|HIV drugs||AZT/PIs||Side effects||General|
|Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study.|| ||Fellay J et al.
| ||"Data on adverse events to antiretroviral treatment have been recorded in clinical trials, post-marketing analyses, and anecdotal reports. Such data might not be an up-to-date or comprehensive assessment of all possible treatment combinations defined as potent antiretroviral treatment. Using a standard clinical and laboratory method, we assessed prevalence of adverse events in 1160 patients who were receiving antiretroviral treatment. We measured the toxic effects associated with the drug regimen (protease inhibitor [PI], non-nucleoside and nucleoside analogue reverse transcriptase inhibitor) and specific compounds using multivariate analyses. 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. Single-PI and PI-sparing-antiretroviral treatment were associated with a comparable prevalence of adverse events. Compared with single-PI treatment, use of dual-PI-antiretroviral treatment and three-class-antiretroviral treatment was associated with higher prevalence of adverse events (odds ratio [OR] 2.0 [95% CI 1.0-4.0], and 3.9 [1.2-12.9], respectively). Compound specific associations were identified for zidovudine, lamivudine, stavudine, didanosine, abacavir, ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, and nevirapine. We recorded a high prevalence of toxic effects attributed to antiretroviral treatment for HIV-1. Such data provides a reference for regimen-specific and compound-specific adverse events and could be useful in postmarketing analyses of toxic effects."|
| ||Lancet. 2001 Oct 20;358:1322-7.||2001|
|Initiating antiretroviral therapy during HIV infection: confusion and clarity.|| ||Pomerantz RJ.
| ||“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]).”|
| ||JAMA. 2001 Nov 28;286(20):2597-9.||2001|
|Plague: AIDS at 20.|| ||Delaney M
| ||"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... 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? ”|
| ||ABC Nightline with Ted Koppel. 2001 Jun 8.||2001|
|Advances in HIV treatment a mixed blessing.|| ||Swick L.
| ||“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.”|
| ||The Toronto Star. 1999 Sep 24.||1999|
|Adverse events from the drug therapy for human immunodeficiency virus disease|| ||Moore RD et al.
| ||“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.”|
| ||American Journal of Medicine (JAMA?). 1996 Jul;101:34-40.||1996|
|Taking a break; Can interrupting their treatment benefit HIV-infected people?|| ||Christensen D
| ||In the words of Kendall Smith from the New York Hospital-Cornell Medical Center, “Right now, the disease is life-threatening, on one hand, and the drugs that we have so far have life-threatening toxicities, on the other hand. It puts us between a rock and a hard place.” .|
| ||Sci. News 2000, 157 248– 249||2000|
|Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions.|| ||Lucas G et al.
| ||“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]”|
| ||Ann Int Med. 1999 Jul 24;131:81-7.||1999|
|The chemical bases of the various AIDS epidemics: recreational drugs, anti-viral chemotherapy and malnutrition|| ||DUESBERG PETER, KOEHNLEIN CLAUS, RASNICK DAVID
| ||Further, a 1-year old HIVpositive, AZT-treated baby girl with severe muscle pain, insomnia, nausea and failure to grow was taken off AZT treatments in 1992 based on our hypothesis; as a result the baby immediately recovered. Now, at the age of 11, she is a completely normal, healthy kid, and a leading player in her schools soccer team (Sheryl and Steve Nagel, personal communication).|
| ||J. Biosc, Vol. 28 No. 4, June 2003, 383–412||2003|
|Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers.|| ||Sadler BM et al.
| ||“[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..."|
| ||AIDS. 2001 May 25;15(8):1009-18.||2001|
|Glaxo plays down Ziagen fear.|| ||Kibazo J.
| ||“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."”|
| ||Financial Times. 2000 Aug 21.||2000|
|Manufacturer's notice|| ||Glaxo SmithKline
| ||"The following table summarizes clinical adverse events or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with 1500 mg/day of Retrovir in the original placebo-controlled study.2 ... severe headache,... were reported at a significantly greater rate in patients receiving Retrovir."|
|Surveillance of HIV infection and zidovudine use among health care workers after occupational exposure to HIV-infected blood.|| ||Tokars JI et al. The CDC Cooperative Needlestick Surveillance Group.
| ||“[this study included US health care workers exposed] to blood from a patient with documented HIV infection [81% had AIDS] as a result of percutaneous injury (for example, a needlestick or a cut from a sharp object), contamination of mucous membranes, or contamination of nonintact skin…From October 1988 to Jun 1992, the period when use of zidovudine [AZT] was studied, 848 workers were enrolled. Postexposure zidovudine was used by 265 (31%) of these workers…in doses range from 200 to 1800 mg/day and for periods of 1 to 180 days…176 (75%) reported one or more symptoms, most commonly nausea, malaise or fatigue, or headache. Symptoms were reported less frequently among workers who did not use zidovudine…Of 175 workers who completed 21 or more days of [AZT] prophylaxis, 51 (29%) had paired hemograms at least 21 days apart…7 (14%) had a 10% or greater reduction in hemoglobin or hematocrit values…74 (31%) of workers did not complete their planned regmine of zidovudine because of adverse symptoms (73) or reduction in hemoglobin level (1)…28 (12%) of workers were absent from work for periods ranging from 1 to 49 days because of adverse events attributed to zidovudine…because of uncertainty about efficacy and safety, the Public Health Service concluded in January 1990 that a recommendation for or against the use of postexposure zidovudine could not be made.”|
| ||Ann Intern Med. 1993 Jun 15;118(12):913-9.||1993|
|A phase I/II evaluation of Stavudine (d4T) in children with human immunodeficiency virus infection.|| ||Kline MW et al.
| ||“Thirty-five of 37 subjects experienced serious clinical adverse events... 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%)”|
| ||Pediatrics. 1995;96:247-52.||1995|
|Lamivudine in children with human immunodeficiency virus infection: a phase I/II study.|| ||Lewis LL et al.
| ||“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...”|
| ||JID. 1996;174:16-25.||1996|
|Adverse effects of antiretroviral therapy.|| ||Carr A, Cooper DA.
| ||“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; heppatic 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 lioatrophy in the face, limbs and buttocks) and central fat accumulation (within the abdomen, breats 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 lipdystrophy and protease-inhibitor therapy include hypertriglyceridaemia, hypercholesterolaemia, insuilin resistance...and type 2 ...diabetes mellitus. Dyslipidaemia at concentrations associated with increased cardiovascular disease occurs in about 70% of patients. These metabolic abnormalitis 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 (burising, 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.”|
| ||Lancet. 2000 Oct 21;356:1423-0.||2000|
|HIV viral load response to antiretroviral therapy according to baseline CD4 cell count and viral load.|| ||Phillips et al
| ||"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." (page 2565)|
| ||JAMA 286(20); 2560-2567.November 28, 2001||2001|
|Lamivudine-Zidovudine Combination for Prevention of Maternal-Infant Transmission of HIV-1.|| ||Madelbrot L et al.
| ||“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) 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.”|
| ||JAMA. 2001 Apr 25;285(16):2083-93.||2001|
|Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. The AIDS Clinical Trials Group.|| ||Lenderking WR, Gelber RD, Cotton DJ, Cole BF, Goldhirsch A, Volberding PA, Testa MA
| ||"For asymptomatic patients treated with 500 mg of zidovudine, a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with a delay in the progression of HIV disease". It remains unclear, however, how one gains 0.5 months "without disease progression" while one has "severe adverse effects" 0.6 months sooner.|
| ||N Engl J Med 1994 Mar 17;330(11):738-43||1994|