Harmful Side Effects of AZT, General

“It was often difficult to distinguish adverse events possibly associated with administration of RETROVIR® (AZT™) from underlying signs of HIV disease or intercurrent illnesses”

“Perinatal treatment with 3'-azido-3'-deoxythymidine (AZT) has been found to reduce the rate of maternal-infant transmission of HIV; however, AZT is clastogenic at therapeutic doses in adult patients and induces cancers in the offspring of mice treated in utero. The purpose of the present study was to investigate the mutagenicity of AZT at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus of the human lymphoblastoid cell line, TK6, following in vitro exposures. ..There was a significant increase over background in hprt Mfs [mutation frequencies] in TK6 cells exposed to 300mM AZT for 3 days (1.8-fold increase). In cells exposed for 6 days, there was a decrease in...cell survival. ..These preliminary results indicate that AZT treatment is mutagenic and produces large deletions in human cells.”

“The incidence of adverse reactions appears to increase with disease progression, and patients should be monitored carefully, especially as disease progression occurs…Myopathy and myositis with pathological changes similar to that produced by HIV disease have been associated with prolonged use of zidovudine. Reports of hepatomegaly with steatosis, hepatitis, pancreatitis, lactic acidosis, sensitization reactions (including anaphylaxis in one patient), hyperbilirubinemia, vasculitis, and seizures have been rare. These adverse events, except for sensitization, have also been associated with HIV disease…Several serious adverse events have been reported with the use of zidovudine in clinical practice. Myopathy and myositis with pathological changes similar to that produced by HIV disease have been associated with prolonged use of zidovudine.”

“AZT … induces significant toxic effects in humans exposed to therapeutic doses...Cytogenetic observations on H9-AZT cells showed an increase in chromosomal aberrations and nuclear fragmentation when compared with unexposed H9 cells...The toxicities explored here suggest that the mechanisms of AZT induced cytotoxicity in bone marrow of the patients chronically exposed to the drug in vivo may involve both chromosomal and mitochondrial DNA damage.”

“Clinical manifestations of ANA [Antiviral Nucleoside Analogs, such as AZT] toxicity: It is self-evident that ANAs, like all drugs, have side-effects. However, the prevalent and at times serious ANA mitochondrial toxic side-effects are particularly broad ranging with respect to their tissue target and mechanisms of toxicity: … Haematalogical toxicity [anemia, and other blood disorders] … Myopathy [muscle disorders] … Cardiotoxicity [heart disorders] … Hepatic toxicity [liver disorders] … Peripheral neuropathy [nerve damage]”

“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]…Patients with previous ZDV exposure had a higher incidence of advanced HIV disease and tended to have lower, but not [statistically] significant, pretreatment CD4 lymphocyte counts”

“among the subjects with CD4+ [immune system] cell counts < 200/mm3, the risk of developing HIV dementia among those reporting any antiretroviral use (AZT, ddI, ddC, or d4T) was 97% higher than among those not using this antiretroviral therapy...In addition, the findings of our analysis seem to confirm previous observation of a neurotoxic effect of antiretroviral agents. Numerous studies have linked the use of ddI, ddC, and d4T [nucleoside analogs] to the development of toxic sensory neuropathies, usually in a dose-dependent manner”

“[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…The proportion of enrolled workers using zidovudine increased from 5% in the fourth quarter of 1988 to 50% in the third quarter of 1990 and has been stable subsequently…no seroconversions occurred among 301 workers not using zidovudine, and 1 seroconversion occurred among 143 workers using zidovudine…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 posexposure zidovudine could not be made.”

“A manic syndrome in eight patients with AIDS is described. On the basis of clinical, neuropsychological, laboratory, magnetic resonance imaging, and epidemiological evidence, the authors suggest that the manic syndrome was secondary to HIV infection. The patients also developed concomitant cognitive impairment…[but] two patients also had histories of intravenous drug abuse…Five patients had been taking zidovudine [AZT] prior to admission and one was started on the drug during hospitalization.”

“ZDV [AZT] treatment results in a significant increase in chromosomal aberrations…[in this study] There was a 16-fold increase in the frequency of aberrant cells in the ZDV-treated group…These data suggest that ZDV has the ability to induce genetic damage at therapeutic levels of dosing, which could produce a potential increase in carcinogenic risk associated with its prolonged intake.”

“Zidovudine was reasonably well tolerated in this study...27% [remained] on full dose at the end of the first year of therapy. The full daily (1.2 g) was received by 68 patients (24%) for the entire duration of their time on therapy. Of these full-dose patients, six died within 6 weeks of commencing therapy...172 patients (56%) developed a new AIDS-defining condition during therapy; 130 patients [42%] developed the condition more than 6 weeks after commencing zidovudine therapy...Anemia was the most frequently reported adverse experience during zidovudine therapy. Transfusions were reported necessary for 155 patients (50%) while on zidovudine, 91 patients (representing 29% of the total) required transfusions on more than one occasion.”

“Of the 524 subjects enrolled [in this study of people in the early stages of AIDS and HIV antibodies], 4 never received zidovudine [AZT], 41 completed the study, and 479 were withdrawn from zidovudine treatment [i.e. virtually everyone]. The reasons for withdrawal from zidovudine were the development of an opportunistic infection or a neoplasm [cancer]...(54 subjects); death (43); toxic reactions (183); withdrawal by the subject (169) and other reasons (30)...[of the] 183 subjects withdrawn...because of toxic reactions, zidovudine was discontinued earlier in more subjects in the standard-treatment group than in the low-dose group [40% vs. 29%]. Among the symptoms only headache was noted more frequently in the low-dose group...22 subjects (8%) in the standard-treatment group and 27 (10%) in the low-dose group had elevated levels of hepatic [liver] enzyme...178 subjects (34%) had a hemoglobin concentration below 5 mmol per liter [anemia]...134 subjects (26%) received red-cell transfusions (65 in the standard-treatment group and 69 in the low-dose group)...230 subjects(44%) had a [low] neutrophil [infection fighting white blood cells] count...134 (51%) in the standard-treatment group and 96 (37%) in the low-dose group...22 subjects (4%) had a [low] platelet [blood clotting cells] count”

“Of the 265 patients who withdrew from study treatment voluntarily, 44 listed medical symptoms as the primary reason. Of these 44 withdrawals, 8 occurred in the placebo group, 13 in the 500-mg[per day] zidovudine [AZT] group and 23 in the 1500-mg zidovudine group…the most common [symptoms reported by these people] were gastrointestinal upset, confusion and malaise…The overall benefits of the treatment of early HIV disease with zidovudine must be weighted against potential toxicity and the costs associated with therapy, as well as the uncertainty that it will confer a long-term benefit in survival.”

“AZT inhibition of DNA synthesis in 3 hr bone marrow cultures is relatively consistent in a variety of hematologic disorders. As approximately two-thirds of AIDS patients appear to be [deficient in] folate and/or vitamin B12, the fact that AZT-induced inhibition of pyrimidine incorporation into DNA [required for DNA elongation] is occurring in cells which may be megaloblastic, i.e., in a state of impaired DNA synthesis, suggests that these cells may be more susceptible to AZT toxicity. The data also support the notion that AZT inhibition results predominantly from termination of DNA chain elongation.”

“16 of 38 patients developed nail discoloration after zidovudine therapy was begun. Dyschromia was usually apparent within 4 to 8 weeks but also occurred as late as 1 year”

“58% of all subjects with AIDS and AIDS-related complex receiving zidovudine experienced granulocytopenia of grade 3 or higher...Serious anemia occurred in 32% of all subjects receiving zidovudine...and could be typically managed by dose attenuation, temporary dose interruption of zidovudine therapy and/or red blood cell transfusions...12% of subjects...had an episode of thrombocytopenia [low platelet count] after the initiation of zidovudine therapy...Ten patients had liver enzyme levels elevated...and were managed with dose attenuations or interruptions of zidovudine therapy...One report of a grand mal seizure, two events associated with cardiac dysfunction, and five reports of myopathy were the only new serious potentially drug-related adverse events reported during extended periods of zidovudine administration.”

“We report a patient who experienced acute cholestatic hepatitis on initial exposure to and rechallenge with zidovudine and, as a result, was unable to receive further therapy with the drug...Seven days [after starting AZT therapy] the patient presented with a 2-day history of intermittent fevers and abdominal discomfort...Seven days [after re-starting AZT therapy once the initial symptoms resolved] the patient again experienced fever, right upper quadrant pain, nausea, and headache...One month later [after discontinuing AZT] the liver function tests had almost completely returned to normal and remained without significant abnormalities.”

“AZT was started at full dose in 260 patients, 64 with ARC and 196 with AIDS. In 58 of these patients, AZT had to be stopped at least once for a minimum of 7 days. In 142 other patients, dosage was reduced by half because of leucopenia (79), leucopenia and anaemia (32), anaemia (20), rash (3), vomiting (3), headaches and insomnia (2), myalgia (2), or hepatitis (1). 3 patients reduced the dose with no medical reason. Later on, progression of toxicity led to suspension of AZT (for at least 7 days) in 85 of the 142 patients whose treatment had been reduced to half dose. Thus AZT was stopped at least once in 143 (55%) patients who began the full-dose regimen. Because of their initial haematological status 105 (28.8%) patients were treated from the start with half-dose AZT - toxicity led to cessation of treatment in 71 (67.6%) cases”

“[adverse reactions] reported were one case of Stevens-Johnson syndrome in a severely atopic [allergic] patient and 32 reports of seizures.”

“In a cytogenetics study performed in cultured human lymphocytes, dose-related structural (but not numerical) chromosomal alterations were noted at concentrations of 3 micrograms/ml and higher”

“the most promising agents effective against AIDS are 3’-azidothymidine (AZT) [approved this same year, 1987] and 2’,3’-dideoxycytidine (DDC) [approved in 1991]…The severe toxicity of AZT to bone marrow, as well as unexpected interactions of other drugs with AZT, indicate the importance of knowing rhore about the effects of the compound.”