the United States]. HIV drugs with >10 case reports each were zidovudine [AZT] (177), lamivudine [3TC] (57), nelfinavir (56), and nevirapine (44). Without data about how frequently these drugs were prescribed to prevent HIV transmission, it is not possible to tell whether zidovudine was more toxic in this therapeutic setting than similar drugs…A wide spectrum of adverse events were associated with the HIV-related drugs, including 110 cases (35%) with an outcome of congenital defect or permanent disability, 103 (34%) cases involving initial or prolonged hospitalization or a life-threatening event, and 23 (7%) with death as the reported outcome. [Note that it is estimated that only 1% to 10% of adverse drug reactions are reported]” “In nonfasting and fasting conditions, [HIV-positive] children of the PI [Protease Inhibitor taking] group had higher total cholesterol, triglycerides, and LDL [Low Density Lipoprotein] cholesterol levels compared with the non-PI group…After fasting, 8 (47%) of 17 patients in the PI group presented with hypercholesterolemia [high blood cholesterol] as a result of an increase of LDL cholesterol and 11 (65%) had hypertriglyceridemia…The long-term complications of dyslipidemia [disruption of fat metabolism] are of major concern in the growing HIV-infected child.” “The association of
HIV-1-related immune deficiency with a low rate of pre-eclampsia [eclampsia is a serious pregnancy disorder characterized by convulsions, coma, high blood pressure, protein in the urine, accumulation of fluids and about a 25% rate of fetal mortality]
the restoration of this rate in women treated with triple antiretroviral
therapy to the expected rate indicates a pivotal role of the immune
system in the pathogenesis of pre-eclampsia…Seven of the nine patients had unusually severe preeclampsia.
4 [of the 9 HIV+ women on HAART with pre-eclampsia] had HELLP syndrome (haemolysis,
elevated liver enzymes, and low platelets) and 3 had
intrauterine deaths (table 1)” “Our study shows that cardiac dysfunction [heart problems] occurs frequently in children with HIV infection…The relative risk of death during the 5-year follow-up period in children who had cardiac impairment or CHF [congestive heart failure] was 8.5 to 14.6 times higher than in the children without these complications…The majority of patients in this study were treated with a wide variety of antiretroviral agents available between 1990 and 1996 or intravenous immunoglobulin…some HIV-infected children continue to have evidence of cardiac dysfunction even with an undetectable HIV viral load [indicating that the cardiac dysfunction is probably not due to HIV]…Several isolated reports have described the HIV virus in myocardial or pericardial tissue, whereas others have proposed that HIV cardiomyopathy may be related to antiretroviral medications.” “We report the case histories of two HIV-1 positive women in the third trimester of pregnancy who presented with acute lactic acidosis and acute pancreatitis, respectively. One case was fatal for mother and baby. Both women had been stable on regimens containing stavudine and didanosine for at least 2 years before their acute presentations. We speculate on the differential diagnosis, discuss possible reasons for an increased risk of these presentations in pregnant women taking antiretrovirals, and advocate increased vigilance of these women, particularly in the last trimester.

” “There were statistically significant differences among the five groups of children [1. control group children of HIV-negative mothers given no drugs, 2. children given Nevirapine [NVP] and AZT born of HIV+ mothers given NVP, 3. children given NVP of HIV+ mothers given NVP, 4. children given NVP and AZT of HIV+ mothers given no drugs and 5. children given NVP of HIV+ mothers given no drugs] at 6 weeks of age (P , 0.0001): mean ALT [Serum alanine aminotransferase, a measure of liver enzymes] values were higher among children who received treatment compared with control children. In addition, compared with mean ALT values at birth, the mean ALT values declined among the control group but increased in three of the four treated groups. However, among the four groups of children who received antiviral treatment there were no statistically significant differences in mean value of ALT at 6 weeks of age. Based on conventional tables currently used to assess severity of this parameter (see Methods), the increases in ALT values were mild (grade 1 only)...At 6 weeks of age, both hemoglobin and hematocrit values were significantly lower among antiviral drug-treated groups of infants. The hemoglobin mean value was 11.7 g/dl in the control group versus 10.4–10.9 g/dl among treated groups; hematocrit mean value was 34.2% in the control group versus 30.7–31.8% for the treated groups...At 6 weeks of age, platelet [clotting cell] counts were significantly lower among the treated groups of children compared with control children...In the control group, 82% of 133 infants had a normal hemoglobin level (> 9.5 g/dl) compared with 70–78% among the treated groups...More treated infants showed grades 1 and 2 severity compared with control infants: 12.8–15.1% among treated groups of infants compared with 9.8% among control infants had grade 1 severity; 5.3–9.7% among treated groups of infants compared with 3.8% among control infants had grade 2 severity...the hematological changes were more noticeable among HIV-infected children, with the exception of granulocyte percentage which was lowest among infants whose mothers had received intrapartum NVP. These data suggest that infection with HIV also contributes to these changes. Distinguishing between the adverse effects of short term antiretroviral drugs and HIV infection of the infant could be difficult. This is a potential limitation of this study. No reference values are available for HIV-exposed but untreated infants and we were not able to recruit a comparison group for ethical reasons. Our data did not show significant differences among the four treated groups of children either at birth or at 6 weeks of age. Therefore, it is not possible to distinguish between effects due to NVP alone or to its combination with ZDV. This is further compounded by the fact that both NVP and ZDV have been reported to be associated with hematologic abnormalities....We have monitored some important safety parameters among Malawian infants. Although hepatic and hematological changes were observed with these ultra-short post-exposure prophylaxis antiretroviral regimens, these alterations were minimal and within expected limits based on previous studies. Assuming that most HIV infections of the neonate occur intrapartum or close to the time of delivery, it appears that both acquisition of HIV infection and antiretroviral drugs contribute to hepatic and hematological changes in the neonate. We will continue to monitor the clinical conditions and hematological parameters of these infants up to the age of 2 years. These results could guide the implementation of antiretroviral treatment programs in similar pediatric populations.” “The cohort comprised 2123 women who received antiretroviral therapy during pregnancy…and 1143 women who did not…After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not; the rate of low birth weight (<2500g) was [also similar]; and the rate of very low birth weight (<1500g) was 2% for the group that received antiretroviral therapy and 1% for the group that did not [that’s double]. The rates of low Apgar scores (<7) and stillbirth were also similar…[What the abstract omits is the evidence that combination antiretroviral therapy with protease inhibitors shows some worrying results (although not always statistically significant, because of the small size of this group (137 women)). Table 4 shows, after adjustment for other risk factors, a 50% greater risk of premature delivery (compared with no therapy), 36% of very premature delivery (<32 weeks), 70% of low birth weight and 142% increased risk of very low birth weight (<1500g). Obviously this means that the risks of these events were lower with monotherapy and combination therapy without a Protease Inhibitor. However, the abstract also does not mention that some baseline variables in the no-therapy group were distinctly different, and may represent important confounding factors. Women with no therapy all delivered in 1990-1994 versus 1994-1998 for women taking therapy during pregnancy. The rate of tobacco use was significantly higher in women taking no therapy (55% versus 34%), the rate of alcohol use (41% versus 23%) and, most importantly, the rate of illicit drug use during pregnancy (42% versus 23%)]…[This study] did not have information on early pregnancy loss, congenital abnormalities, or long-term outcomes for the infants. We were unable to assess the effect of the duration of antiretroviral therapy on the outcomes of pregnancy…some women [may have] started antiretroviral therapy too late to be at risk for premature delivery [i.e. after 32 weeks or after 37 weeks]” “Antiretroviral nucleoside analogue drugs are a major constituent of highly active antiretroviral therapy (HAART) . . . Currently, HAART combinations that include zidovudine (ZDV [AZT]) and lamivudine (3TC) are highly effective in preventing HIV-1 vertical transmission; most children are born with no evident adverse clinical effects. However, ZDV is a moderately strong transplacental carcinogen in mice, and potential long-term consequences of fetal exposure to most HAART combinations remain unknown . . . experiments were performed in Erythrocebus patas monkeys given human-equivalent drug exposure protocols. Pregnant monkeys were dosed with either no drug (n = 2), 40.0 mg ZDV/day . . . for the last 50% (10 weeks) of gestation (n = 3), or with the same regimen of ZDV plus 24.0 mg 3TC/day . . . for the last 20% (4 weeks) of gestation (n = 3). Multiple fetal organs were examined at term for DNA incorporation of ZDV and 3TC…values for ZDV-DNA incorporation were similar in fetuses exposed to ZDV alone and those exposed to ZDV plus 3TC. Values for 3TC-DNA in fetal organs were greater than or equal to values for ZDV-DNA, indicating that the total DNA damage sustained by fetuses exposed to both drugs was at least double that observed in fetuses exposed to ZDV alone. Telomere shortening, determined by Southern blot with a telomeric probe, was observed in most organs of the three animals exposed in utero to ZDV plus 3TC [but not with just ZDV/AZT]. Overall, these studies demonstrate that monkey fetuses exposed in utero to the combination ZDV plus 3TC sustain a higher level of drug-DNA incorporation and show evidence of more telomere damage than monkey fetuses exposed to ZDV alone.” “149 (78%) of 192 children experienced moderate or worse toxicity while receiving initial therapy [in this trial of various combinations of 3 or 4 AIDS drugs], and 44 (23%) of 192 experienced severe or worse toxicity…The most commonly observed adverse events were skin rash (53(28%)); nausea/vomiting (44(23%)); and temperature >= 38.5C (40(21%))…Administration of initial randomized study treatments was permanently discontinued for children with (1) an HIV RNA copy number > 10,000 copies/ml (32(17%)); (2) toxicity of medication intolerance (13(7%)); or (3) other reasons, including poor adherence to the study regimen and parental request for withdrawal of the patient from the study (29(15%))” “Although 17 (53%) of 32 patients [Dutch children who had not previously used protease inhibitors] experienced adverse events, combination therapy was well tolerated by almost all children…The most common indinavir-related side effects were as follows: diarrhea (in 6 children), vomiting (in 6), loss of appetite (in 5), headache (in 3), abdominal pain (in 4), and hematuria (in 5) [note that diarrhea and weight loss (associated with vomiting and loss of appetite) are two of 4 symptoms needed for an AIDS diagnosis in third world countries]” “130 children were randomised [to placebo or 3 combinations of zidovudine, lamivudine and abacavir]...24 serious adverse events occurred in 18 children. Of these, four were clinical events: 1 death, one hypersensitivity reaction to abacavir, one stroke, and one vomiting [none on placebo]. Of the 20 laboratory grade 3 or 4 events, most frequent were neutropenia (12) and thrombocytopenia (3). 3 children in each of the NRTI groups had one or more episodes of neutropenia...6 children permanently stopped drugs after minor adverse events: vomiting, cutaneous reaction, fever assumed to be early hypersensitivity and anemia. 2 other children stopped abacavir permanently because of hypersensitivity reactions thought to be associated with abacavir [but later ‘judged’ not to be]” “The frequency of seizures was studied in a prospective cohort of French children born to HIV-1-infected mothers. The analysis was restricted to the 4426 uninfected children, whether or not exposed to antiretrovirals....exposure to antiretrovirals was significantly associated with the risk of febrile [fever-associated] seizure: 24 of the 30 children who experienced such seizures had been exposed to antiretroviral drugs. The cumulative risk at 18 months was 11 [treated children] versus 4.1 not treated per 1000 [the paper notes that the risk in the general population the risk by 18 months was about 50% higher than in the untreated children, implying that due to limitations in the study the rate in the treated children might be similarly higher as many occurrences may have gone untreated]” “From 1984 to 2000, 357 HIV positive pregnant women were assisted in the Hospital Universitario La Fe, Valencia (Spain). A total of 163 were under antiretroviral treatment: 71 zidovudine monotherapy, 44 polytherapy including a PI [Protease Inhibitor], and 48 polytherapy without a PI...there were seven stillborn children: one (0.5%) in women without treatment, two (2.8%) in the monotherapy group, none in the group with polytherapy without a PI, and four (9.1%) with polytherapy including a PI...Further studies should be carried out to assess the safety of these therapies [drug regimes including protease inhibitors]” “The authors report a case of a full-term male neonate [baby] born to a 34-year-old woman with heterosexually acquired asymptomatic HIV infection...receiving zidovudine, stavudine and efavirenz therapy before pregnancy...[once she was determined to be pregnant] antiretroviral therapy was switched to...lamivudine, stavudine and nelfinavir at 24 weeks of pregnancy...The baby was born at the 38th week...presenting with a lumbo-sacral mass compatible with a myelomeningocele [sac containing part of the spinal cord and cerebrospinal fluid caused by failure of the neural tube to close. In the accompanying photo this is approximately the size of the baby’s head]...In animal studies, efavirenz crosses the placenta...Teratogenic effects have been observed in 3 out of 20 fetuses from efavirenz-treated cynomolgus monkeys [but teratogenic effects have also been observed with AZT]” “CD4 cell percentage decrease in group 1 [HIV-positive children with normal CD4 cell counts], despite HAART. In CDC groups 2 [moderately low CD4 cell counts] and 3 [low CD4 cell counts], the percentage increased with slopes of 0.057 [hardly at all] and 0.3 [moderately]…The effect of HAART on HIV-1 load in our group of children did not differ significantly on the basis of immunologic status at the time of initiation of HAART. Total virus suppression by current methods of detection was achieved in 34.8%, 25% and 32% [in children in groups 1, 2 and 3]” “The optimum time to initiate HAART [Highly Active Anti-Retroviral Therapy] in asymptomatic HIV disease remains controversial because of difficulties with long-term adherence, the occurrence of drug resistance, and the development of side effects that are not benign [i.e. potentially fatal], such as lipodystrophy [fat redistribution], hyperlipidemia [serious metabolic abnormality] with associated diabetes mellitus and cardiovascular complications, lactic acidosis [build up of lactic acid in the blood], and mitochondrial toxicity [mitochondria are energy regulating organelles found in every cell in the body]. Long-term effects on growth and health are not known because controlled studies were limited to 2 years of follow-up...In our study, HAART had the greatest effect on immune reconstitution when started in patients with the greatest immunosuppression [lowest CD4 cell counts]. The effect on virus load was similar among the groups, as described elsewhere for adults [i.e. HAART does not suppress ‘viral load’ believed by some to be a measure of the amount of HIV]. These observations raise doubt of the need to start potent antiretroviral therapy in asymptomatic HIV infection when significant viremia is used as the only decision criterion...Our results support the delay of HAART for asymptomatic HIV infection until more advanced stages (immunological or clinical) of the disease occur. Additional long-term clinical studies are needed to adequately assess the safety of delaying early HIV-1 treatment with HAART in children. Such studies should assess, in particular, the risk of central nervous system HIV infection and the clinical use of markers of disease progression in addition to or in lieu of HIV titer in children.” “The effect of highly active antiretroviral therapy (HAART) in 85 children infected with human immunodeficiency virus type 1 (HIV-1) was compared retrospectively among Centers for Disease Control and Prevention (CDC) immunologic groups 1-3...The results support the option of delaying HAART in early asymptomatic HIV-1 disease in children and the use of other markers of disease progression, in addition to virus load.
” “children who had received combination therapy were estimated to have a non-[statistically-]significantly increased rate of clinical progression” “The study cohort included 92 HIV-1-infected and 439 uninfected children...FTT [failure to thrive among children of HIV-positive women] was associated with a history of pneumonia, maternal use of cocaine, crack or heroin during pregnancy, infant CD4+ T-cell count and any antiretroviral therapy by 3 months of age...Antiretroviral therapy (nonprotease inhibitor) was independently associated with FTT in our cohort...ZDV [AZT], in particular, alters mitochondrial metabolism and may have direct nutritional effects” “[Of 195 mother-infant pairs] 9 children (4.6%) with congenital abnormalities were reported. Compared with the 148 infants not exposed to ART or folate antagonists [including PCP therapy with cotrimoxazole or pyrimethamine] during the first trimester, first trimester exposure to both therapies (n=13 [23%]) was associated with a 7-fold increased risk of congenital abnormalities. No congenital abnormalities were observed in the 34 infants exposed to either ART alone or folate antagonists alone during the first trimester…severe immunosuppression [very low CD4 cell counts] has so far not been associted with fetal abnormalities and is unlikely to be a confounder” “Bone mineral density (BMD) of total body and lumbar spine (L2-L4) was assessed by dual-energy X-ray absorptiometry in 40 children vertically infected with HIV: 35 taking HAART and 5 naive to any antiretroviral treatment (untreated). 6 HAART-treated children showed clinical evidence of lipodystrophy [abnormal fat redistribution]...HAART-treated children showed lower spine BMD values than untreated (P = 0.045) and healthy (P = 0.004) children and lower total body BMD values than untreated (P = 0.012) and healthy (P < 0.0001) children. Spine and total body BMD were similar between untreated and healthy children.” “Analyzing simple weight measurements enabled us to determine that maternal illicit drug use during pregnancy, the child's CD4+ T-cell count, history of pneumonia, and exposure to antiretroviral therapy were significantly associated with failure to thrive(FTT) in HIV-1-infected children.” “Risk of progressing to severe immunodeficiency [abnormal CD4 cell counts] was 64% higher [in this group of HIV-positive European children, mostly with mothers involved with intravenous drugs] when receiving ART [Anti-Retroviral Therapy] [Note that the risk of death was higher in untreated children in the first year and 6th to 10th year, but lower in the 2nd to 5th year. No information was given on the association between living conditions, fetal exposure to drugs and illness.]” “A total of 397 adverse events, 180 biological (ie, involving hematologic or blood chemistry alterations) and 217 clinical in nature, were reported among 238 of the 452 children in the lamivudine[3TC]- zidovudine[AZT] cohort. Altogether, 151 hematologic adverse events, defined as moderate to severe according to the age-adjusted ACTG classification,17 occurred during exposure to study drugs. These mostly consisted of neutropenia (81 cases) or anemia (68 cases), leading to blood transfusion because of clinical symptoms in 9 infants (5 had mild symptoms (pallor or tachycardia [abnormally rapid heartbeat]) and 4 had severe symptoms (cardiac insufficiency or dyspnea)) and to premature treatment discontinuation for 19 children. Of the children with hematologic...Liver abnormalities without proven cause were recorded in 6 children ...Of the 217 clinical adverse events reported among children, most were [judged to be] due to a known cause unrelated to study drugs [but without a true control, this is impossible to say with assurance]... 16 children (4%) had major birth defects, including 4 cardiac malformation cases, 4 cases of polydactyly, 3 talipes cases, and 1 case each of congenital diaphragmatic hernia, hydronephrosis, imperforate anus, genu recurvatum with a suburethral cyst, and hypospadia. 1 child each had Down syndrome, Ito nevus, and sickle cell anemia...Neurologic signs/symptoms were reported in 12 children who did not have HIV infection and had no other known infectious or genetic disease.” “Adverse Events in the Lamivudine-Zidovudine Group: 124 adverse events were reported in 99 [pregnant] women. Most of these events were [judged to be] related to documented pregnancy-related or postpartum complications [but without a placebo-control group, this cannot be verified]. 2 women discontinued study drugs because of elevation of transaminase levels...Hemoglobin levels of less than 8 g/dL occurred in 29 women, half of whom had a known cause of anemia not related to study drugs. There were no cases of lactic acidosis. 38 adverse events were reported related to fetal well-being in 37 pregnancies” “[A news article on this oral abstract] reported three cases of unexplained neonatal lactic acidosis and hypoglycemia, either alone or in combination, in non-HIV-infected infants exposed perinatally to Retrovir (zidovudine, AZT), Epivir (lamivudine, 3TC) and Viramune (nevirapine). At birth, two of the three infants had severe acidosis, with a pH less than 7.1, and the third infant, as well as one of the 2 infants with lactic acidosis, had severe and persistent hypoglycemia.” “A total of 195 children were randomised to zidovudine (immediate [IMM]) or matching placebo (deferred[DEF]) in a multicentre double blind trial in vertically HIV infected children with early disease (the PENTA 1 trial). Median follow up in the blinded phase was 1.9 years. Thereafter, individual children were unblinded...Four children (three IMM, one DEF) died during the blinded phase. In two (both IMM) children, death was HIV related...There was an early delay in progression to AIDS in favour of the IMM group during the first year of follow up, followed by a non-significant reversal of that trend in years 3 to 5...Grade 3 or 4 neutropenia [abnormally low neutrophil white blood cell counts] was the most frequent serious adverse event (seven events in four IMM; two events in two DEF). Two children in each group had grade 4 elevations of transaminases [liver enzymes]. Significantly more children in the IMM (n = 13) compared with the DEF (n = 3) group stopped therapy because of an adverse event (all grades, p = 0.02), most commonly because of neutropenia (three IMM, zero DEF), or nausea or vomiting (nine IMM, two DEF)...Our data show that after 3 months of age, many vertically infected children have slow progression of disease, in the absence of therapy. With uncertainties about long term efficacy and toxicity, a case can be made for delaying ART in the well asymptomatic child.” “Doctors throughout Europe are being warned of a potentially fatal side effect if pregnant women infected with HIV take Bristol-Myers Squibb's AIDS drugs Zerit (stavudine) and Videx (didanosine)...the European Medicines Evaluation Agency (EMEA) said seven cases of lactic acidosis--three of them fatal--had been reported worldwide in pregnant women taking the two drugs in combination...Lactic acidosis occurs when the body's cells are unable to convert food into usable energy. The condition causes excess acid to accumulate in the body, potentially damaging vital organs such as the liver and pancreas...the EMEA pointed out that lactic acidosis is a known side effect of the class of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs). The use of this class of drugs is not recommended during pregnancy unless the potential benefit clearly outweighs the potential risks [note that AZT is a drug in this class that is heavily promoted for use during pregnancy].” “Examination of the genotoxic and mutagenic effects of two NRTIs [Nucleoside Reverse Transcriptase Inhibitors], zidovudine (AZT) and didanosine (ddI) in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure...Dose-related increases in DNA incorporation of AZT and mutagenicity at the HPRT and TK loci...were observed in cells exposed in culture to AZT, or equimolar combinations of AZT + ddI, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans...children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life” “Newborn outcomes [27 pregnancies mostly among women who tested positive for illegal drugs]…[include] 5 infants born with birth weights less than 2500g [5-1/2 lb] were born to women who received a protease inhibitor…There was 1 full-term, unexplained stillbirth with no gross birth defects. The mother had started taking zidovudine [AZT] and lamivudine at 15 weeks’ gestation. The infant with microcephaly [abnormally small head] was born [to a mother] taking zidovudine during the first trimester, and lamivudine was added at 16 weeks’ gestation. She received methadone, used heroin” “Two popular HIV drugs may cause birth defects and should be avoided by pregnant women until more is known about their effects, German researchers said on [September 28, 1999]. They found the two drugs, both members of a class known as protease inhibitors, caused abnormal eye development in baby rats. Kai Riecke and colleagues at Freie Universitat Berlin gave the two drugs, Merck's indinavir, known as Crixivan, and Abbott Laboratories' Norvir, or ritonavir, to pregnant rats. They had to stop the ritonavir after a week because it made the rats sick. The rats stayed on the indinavir for the full terms of their pregnancies. Seven of the 236 baby rats exposed to indinavir in the womb were born missing one eye, and two of the 113 baby rats exposed to ritonavir had a missing eye, Riecke's team reported. Fur and teeth also developed later than normal in some of them, they said.” “Adverse events and toxic effects: The rates of maternal serious adverse events were similar in the two groups (4·4% in the zidovudine group, 4·7% in the nevirapine group [and there was no placebo]). One mother in the zidovudine group died 2 weeks after delivery and had bronchopneumonia. One serious event, anaemia, was possibly associated with zidovudine, but excessive blood loss at delivery may have accounted for the anaemia. The occurrence of clinical or laboratory abnormalities in mothers was similar in the two groups (82·2% in the zidovudine group and 80·7% in the nevirapine group had at least one such event). The most frequent adverse clinical event was bacterial or viral infection, occurring in 18·2% of women receiving zidovudine and 20·4% of those receiving nevirapine, followed by parasitic infection in 12·4% and 15·0%, respectively, followed by anaemia in 10·5% and 13·1%, respectively. Nine mothers (four in the zidovudine group, five in the nevirapine group) had maculopapular rash, but no case was serious.

In babies, adverse events were uniformly recorded up to age 6 weeks, whereas only serious adverse events continued to be recorded at each visit up to age 18 months. The rate of serious adverse events in the two groups was similar up to the 18-month visit (19·8% in the zidovudine group, 20·5% in the nevirapine group), with the median age at last visit being 183 days (IQR 102–276). 38 (6·8%) babies died (22 [7·9%] in the zidovudine group, 16 (5·7%) in the nevirapine group). The most frequent cause of death was pneumonia, followed by gastroenteritis, diarrhoea, dehydration, and sepsis. The most frequent causes of serious adverse events within 56 days of birth were sepsis, pneumonia, fever, congenital anomaly, asphyxia, and dyspnoea. Of the 59 serious adverse events reported in the first 56 days of life, those that occurred in four (1·4%) babies in the zidovudine group and in two (0·7%) babies in the nevirapine group were judged to be possibly, but unlikely to be, related to study drug. In the four babies in the zidovudine group, adverse events were sudden-infant death syndrome 24 h after delivery, transient tachypnoea at birth requiring oxygen, birth asphyxia with death due to fetal distress after caesarean section, and presumed pneumonia 4 days after birth. In the two babies in the nevirapine group, adverse events were transient respiratory distress at birth with meconium staining requiring oxygen, and a non-macerated stillbirth to a mother who received nevirapine 3·5 h before delivery.

18 babies had maculopapular rash, no case of which was serious (nine in the zidovudine group, nine in the nevirapine group). Within the first 56 days of life, 22 babies had grade 3 anaemia (nine in the zidovudine group, 13 in the nevirapine group), with haemoglobin values ranging from 85–118 g/L. No case was judged to be serious or clinically important. The frequency and severity of laboratory-detected toxic effects, including neutropenia, thrombocytopenia, and abnormalities in creatinine or bilirubin, were similar in the two groups.” “There were 5 serious adverse events [out of 8 participants!] including two deaths in the infants in cohort 1 [Nevirapine to mother only]. Only one of the five serious adverse events was thought by the investigators to be possibly, but not likely study drug related [but, without a control group, it is possible that all adverse events were related]...In cohort 2 [Nevirapine to mother and child] there were 7 serious adverse events [out of 13 participants!], including 2 infant deaths, although none were related to the study drug” “11 [of 90] children had been withdrawn from study for disease progression [in other words, it didn't work for them] and 10 because of possible lamivudine-related toxicity, and 6 had died...In summary, this study confirms that lamivudine can be safely given to children with HIV infection and that it has a favorable pharmacokinetic profile and evidence of antiretroviral activity” “Stavudine [d4T] was well-tolerated [by a group of 37 HIV+ children] and there were no dose-related clinical or laboratory adverse events...Thirty-five of 37 subjects experienced serious clinical adverse events, including infection (33 subjects), lymphadenopathy (19 subjects), hepatosplenomegaly (15 subjects), chills and fever (12 subjects), and development of an AIDS-defining condition (four subjects)...Clinical adverse events of lesser severity that were reported by more than 20% of subjects included rhinitis (76%), cough (70%), diarrhea (68%), rash (62%), nausea and vomiting (51%), abdominal pain (43%), anorexia (41%), respiratory disorder (38%), headache (35%), pharyngitis (32%), pruritis (30%), pain (22%), peripheral neurologic symptoms (22%), and nervousness (22%)” “Transfusion was required in 14 patients because of low levels of hemoglobin. Dose-limiting neutropenia occurred in most patients who received doses of 1.4 mg per kilogram per hour or more...The major limitation of the therapy was hematologic toxicity--a decrease in both the hemoglobin concentration and the white-cell count...Regardless of the starting dose, nearly all patients had a transient drop in their neutrophil counts within 10 days of the initiation of AZT therapy...In three of the five children who died, evidence of a response to AZT, particularly neurodevelopmental improvement, was present at the time of death [i.e. the children were getting better, only they died first]”

Resistance to Therapy

Resistance to therapy is often blamed for the inability of AIDS therapy to affect 'surrogate markers', such as CD4 counts and viral load used to monitor the progress of therapy. Resistance is very difficult to accurately measure, but is a convenient scapegoat. Furthermore, even when therapy does affect surrogate markers in the hoped-for manner it doesn't necessarily result in better health (but that's a different issue).

“Results: Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 102 to 105 copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03).”

“Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.”