“Zidovudine (ZDV) [AZT] is the preferred nucleoside reverse transcriptase inhibitor in the first line antiretroviral regimen in India. It is known to be associated with life threatening toxicity like anaemia. This study was aimed at determining the prevalence of ZDV induced anaemia in HIV infected patients initiated on ZDV containing antiretroviral therapy regimen and also to find out the correlates, if any, for causing ZDV induced anaemia. This retrospective study was carried [out] in ART Centre, Sir Sunderlal Hospital, Banaras Hindu University, Varanasi between March 2005 to December 2007…Patients (n=1256) with haemoglobin (Hb) >8 g/dl were prescribed ZDV based antiretroviral therapy regimens…203 (16.2%) patients on ZDV regimen developed anaemia; 7.9% of these developed severe anaemia. Females were more prone to develop anaemia. Age, weight, WHO clinical stage and CD4 counts had no relation to development of anaemia”

“Zidovudine, a Nucleoside Reverse Transcriptase Inhibitor (NRTI) is one of the earliest antiretroviral agents used as a combination in the Highly Active Antiretroviral Therapy (HAART) for the treatment of HIV infection. Its use is however not without adverse effect particularly bone marrow aplasia leading to varying degrees of cytopenias [blood cell deficiencies] predominantly anaemia. This calls for adequate evaluation and monitoring of patients on this drug. Its major side effect of anaemia limits its use in some patients. We report a case of Zidovudine induced anaemia and bone marrow aplasia in a patient infected with HIV. The Hospital case note of a 27 year old widow with HIV infection and anaemia, who has been on HAART (Zidovudine, Lamivudine and Nevirapine) for one year, was reviewed. She presented with severe anaemia, White cell and platelet counts were within normal limits and reticulocyte count of 0.001%. Bone marrow aspiration and biopsy were diagnostic of pure red cell aplasia on a background hypocellular marrow. She was transfused with four (4) units of packed cells and Zidovudine was replaced with Stavudine. She made remarkable improvement and remains transfusion independent afterwards. Zidovudine is well a known cause of anaemia and thus should be used with caution in the initiation of antiretroviral therapy.”

“Macrocytosis, generally defined as a mean corpuscular volume [MCV] greater than 100 fL, is frequently encountered when a complete blood count is performed. The most common etiologies are alcoholism, vitamin B12 and folate deficiencies, and medications…Treatment of HIV with reverse transcriptase inhibitors (e.g., stavudine [Zerit], lamivudine [Epivir], zidovudine [Retrovir/AZT]) will cause macrocytosis because they interfere with DNA production, which may lead to megaloblastic changes. Most patients with HIV who are being treated with reverse transcriptase inhibitors will display macrocytosis without anemia. This indicates medication compliance by the patient, and no treatment is necessary [except that anemia is one of the leading side effects of these drugs, so this is clearly not true]”

“Reversible pure red cell aplasia is a recognized complication of both zidovudine and lamivudine, typically occurring within the first 3 months of therapy [1,2]. We report the case of a 29-year-old man with HIV, severe haemophilia A and hepatitis C, who developed reversible pure red cell aplasia 4 years after commencing zidovudine.”

“For this study, 1278 patient charts were screened, and 758 were included in the study…Of [these], 30.3% (230) were anemic (Hb [hemoglobin] level of 12.5 g/dL or less) at some time during the study…The majority of the ever-anemic patients (67%; 154 of 230) had a nadir [lowest] Hb level of 12.0 to 12.5 g/dL, which was considered mild to moderate anemia…Anemia was significantly more prevalent in patients who were currently being treated with HAART regimens containing zidovudine [AZT]…The presence of an AIDS diagnosis was not an independent risk factor for anemia in multivariate logistic regression analysis, although markers of disease progression, such as decreasing CD4+ cell count and increasing viral load, remain independent predictors of risk.”

“Zidovudine [AZT] was generally well tolerated in this high-risk population…[from Table II: 32%-Anemia grade >=2; 11%-Neutropenia; 13%-Thrombocytopenia; 45%-Received transfusion; 26%-Received erythropoetin; 11%-HIV infection; 8%-Died]…Slightly more than half of the subjects had anemia severe enough to require a transfusion [giving new meaning to the term 'well tolerated']”

“Recent epidemiologic studies of HIV-related anemia have strongly and repeatedly associated low hemoglobin level with disease progression and mortality. Patients who are at greater risk for anemia may include those of African-American ancestry, and those with low CD4 cell counts, high virus load, and low mean corpuscular volume and those receiving zidovudine [AZT]…[in one study] for patients without anemia, 3.1% died by 12 months. In contrast, for patients with mild anemia, 15.9% had died, and for patients with severe anemia, 40.8% had died [this association remained even after controlling for CD4/viral load measurements]”

“We conducted a longitudinal study of 797 human immunodeficiency virus (HIV) positive women (7732 visits) and 389 HIV-negative women (3651 visits) to characterize anemia...Risk factors for anemia [included] zidovudine use [1.14 times more likely]. Anemia was common and associated with an increased risk of death (hazards ratio, 1.64; 95% CI, 1.21 2.23) among HIV-positive women...the mortality rate during the follow-up period was 37% in those who were anemic at enrollment and 22% in those who were not anemic at enrollment”

“1 patient [out of a grand total of 10 in this clinical trial] suffered from severe anemia resulting from ZDV [AZT] therapy”

“In a retrospective evaluation of medical records of 32,867 HIV-infected persons followed in nine cities in the United States, the 1-year incidence of anemia, defined as a hemoglobin level <10 g/dl or a physician’s diagnosis of anemia, was approximately 37% for patients with a clinical AIDS-defining condition; 12% for those with immunologic AIDS, defined as a CD4 count <200; and 3% for persons without either of these conditions…Use of ZDV either currently or in the past 6 months was associated with anemia…A total of 41.5% of those with a history of ZDV in the past 6 months and 27.7% of those without such history were anemic at baseline…The strong statistical associations between worsening parameters of HIV disease and increased likelihood of anemia…suggest that effective antiretroviral therapy may be associated with improvement in Hb [hemoglobin] levels [!]”

“Of variables related to HIV infection, low CD4+ cell count, AIDS diagnosis and receiving zidovudine [AZT] therapy were predictive for prevalent anemia”

“We found that 78.2% of the patients with mild or severe anaemia at baseline had received zidovudine [AZT]”

“While effective [effective at what?] drug therapy is continued in zidovudine[AZT]-treated HIV-infected patients…PROCRIT Reduces Transfusion Requirements and Helps Lift the Burden of Anemia. PROCRIT enables physicians to effectively: 1) Manage anemia with an easily administered, well-tolerated theerapy that allows continuation of zidovudine [AZT]-based regimens for HIV infection. 2) Help mildly anemic patients…3) Eliminate transfusion complications and inconvenience in patients who become transfusion-independent.

PROCRIT increases HCT [hematocrit, percentage of blood that is composed of red cells] significantly during myelosuppressive [bone marrow destroying] zidovudine therapy.”

“Anemia occurred in 22% of the infants who received zidovudine”

“A third possible cause of excessive tissue iron is the use of zidovudine [AZT]. The drug interferes with heme synthesis and, in an animal model, has been shown to upregulate iron acquisition. Although may of the reports of iron-loading cited herein involved patients in the first half of the 1980s, before the routine use of zidovudine.”

“Toxicity studies of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) were conducted in F344/N rats and B6C3F1 mice…AZT and ddC produced dose-related, poorly regenerative, macrocytic anemias as evidenced by decreases in erythrocyte counts, hematocrits, and hemoglobin concentrations and increases in mean corpuscular hemoglobin and mean corpuscular volume. Bone marrow samples in rats treated with AZT were hyperplastic whereas those in mice treated with AZT and rats and mice treated with ddC were hypoplastic. The hematologic toxicity of AZT was more severe than that of ddC. Generally, toxic effects of either chemical were greater in mice than in rats and more pronounced in female than in male animals. After 30 days without dosing, hematologic effects either resolved or dramatically improved…These studies demonstrated the early and progressive time course of toxicity of AZT and ddC”

“the drug [AZT] has some serious side effects, the most important of which is myelosuppression [damage to the ability of the bone marrow to produce new white blood cells]”

“The majority of patients had a macrocytic anemia (70%); however, all of these patients were also receiving zidovudine”

“Long-term tolerance of zidovudine [AZT] treatment was retrospectively analysed in 97 patients with AIDS or AIDS-related complex. After one year of treatment 68% and after two years 87% of the patients had had at least one dose adjustment during their course of therapy. Myelotoxicity [damage to the blood forming tissues] was the most common cause (58% of all cases) of dose reductions and therapy interruptions (dose adjustments). At the time of the first dose adjustment 33 patients (34%) were suffering from anaemia ([hemoglobin] less than 6.0 g/dl), 20 patients (21%) from leukopenia (leukocytes less than 1.5 x 10^9], and 10 patients (10%) from thrombocytopenia (thrombocytes less than 75 x 10^9]. 56 patients (57%) needed one or more blood transfusions during therapy. The median time from the start of therapy to the time of the first dose adjustment was 14 weeks in patients who had a first dose adjustment because of anaemia without co-existing leukopenia or thrombocytopenia…only a minority of patients with severe symptomatic HIV-1-related diseases can tolerate full-dose zidovudine regimens for prolonged periods [AZT doses are now generally much lower, but adherence still remains a challenge for people taking this drug or other nucleoside analogs]”

“178 subjects (34%) had a hemoglobin concentration below 5 mmol per liter [anemia]...A greater proportion of subjects in the standard-treatment [high dose AZT] group had a first episode of severe anemia earlier in the study, as compared with the proportion in the low-dose group. 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.”

“[in mice] AZT had a profound effect on the number of erythrocytes [mature red blood cells] and a small effect on the number of leukocytes [white blood cells]…anemia was seen in all the mice tested at 1,000 mg/kg per day”

“The occurrence of severe anemia, although more common in the 500-mg[per day] zidovudine [AZT] group than the placebo groiup (5 cases vs. 1 case), was rare in both grouips. The subjects in the 1500-mg group, however, had higher rates of anemia (6.3%) and neutropenia (6.3%).”

“One or more transfusions were reported for 19.7% of patients [taking AZT], but anemia was reported as a serious adverse event in only 11.4% of patients. The mean time to first transfusion was 98 days after beginning therapy.”

“Zidovudine is well known to produce haematological toxicity in vitro and in some patients...It is worrying that bone marrow changes in patients on zidovudine seem not to be readily reversed when the drug is withdrawn…These findings have serious implications for the use of zidovudine in HIV positive but symptom-free individuals.”

“Between 10% and 25% of patients experienced decreases in granulocyte counts to less than 750/cubic-mm during each month of therapy…The incidence of anemia remained relatively constant over time. Approximately 10% of patients per month reported with hemoglobin levels less than 7.5 g/dl, and fewer than 5% were reported with levels less than 6.5 g/dl…At the physicians’ discretion, transfusions with packed red blood cells were used to manage hemoglobin levels in patients with anemia [Figure 4 shows that 20-25% of patients required transfusions during the main portion of the trial (12-52 weeks)]…Anemia and granulocytopenia remained the major reasons for dose reductions or discontinuation of zidovudine treatment.”

“nearly one half of patients treated with AZT for [HIV]-associated disease develop transfusion-dependent anaemia due to bone marrow depression…Here, we have probed the mechanism by which cytopenias [blood cell deficiencies] develop by measuring the effects of AZT on the proliferation of normal human bone marrow progenitor cells. Our results suggest that AZT impairs proliferation of haematopoietic progenitors [blood cell producers] of all types assayed, and that cells of the erythroid [red blood cell] lineage are particularly sensitive to this effect…at a pharmacologic concentration of the drug…Of particular interest is our finding that the antiproliferative effects of AZT are overcome by addition of thymidine [AZT is an imitator of this nucleoside] to culture. This suggests that AZT and thymidine compete for an effect on cultured haematopoietic cells”

“Blood transfusion is often necessary in patients with AIDS, especially in those receiving AZT, a drug which produces severe anaemia in a proportion of recipients. Forty nine (36%) of 138 patients treated with AZT … required blood transfusion at least once.”

“In the current study, transfusion-dependent anemia occurred in 6 of 15 patients with AIDS and Kaposi sarcoma who were receiving zidovudine therapy. All 6 affected patients required their first blood transfusion between 3 and 9 weeks after starting zidovudine therapy, and each required 4 to 14 units of packed erythrocytes to maintain a hemoglobin level above 100 g/L over a 12-week study.”

“The hematocrit [red blood cell count] decreased in the same patients...with three of eight patients requiring red-cell transfusion by the fourth week of treatment.”

“Four patients with [AIDS], and a history of Pneumocystis carinii pneumonia developed severe pancytopenia [marked decrease in all types of blood cells]…12 to 17 weeks after the initiation of azidothymidine (AZT) therapy…Partial bone marrow recovery was documented within 4 to 5 weeks in three patients, but no marrow recovery has yet occurred in one patient during the more than 6 months since AZT treatment was discontinued.”

“31% of the AZT recipients and 11% of the placebo recipients were given red-cell transfusions during the study. Transfusions were required on more than one occasion by 21% of the AZT recipients and 4% of the placebo recipients…Anemia developed as early as week 4 of therapy but most frequently occurred during weeks 6 and 8. Hemoglobin levels fell suddenly in some patients…Red-cell transfusions were required to continue therapy in many of the AZT recipients. Despite stabilization of anemia by dose reduction or transfusion, neutropenia often ensued. These manifestations of drug toxicity are potentially life-threatening…Anemia…developed in 24% of AZT recipients and 4% of placebo recipients (P<0.001). 21% of AZT recipients and 4% of placebo recipients required multiple red-cell transfusions (P<0.001). Neutropenia (<500 cells per cubic millimeter) occurred in 16% of AZT recipients, as compared with 2% of placebo recipients (P<0.001).”

“more than half of all AIDS patients may not benefit from the drug because it is more toxic for them than their AIDS infection. The most serious side effect of AZT is to suppress the bone marrow, leaving patients highly vulnerable to bacterial infections”

“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.”

“mice were treated with AZT for 35 days (10 mg/kg/day) in drinking water. Animals treated with antioxidant vitamins were fed the same diet as controls but supplemented with vitamins C (ascorbic acid, 10 g/ kg diet) and E (alpha-dl-tocopherol, 0.6 g/kg diet) for 65 days before sacrifice…Cardiac mitochondrial DNA (mtDNA) of mice treated with AZT had over 120% more oxo-dG (8-oxo-7,8-dihydro-2'-deoxyguanosine, which is a biomarker of oxidative damage to DNA) in their mitochondrial DNA than untreated controls. AZT treatment also caused an increase in mitochondrial lipid peroxidation and an oxidation of mitochondrial glutathione…The oxidative effects of AZT are probably due to an increase in production of reactive oxygen species by mitochondria of AZT-treated animals, raising the possibility that oxidative stress may play an important role in the cardiotoxicity of AZT.”

“At term, AZT was found to be incorporated into fetal mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed mitochondrial membrane compromise, mitochondrial proliferation, and damaged sarcomeres [a type of muscle cell], while mitochondria in brain cerebrum and cerebellum were morphologically normal.”

“Antiretroviral nucleoside analogue drugs are a major constituent of highly active antiretroviral therapy (HAART), the most advanced form of treatment for HIV-1 infection. 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. To model human transplacental ZDV and 3TC exposures, 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/d (about 6 mg/kg body weight/d) for the last 50% (10 weeks) of gestation (n = 3), or with the same regimen of ZDV plus 24.0 mg 3TC/d (about 3.6 mg/kg body weight/d) for the last 20% (4 weeks) of gestation (n = 3). Multiple fetal organs were examined at term for DNA incorporation of ZDV and 3TC using two separate radioimmunoassays (RIAs). 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. No telomere shortening was evident in the unexposed fetuses, and occasional telomere shortening was found in fetuses exposed to ZDV alone. 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.”

“3'-azido-3'-deoxythymidine (AZT) is given to pregnant women positive for the human immunodeficiency virus type 1 (HIV-1) to reduce maternal-fetal viral transmission. To explore fetal mitochondrial consequences of this exposure, pregnant Erythrocebus patas monkeys were given daily doses of 1.5 mg (21% of the human daily dose) and 6.0 mg (86% of the human daily dose) of AZT/kg body weight (bw), for the second half of gestation. At term, electron microscopy of fetal cardiac and skeletal muscle showed abnormal and disrupted sarcomeres with myofibrillar loss. Some abnormally shaped mitochondria with disrupted cristae were observed in skeletal muscle myocytes. Oxidative phosphorylation (OXPHOS) enzyme assays showed dose-dependent alterations. At the human-equivalent dose of AZT (6 mg of AZT/kg bw), there was an approximately 85% decrease in the specific activity of NADH dehydrogenase (complex I) and three- to six-fold increases in specific activities of succinate dehydrogenase (complex II) and cytochrome-c oxidase (complex IV). Furthermore, a dose-dependent depletion of mitochondrial DNA levels was observed in both tissues. The data demonstrate that transplacental AZT exposure causes cardiac and skeletal muscle mitochondrial myopathy in the patas monkey fetus.”

“CD-1 mice exposed prenatally to 12.5 and 25.0 mg of AZT...had statistically significant increases in numbers of liver, lung and female reproductive tract tumors. These observations have been extended to offspring at 2 years of age...there was a 2- to 3-fold increase in the incidence (from 20% in controls to 55-60% in AZT groups) and multiplicities of lung tumors in AZT-exposed mice. The incidence of hepatocellular adenomas in the female mice exposed to prenatal AZT increase from 0 in the control group to 20% in the high dose AZT group, and hepatocellular carcinomas metastasizing to lungs were observed only in AZT-treated mice. Prenatal administration of AZT also increased the incidence of neoplasms of reproductive tract, female mammary gland epithelium and squamous cell epithelium of forestomach. AZT...significantly reduced the incidence of hematopoietic tumors”

“The AZT animals [Macaques given AZT during pregnancy] developed an asymptomatic macrocytic anemia, but hematologic parameters returned to normal when AZT was discontinued. Total leukocyte count decreased during pregnancy and was further affected by AZT administration. AZT-exposed infants were mildly anemic at birth. AZT caused deficits in growth, rooting and snouting reflexes, and the ability to fixate and follow near stimuli visually”

“At 1 year of age, the offspring of AZT-treated mice exhibited statistically significant, dose-dependent increases in tumor incidence and tumor multiplicity in the lungs, liver and female reproductive organs. AZT incorporation into nuclear and mitochondrial DNA was detected in multiple organs of transplacentally exposed mice and monkeys...AZT is genotoxic in fetal mice and monkeys and is a moderately strong transplacental carcinogen in mice examined at 1 year of age”

“At 1 year of age, the offspring of AZT-treated mice exhibited statistically significant, dose-dependent increases in tumor incidence and tumor multiplicity in the lungs, liver, and female reproductive organs. AZT incorporation into nuclear and mitochondrial DNA was detected in multiple organs of transplacentally exposed mice and monkeys. Shorter chromosomal telomeres were detected in liver and brain tissues from most AZT-exposed newborn mice but not in tissues from fetal monkeys. Conclusions: AZT is genotoxic in fetal mice and monkeys and is a moderately strong transplacental carcinogen in mice examined at 1 year of age.”

“…in adult mice, lifetime AZT administration induces vaginal tumors at a 10-20% incidence...In newborn monkeys and mice, AZT was incorporated into DNA of many fetal tissues...AZT appears to be a moderately-strong transplacental carcinogen [i.e. it crosses the placenta and may cause cancer in the fetus]”

“Significant dose-related increases in the percentage [of] micro-nucleated erthyrocytes [red blood cells] in the peripheral blood were observed in mice treated with ZDV [AZT]…Bone marrow micronucleus frequencies were also elevated in mice and rats treated with ZDV at 500 mg/kg/day for 4 (mice only) and 7 days…seven late-appearing vaginal epithelial cell tumors were seen in mice given 40 mg/kg/day…Spontaneous tumors of the vaginal epithelium are rare in rodents, and reports of chemically induced vaginal tumors are also uncommon. Of 222 chemicals evaluated for carcinogenicity in rats and mice in the National Toxicology Program, none induced tumors in the vagina…In the CRC 'Handbook of Identified Carcinogens and Noncarcinogens' (1982), 356 of the 811 compounds listed were shown to be carcinogenic in rodents. Of the 356 positive chemicals, only 3 caused vaginal neoplasms, DES [diethylstilbestrol, associated with major genital deformities in humans], estradiol 3-benzoate, and 17 Beta-estradiol”

“Hemoglobin dropped significantly in the AZT-treated animals [Macaques] after treatment began and remained low until the end of the study...Postnatal weight increase was significantly lower in AZT-exposed infants...Infant hematocrits taken at time of birth were lower in the AZT-exposed group...AZT-exposed infants took three times as many sessions as controls to meet criterion on Black-White Learning, a simple discrimination task...It took significantly more matings to achieve the six AZT pregnancies than the six control pregnancies”

“we have found positive correlations between the dose of AZT administered to female CD-1 mice, the incorporation of AZT into vaginal DNA, the hyperproliferation of the vaginal epithelial basal layer, and the aberrant expression of alpha-6 integrin toward the epithelial suprabasal strata of the vagina, a target organ for carcinogenesis in mice. These results suggest that there is an ordered progression of abnormal events leading to tumorigenesis in vaginal epithelial tissues.”

“It previously has been demonstrated that zidovudine (AZT) is lethal to early murine [mouse] embryos. The effect of the drug on pre- and postimplantation embryos was examined to delineate the timing of this toxicity and to investigate its possible mechanisms. Embryos exposed in the whole mouse during preblastocyst development were unable to proceed beyond the blastocyst stage [i.e. failed to implant in the uterine wall]. Similarly, when two-cell embryos harvested from unexposed females were exposed to low-concentration (1 microMole) AZT in vitro over 24 h, development beyond the blastocyst stage was inhibited. In contrast, drug exposure during in vitro blastocyst and postblastocyst development resulted in little or no morphologic toxicity. Further investigation revealed that preblastocyst AZT exposure resulted in the development of blastocysts with significantly lower cell numbers than control embryos. While embryonic exposure to AZT at the blastocyst and postblastocyst stages also resulted in retarded cell division, the effects were milder than those recorded after preblastocyst exposure. These data demonstrate that the critical period of AZT toxicity toward murine embryos is between ovulation and implantation and indicate that AZT directly suppresses cell division in the preimplantation embryo.”

“6 adult…rats were treated intraperitoneally either with AZT or with normal saline twice daily for 3 months. The AZT was used at doses equivalent to the high therapeutic dose administered daily to patients with AIDS…The AZT-treated animals lost 10% of the original weight by the end of the 3rd month…the animals appeared sluggish and at times drowsy. Serum creatine kinase was dramatically increased in the AZT-treated animals…Serum lactate was increased in the treated animals…Slight anemia with hematocrit as low as 35% (normal 40 to 49%), thrombocytopenia with platelet count between 119 to 508/cubic-mm (normal 610 to 1,610) and lymphocytopenia with white blood cell count ranging from 2,900 to 4,200 (normal 9,400 to 14,900) were noted in the AZT-treated group. The animal that received the highest dose of AZT developed hyperglycemia with blood sugar up to 500 mg/ml (upper limit of normal 120 mg/ml). Muscle biopsies from the AZT-treated rats, but not the controls, showed subsarcolemmal accumulations…suggesting early formation of ‘ragged red’ fibers. With electron microscopy, there was clear evidence of abnormal mitochondria”

“Striking differences between the AZT-treated hearts and control rat hearts were found ultrastructurally. Myocardial [heart muscle] samples from the AZT-treated group revealed widespread cardiac myocyte mitochondrial disruption and fragmentation of cristae. Some mitochondrial cristae appeared focally dissolved and poorly organized…Other zones showed mitochondrial cristae that were clumped and focally swollen. Mitochondrial findings were consistently present in multiple samples of myocytes from AZT-treated rat hearts and conspicuously absent from samples of hearts of untreated rats.”

“The most consistent hematologic effect from treatment with AZT [in mice] was a poorly regenerative, macrocytic anemia”

“Mice receiving AZT during gestation yielded fewer fetuses…and greater numbers of resorptions [fetal death]…Exposure to AZT was highly correlated with failure to develop to the blastocyst stage…These data indicate that AZT has a direct toxic effect on the developing mouse embryo.”

“[in mice] AZT had a profound effect on the number of erythrocytes [mature red blood cells] and a small effect on the number of leukocytes [white blood cells]…anemia was seen in all the mice tested at 1,000 mg/kg per day”

“Male and female cynomolgus monkeys were given zidovudine [AZT], 35 to 300 mg/kg per day orally, in studies of 3 and 6 months’ duration…the only treatment-related alteration noted was a reversible, mild to moderate, dose-related, macrocytic anemia…In the 6-month study, bone marrow cytology…revealed a retardation in the maturation of all cell lines, with the ertythroid elements [red blood cells] being affected to the greatest degree…Dams [pregnant female rabbits] given 500 mg/kg per day gained less weight during the dosing period, developed anemia, and showed an increased incidence of late fetal resorptions. No evidence of teratogenicity [birth defects] was seen, even though it was shown that zidovudine crossed the placenta…Zidovudine was also studied for its ability to morphologically transform cultured BALB/c-3T3 mouse cells and was found to be positive at concentrations of 0.5 micrograms/ml and higher…From the Department of Toxicology and Experimental Pathology. Burroughs Wellcom Co. [the manufacturer of AZT]”

“Effective December 18, 2009, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency is adding the chemicals identified below to the list of chemicals known to the state to cause cancer or reproductive toxicity, for the purposes of Proposition 65…zidovudine (AZT) [is] being added to the list as known to the state to cause cancer.”

“The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is used successfully for reduction of perinatal viral transmission. However toxic side effects including carcinogenesis are possible. To test this, pregnant CD-1 Swiss mice were given 25.0 or 12.5 mg AZT on gestation days 12-18… Findings for all remaining offspring [not killed for an earlier report] up to 2 years old are reported here. AZT effects were most prominent in female offspring, with a significant threefold increase in lung tumors, a reduction in lymphoblastic and follicle center cell lymphomas, and a significant increase in histiocytic sarcomas (0 in controls, 3% after low-dose AZT, and 8% after high-dose AZT, p = 0.022). Dose-dependent incidences of mammary gland, ovarian, and seminal vesicle tumors were low but significant: 0/106 controls, 3/105 low-dose, and 8/105 high-dose mice presented one of these neoplasms (p = 0.0025). Incidences of females showing any clearly AZT-related neoplasm, in lung, liver, ovary, or mammary gland or histiocytic sarcoma, in the second year, were 12/32 after the low dose and 14/27 after the high dose vs 3/23 controls (p = 0.0045). Also, the sensitivity of neonatal mice was assessed by administration of 25, 50, 100, or 200 mg/kg AZT on postnatal days 1 through 8. The effects at 2 years were similar to those seen after transplacental exposure, with significant increases in lung, liver, and mammary tumors in females…AZT had a much greater perinatal carcinogenic potency than it exhibited after administration to adult mice…the most worrisome new finding was the appearance, in the AZT exposure groups, of reproductive system tumors that were completely absent from untreated controls in this study, including mammary ademocarcinomas, ovarian tumors, seminal vesicle tumors, and testicular tumors.”

“727 infants with known ZDV [AZT] exposure prospectively followed from birth between 1989 through May/June 1996 were included…115 (61%) of ZDV recipients in PACTG 076 [a clinical trial giving AZT to mothers; 39% did not agree to continue with followup, a potential source of bias]…Also included…are 612 infants enrolled into the WITS study…Mean infant follow-up was longer for PACTG 076/219 participants at 38.3 months…[WITS participants had] a shorter mean follow-up of 14.5 months…The longest reported follow-up for infants was just over 6 years…In the cited rodent study, mice with in utero [in the womb] ZDV exposure…[had tumors] documented only in mice sacrificed at or after the human equivalent of the second decade [i.e. this study is worthless for determining whether there is a mid- to long-term risk of cancer from AZT exposure in the womb]”

“CD-1 mice exposed prenatally to 12.5 and 25.0 mg of AZT...had statistically significant increases in numbers of liver, lung and female reproductive tract tumors. These observations have been extended to offspring at 2 years of age...there was a 2- to 3-fold increase in the incidence (from 20% in controls to 55-60% in AZT groups) and multiplicities of lung tumors in AZT-exposed mice. The incidence of hepatocellular adenomas in the female mice exposed to prenatal AZT increase from 0 in the control group to 20% in the high dose AZT group, and hepatocellular carcinomas metastasizing to lungs were observed only in AZT-treated mice. Prenatal administration of AZT also increased the incidence of neoplasms of reproductive tract, female mammary gland epithelium and squamous cell epithelium of forestomach. AZT...significantly reduced the incidence of hematopoietic tumors”

“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.”

“Similar levels of AZT-DNA incorporation were detected in peripheral blood from HIV-1-positive mothers and cord blood from their infants and tissues from newborn mice exposed to tumorigenic [cancer-causing] doses of AZT in utero. Therefore, the biologically effective dose (i.e. the amount of AZT that incorporated into DNA) was similar in both species even though the mouse daily dose of AZT was much higher than that received by humans.”

“At 1 year of age, the offspring of AZT-treated mice exhibited statistically significant, dose-dependent increases in tumor incidence and tumor multiplicity in the lungs, liver and female reproductive organs. AZT incorporation into nuclear and mitochondrial DNA was detected in multiple organs of transplacentally exposed mice and monkeys...AZT is genotoxic in fetal mice and monkeys and is a moderately strong transplacental carcinogen in mice examined at 1 year of age”

“…in adult mice, lifetime AZT administration induces vaginal tumors at a 10-20% incidence...In newborn monkeys and mice, AZT was incorporated into DNA of many fetal tissues...AZT appears to be a moderately-strong transplacental carcinogen [i.e. it crosses the placenta and may cause cancer in the fetus]”

“we have found positive correlations between the dose of AZT administered to female CD-1 mice, the incorporation of AZT into vaginal DNA, the hyperproliferation of the vaginal epithelial basal layer, and the aberrant expression of alpha-6 integrin toward the epithelial suprabasal strata of the vagina, a target organ for carcinogenesis in mice. These results suggest that there is an ordered progression of abnormal events leading to tumorigenesis in vaginal epithelial tissues.”

“[Dr. Michael Lange, Head of AIDS Programme, St. Lukes Hospital, New York replied, when asked ‘Are you convinced that lymphoma is a natural consequence of living longer with AIDS?’ ]’No I’m not. The major reason for that is that most, almost all the lymphoma that I have seen was the first AIDS event and occurred not at at the late stages of the disease but was the diagnosis that was made that made that patient an AIDS patient and prior to AZT coming along I never saw lymphoma in people who had had several opportunistic infections as a late stage event.’…[BBC] Dispatches has been advised by leading Counsel that the false and misleading claims about AZT described in this programme could amount to a breach of the Medicines Act which if successfully prosecuted would constitute a criminal offence.””

“after starting antiretroviral treatment...the estimated probability of developing lymphoma ...by 36 months, [was] 46.4% (CI, 19.6% to 75.5%)...a direct role of therapy itself cannot be totally discounted...Zidovudine [AZT] can act as a mutagen”

““From ‘87 [the year that AZT was approved], all we [hemophiliacs and their families] saw was people dying,” said Alice, her hair white at 51. “And believe me, when you see someone dying of AIDS, it’s really bad. It’s different each time. No one dies the same way.””

“participants of open-label ZDV [AZT] still had four to five times the incidence of ARC/AIDS/death of participants on blinded therapy [of which approximately half were on AZT and half on placebo]...The unadjusted hazard of ARC/AIDS/death was 4.6 times higher for participants [in the deferred group] who had received ZDV...after adjustment for latest CD4 this became 1.6...There was a suggestion of a benefit in terms of [slower] progression to ARC, AIDS or death [with AZT], no effect on progression to AIDS or death, and a suggestion of an increase in mortality.”

“Extended follow-up of patients in one [AZT] trial, the Concorde study, has shown a significantly increased risk of death among the patients treated early...where is the evidence that for a patient with a CD4 count of 450 cells per cubic millimeter and a low plasma viral level, it would not be better to wait before initiating therapy?...In 1990...a patient with a CD4 count of 450 cells per cubic millimeter would have been advised to start monotherapy with zidovudine. We now tell such a patient that, in fact, follow-up data for up to 4.5 years since that time have shown no survival benefit”

“The mortality rate was significantly higher among [a group of 1372] patients who had received antiretroviral therapy [principally AZT] before enrollment in the clinic”

“despite the evidence that purified [blood clotting] factor VIII is beneficial in maintaining or even increasing T-cell counts, several studies testing purified factor VIII [as opposed to the older forms of Factor VIII which were 99% to 99.9% impurities] are ambiguous about its effectiveness in preventing or treating AIDS. Some of these studies have only tested partially purified, i.e. 2-10 units/mg, instead of highly purified, i.e. 2000-3000 units/mg, factor VIII. But each of the studies that are ambiguous about the benefits have also treated their patients with toxic antiviral DNA chain terminators like AZT. Indeed the study by de Biasi et al. was the only one that has tested purified factor VIII in the absence of AZT. The study by Seremetis et al. initially called for no AZT, but later allowed it anyway. Thus in all but one study, the potential benefits of highly purified factor VIII have been obscured by the toxicity of AZT.”

“None of the LTAs [long term asymptomatics] received any antiviral drugs during the study; however, 3 [of 6] rapid progressors…were treated with zidovudine…[and] a rapid progressor was treated with didanosine during the study.”

“Adjusted for baseline CD4 [immune cell counts] and age [correlated with lifetime exposure to clotting factor infusions], subjects [hemophiliacs] who had started on zidovudine [AZT] had increased risks, especially for AIDS [4.46 times greater risk!] and death [2.37 times]”

“Only 38% of the HLP [Healthy long-term positives] had ever used zidovudine [AZT] or other nucleoside analogues, compared with 94% of the progressors.”

“A total of 172 (96 Imm, 76 Def) participants died [169 who had taken some AZT, 3 who had only taken placebo]...The results of Concorde do not encourage the early use of zidovudine in symptom-free HIV-infected adults. They also call into question the uncritical use of CD4 cell counts as a surrogate endpoint for assessment of benefit from long-term antiretroviral therapy...Representatives of the Wellcome Foundation [Glaxo Wellcome manufactured AZT then, it is now known as GlaxoSmithKline] who were also members of the Coordinating Committee have declined to endorse this report.”

“Leukopenia [white blood cell deficiency] occurred in 82% of the patients receiving early therapy and 77% of those receiving late therapy [AZT only when AIDS occurred]; 20% and 16%, respectively, had anemia. 14% and 10%, respectively, had severe leukopenia...and 5% and 2% had severe anemia requiring transfusion. Nausea (or vomiting) and diarrhea occurred more frequently in the early-therapy group than in the late-therapy group (40% vs. 23%, respectively; P <0.01)...The dosage of blinded study medication was reduced because of adverse reactions in 64 [38%] of the patients assigned to zidovudine (early therapy) and in 29 [17%] of those assigned to placebo (late therapy)...Once AIDS developed in patients receiving early therapy, more of them tended to have multiple AIDS diagnoses, a slightly higher proportion died, and the median survival time was slightly shorter than in similar patients who received late therapy”

“None of the asymptomatic individuals was receiving zidovudine[AZT]. The CD4 count of patients receiving zidovudine was lower than that of those not receiving the antiviral (mean of 69 and 217/cubic-mm, respectively)…CD4 numbers were significantly lower in patients who developed HIV-related malignancies while receiving zidovudine”

“after starting antiretroviral treatment[AZT]...the estimated probability of developing lymphoma ...by 36 months, [was] 46.4% (CI, 19.6% to 75.5%)...a direct role of therapy itself cannot be totally discounted...Zidovudine [AZT] can act as a mutagen”

“[Freddie] Mercury discovered he had Aids in 1987. He had a Kaposi’s sarcoma lump on his shoulder. KS is such an advanced symptom of Aids — wasn’t there any preceding sign that he’d been infected with HIV? No, says [his lover Jim] Hutton, nothing. “His attitude was ‘Life goes on’. He took AZT and nearly every other drug available. The doctors came to the house to treat him.” Hutton didn’t take a test himself. “I was afraid.” An HIV test he took in 1990 confirmed that he had the virus. He didn’t tell Mercury until he tested positive again a year later. “All Freddie said was ‘Bastards’.” Hutton was healthy [and still was at the time of this article in 2006, 16 years later]. Mercury was becoming more ill. “The doctors thought he shouldn’t do the Barcelona video. But his attitude was ‘I’m not going to let this thing beat me’. I noticed how skeletal he’d become only on the morning of his last birthday. Maybe I was in denial. But I think Freddie knew when it was the time to let go. He decided to come off his Aids medication three weeks before he died.””

“At 6 weeks, the HIV-1 perinatal transmission rate was significantly lower among those who took nevirapine than zidovudine [AZT] (6.8% versus 30.3%) [This contradicts the normal assumption that AZT reduces the risk from 25% to about 8%!]”

“Median RNA viral load during the first week was not significantly different for children whose mothers had taken zidovudine [AZT], compared with those in the placebo group.”

“The risk for developing AIDS among individuals in the ISS [Italian Seroconversion Study] cohort was less than 50% by 10 years after HIV seroconversion…The relative hazards of developing AIDS in patients who started treatment with zidovudine (AZT) monotherapy was 0.57 [i.e. people starting AZT were only 57% as likely to have AIDS within the first year as others] and 0.92 within the first year and after 1 year from AZT initiation [indicating that the benefit of AZT was short term]”

“for the most extensively used drug, [AZT], whereas phosphorylation to the monophosphate is facile, the product is a very poor substrate for the next kinase in the cascade, thymidylate kinase. Because of this, although high concentrations of the monophosphate can be reached in the cell, the achievable concentration of the active triphosphate is several orders of magnitude lower. [Note that triphosphorylation is necessary for AZT to be active against HIV]”

“A total of 21 of the [125] HIV-1-infected participants died of HIV-related causes during the 3.5-year longitudinal study. Subclinical malnutrition, vitamin B12 deficiency, zinc deficiency, and selenium deficiency over time, but not zidovudine [AZT] treatment, were shown to each be associated with HIV-1-related mortality independent of CD4 cell counts <200/mm3 at baseline, and CD4 counts over time. [i.e. AZT did not reduce the risk of death]”

“The long-term consequences of in-utero and infant exposure to zidovudine [AZT] are unknown. The long-term effects of early or short-term use of zidovudine in pregnant women are also unknown...The incidence of adverse reactions [to AZT] appears to increase with disease progression, and patients should be monitored carefully, especially as disease progression occurs. [i.e. AZT does not prevent progression to AIDS]”

“[AZT may] unmask silent opportunistic infections...Lack of strong evidence exists for sustained immune reconstitution by current therapies...If [immune reconstitution] does not occur with time, despite prolonged viral suppression, then the case for immunorestorative strategies...could be justifiably explored [duh].”

“The transient effect of zidovudine [AZT] on CD4 cell counts and disease progression may have already ended in patients who used antiretroviral agents before (median time, 22.7 months) the start of TMP-SMZ [strong antibiotics] prophylaxis [or maybe the side effects left the patients weakened, and likely to experience the side effects of TMP-SMZ]”

“The comparison of the two studies [one European, one French]…is interesting. Despite the wider and earlier use of zidovudine [AZT] monotherapy in the French study, morbidity or mortality was similar to that in the ECS [European Collaborative Study]. This is further indirect evidence of lack of benefit from long-term zidovudine monotherapy”

“Overall, zidovudine treatment was associated with only a small reduction in circulating levels of plasma RNA...Explanations need to be considered for the apparent lack of association between the observed RNA levels and the effect of zidovudine treatment [i.e. lower rates of transmission from mothers on zidovudine to their children cannot be due to lower levels of virus!]”

“The Concorde trial showed no difference in the survival rates for symptom-free HIV-positive individuals between those given immediate and those given deferred zidovudine, and Chaisson et al found previous use of zidovudine to be a negative indicator, with an increase in the risk ratio for death or disease progression of 1.7”

“The primary data come from the Edinburgh City Hospital Cohort up to 1 January 1992…dominated by a group of young injection-drug-users…recruitment to the cohort began in October 1985…The first nine representatives of the data set are shown in Figure 1 with CD4 graphed on the root scale and simple individual linear regressions superimposed; vertical bars mark the initiation of AZT treatment. (Note that, by chance, this group contains the only member of the 164 study patients to demonstrate an apparent immunological improvement in the study period!) [6 of these graphs have data points after the initiation of AZT and in 5 out of 6 cases, the steady downward trend in CD4 counts continues]…In all our treatment models a significant proportionate change of level emerges, associated with commencement of AZT therapy. However, this effects seems generally to be of a very small magnitude, and it may also be transient in duration. Models which ignore it do not seem to be all that inferior, when ability to predict future counts is compared. We also cannot say whether the small perturbation in CD4 represents a beneficial intervention in terms of slower clinical progression or increased survival, and we note that although the Concorde trial found CD4 count improvements for asymptomatic patients taking early AZT, relative to those deferring AZT until symptoms, it did not find an associated clinical benefit.”

“Of the 1609 subjects who started treatment [with AZT], 591 (37%) voluntarily discontinued the study drug while receiving blinded treatment and 353 (22%) voluntarily discontinued treatment during the open-label portion of the study (when all three groups received zidovudine [AZT])…Neither the 500-mg [per day of AZT] nor the 1500-mg group had significantly longer AIDS-free survival than the deferred-therapy group…Among the 144 deaths, 95 occurred after the development of AIDS [note that AZT was given as soon as AIDS was diagnosed]…We found no additional clinical benefit from the immediate use of zidovudine in asymptomatic, HIV-infected subjects with 500 or more CD4 cells per cubic millimeter as compared with subjects who began to receive zidovudine only when their CD4 cell counts declined below 500 per cubic millimeter. This was the case despite a significant zidovudine-associated slowing in the decline of CD4 cell counts.”

“AZT can be severely toxic, and there is compelling evidence that the drug probably doesn't help infected people live longer unless they already have full-blown AIDS...AZT clearly isn't a very effective anti-AIDS drug.”

“AZT can be severely toxic, and there is compelling evidence that the drug probably doesn't help infected people live longer unless they already have full-blown AIDS...AZT clearly isn't a very effective anti-AIDS drug.”

“The median CD4 lymphocyte count did not differ in the 3 groups: 54 for the group receiving neither antiretroviral nor P. carinii pneumonia prophylaxis, 53 for the group receiving only antiretroviral therapy, and 52 for the combined treatment group. There were also no major differences in the median CD8 lymphocyte count of the 3 groups...Other illnesses now have elevated incidence rates among persons receiving P. carinii pneumonia prophylaxis [and AZT or didanosine]: M. avium complex, nonretinitis cytomegalovirus disease, cytomegalovirus retinitis, candida esophagitis, and wasting syndrome”

“the first results of the Concorde study are a reminder that AZT has limited value when given to patients who do not have advanced disease, and that it is not a very effective drug.”

“the efficacy of zidovudine in preventing HIV infection after initial exposure remains unproven”

“Patients who received zidovudine [AZT] before diagnosis [of AIDS] had a significantly lower CD4 cell count at diagnosis than patients who did not…improved survival [over time,including 1987 when AZT was approved for use] was significant only for patients diagnosed with P carinii pneumonia [if AZT really had anti-HIV activity it should be effective against all AIDS-defining diseases]…Overall survival was significantly shorter for patients who received zidovudine before diagnosis, although the survival for these patients within the first year after the diagnosis tended to be better compared with patients who did not receive AZT”

“When considering patients treated with zidovudine[AZT], the death rate was substantially lower within the first year after initiating zidovudine than the death rate in patients who had never taken the drug. Patients in their second year after starting zidovudine treatement experienced a death rate similar to that observed for patients who had never taken zidovudine. In the third and fourth years after starting zidovudine, the death rate was substantially greater [2-3 times higher in the fourth and fifth years] for zidovudine-treated patients than for patients who had never taken zidovudine”

“Overall, Concorde does not provide compelling evidence that zidovudine is of great use in non-pregnant symptom-free adults with HIV infection.”

“The average time with neither a progression of disease nor an adverse event (symptom or laboratory finding) was 15.7, 15.6, and 14.8 months for patients receiving placebo, 500 mg of zidovudine, and 1500 mg of zidovudine, respectively. The incidence of severe symptoms was 13.8% in the placebo group, 15.2% in the 500-mg group, and 19.9% in the 1500-mg group. After 18 months, the 500-mg group gained an average of 0.5 month without disease progression, as compared with the placebo group, but had severe adverse events an average of 0.6 month sooner.”

“Despite continuous antiviral therapy, the favorable effect of AZT [on viral load, not health] was typically lost within 4-6 months after treatment initiation [Table 1 shows that 5 of 7 people with disease progression took AZT, but none of 11 without disease progression]”

“Given that it is widely believed that the effect of zidovudine is of limited duration, a suggestion that the benefit lasts more than two years should be supported by the demonstration of a statistically significant difference in risk between zidovudine and placebo when one considers only the number of person-years at risk after two years of treatment. The small number of patients with end points after more than two years of therapy [in the study being commented on] makes it doubtful that such a significant difference was present. Therefore, the assertion that zidovudine has a beneficial effect that lasts for more than 2 1/2 years in these patients is not justified on the basis of the results presented.”

“Some HIV-infected individuals have remained healthy for more than 15 years following seroconversion. Lower numbers of CD4+ peripheral blood lymphocytes have generally been found to indicate the advancement of HIV disease... [but] The CD4+ cell counts vary from day to day and laboratory to laboratory, and similar levels do not necessarily reflect the same disease status in all patients. For example, very low CD4+ cell counts (less than 0.05x10**9/L (50/microL)) usually indicate advanced disease; however, some patients with these levels remain asymptomatic for extended periods of time while others succumb rapidly...While knowledge of the clinical use of zidovudine has increased during the last several years, the panel was concerned overall by the drug’s limited effectiveness and durability of response.”

“Early treatment [before any AIDS-like symptoms] with zidovudine [AZT] is expensive and is very sensitive to the cost of zidovudine and to potential reductions in quality of life of patients who experience side effects.”

“some of the typical patterns seen in CD count over time [four patients selected from 120 with enough data]: a decline in CD4 cell count, a transient rise lasting several weeks to months following introduction of ZDV, and continued decline thereafter [in two examples the ‘transient rise’ lasted less than two months and in all four cases it lasted less than a year. No reason was given for why these four graphs, out of 120 available, were chosen.]”

“the high level of plasma virus observed by Piatak et al, was about 99.9 per cent non-culturable, suggesting that it was either neutralized or defective. Therefore, rather than supporting a cytopathic model, this observation actually may help explain the relatively slow dissemination of the infected cell burden and thus the relative ineffectiveness of therapy with nucleoside analogues which target this process.”

“in individuals with fewer than 400 CD4 cells per cubic mm, those treated with AZT for longer than 16 months had the same levels of plasma [HIV] RNA as a similar group of patients who never received antiretroviral therapy.”

“The large Anglo-French Concorde randomized trial of zidovudine in asymptomatic HIV-infected individuals shows that there is no significant clinical benefit in terms of survival or disease progression to AIDS or AIDS-related complex (ARC) in those who started zidovudine immediately rather than those who waited for the onset of symptomatic disease. The 1749 participants were followed up for an average of 3 years.”

“while zidovudine [AZT] and P. carinii pneumonia prophylaxis may have been widely available to insured AIDS patients as early as 1987, cases in men who reported sex with men plateaued in late 1986, before the availability of zidovudine. This pre-zidovudine leveling has been previously reported for AIDS-related mortality in New York City.”

“signs of a progressively increasing level of HIV-1 activity were evident, regardless of antiviral therapy [AZT in 7 patients].”

“[Referring to Fischl MA et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23; 317(4): 185–91.] This internal document from the Food and Drug Administration, the US authority that licensed the drug [AZT], was obtained through the Freedom of Information procedure. Dr. Ellen Cooper, in reviewing the AZT data, writes ‘The fact that the treatment groups [AZT vs. Placebo] unblinded themselves early could have resulted in bias in the workup of patients’”…[Christopher Babick of the People With AIDS Coalition states] ‘] During the Phase 3 trials we received many phone calls in our office from individuals who wanted to know whether or not they were using the placebo or actually receiving AZT and there were three laboratories in New York that could analyze the medication and we would refer individuals there. If in fact they were on placebo they would make arrangements to acquire the drug AZT. Often times they would share with individuals who were in the trials.’…Dr. Michael Lange helped run one of the trial centers, ‘I don’t think they were really blinded because when you take AZT your red blood cells increase in size and this happens after 2 to 3 weeks and you can notice that on an ordinary blood count…this information was available to the investigators’…[Question to Margaret Fischl, lead author] ‘Did you know that the Phase 2 trial became unblinded quite early in the study?’, ‘Oh, I don’t think it became unblinded…Did we know or suspect that some of the patients were on AZT? Of course.’…[BBC] Dispatches has been advised by leading Counsel that the false and misleading claims about AZT described in this programme could amount to a breach of the Medicines Act which if successfully prosecuted would constitute a criminal offence.””

“Replication curves and cytopathic effect of a standard inoculum (1 ng of p24) of 66 primary HIV-1 isolates were similar regardless of the clinical stage of the patient...There was no difference between viruses derived from patients sensitive to zidovudine and those derived from patients resistant to zidovudine”

“Doubts may be raised about the long-term beneficial effects of zidovudine treatment on AIDS-related cognitive impairments”

“treatment with ZDV[AZT] does not decrease the levels of HIV DNA in PBMCs [peripheral blood mononuclear cells]”

“thirteen subjects of 146 tested (9%) who were negative for HIV antigen [although positive for HIV antibodies] before treatment later had detectable levels of antigen during the 128 weeks of treatment [huh? AZT makes you HIV-positive?]”

“a tragic accident in our hospital reveals that even when it is begun very soon after exposure, treatment with zidovudine will not necessarily prevent HIV-1 infection…Within 45 minutes after the recipient's exposure to HIV-1 [a syringe with 100 to 200 microliters of blood from someone dying of AIDS], zidovudine [AZT] treatment was begun [for about 3 months]…On day 30 HIV-1 p24 antigen was detected, and on day 41 there was serconversion for HIV-1 antibodies”

“zidovudine monophosphate concentrations peaked at 1.3µM [1,300 nM] at 2h…diphosphate concentration was on average 18-fold lower…triphosphate peaked 4h after initiation of therapy at 14.5nM [without triphosphorylation, AZT cannot be effective against retroviruses, and this shows that only about 1% of AZT ever is]”

“In the placebo-controlled trial [of AZT], CD4 cell counts increased for four to eight weeks following the initiation of zidovudine [AZT] therapy. Following this initial increase, CD4 counts gradually diminished through week 24,, at which time on average they stabilized at entry values.”

“No experiments have yet been reported to demonstrate that the compounds [AZT and ddC] add to DNA in a terminal position and prevent the further addition of natural deoxynucleotides to the terminated chains.”

“Despite many unresolved physiopathological questions, there are coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to zidovudine [AZT], alone or in combination with lamivudine [3TC]. This effect may be transitory or persistent. Although, the clinical significance of the various biological and/or histopathological mitochondrial anomalies found at birth in NA-exposed animals or children has not been formally established, the high incidence of mitochondrial neurological diseases observed in the French cohort has not been contradicted to date in other cohorts.”

“NRTI [nucleoside reverse transcriptase inhibitor, such as AZT] mitochondrial toxicity limits treatment of HIV infection. NRTI-sparing regimens may obviate some mitochondrial manifestations, but also are limited. Studies here establish that ZDV [AZT] and d4T [Stavudine] (monotherapy, human therapeutic doses) cause mitochondrial structural and functional defects in vivo…NRTIs become toxins at a ‘threshold concentration’ in mitochondria where they may compete with native moieties. As such, they may inhibit intramitochondrial phosphorylation of native nucleotides (by competing as substrates for kinases)…Conversely, ZDV-TP is least likely to be incorporated by DNA pol gamma. However, once ZDV-MP is incorporated, it is inefficiently removed by the DNA pol gamma exonuclease. Inefficiency of removal of ZDV-MP may explain mtDNA depletion in that case.”

“Mitochondrial dysfunction has been reported in HIV-negative children perinatally exposed [in the womb or shortly after birth] to zidovudine [AZT]…Two expert groups conducted a systematic, retrospective review of all cerebral MR [magnetic resonance] images available in a multicentric, nationwide French prospective cohort of children born to HIV-seropositive mothers to identify imaging abnormalities…The incidence of abnormalities was determined and compared with the neurologic presentation and laboratory evidence of mitochondrial dysfunction…MR images from 49 HIV-uninfected children (mean age, 26 months) were available for study. All children were perinatally exposed to zidovudine. 22 had probable or established mitochondrial dysfunction according to their symptoms and laboratory data. 27 children without mitochondrial dysfunction presented with unexplained neurologic symptoms (n=14) or nonneurologic symptoms (n=7), and six were asymptomatic[!].”

“mice were treated with AZT for 35 days (10 mg/kg/day) in drinking water. Animals treated with antioxidant vitamins were fed the same diet as controls but supplemented with vitamins C (ascorbic acid, 10 g/ kg diet) and E (alpha-dl-tocopherol, 0.6 g/kg diet) for 65 days before sacrifice…Cardiac mitochondrial DNA (mtDNA) of mice treated with AZT had over 120% more oxo-dG (8-oxo-7,8-dihydro-2'-deoxyguanosine, which is a biomarker of oxidative damage to DNA) in their mitochondrial DNA than untreated controls. AZT treatment also caused an increase in mitochondrial lipid peroxidation and an oxidation of mitochondrial glutathione…The oxidative effects of AZT are probably due to an increase in production of reactive oxygen species by mitochondria of AZT-treated animals, raising the possibility that oxidative stress may play an important role in the cardiotoxicity of AZT.”

“In umbilical cords from 6 of 9 infants born to HIV-1-infected mothers taking Combivir [combination of the nucleoside analogs AZT and 3TC] moderate to severe mitochondrial morphological damage was observed, while none of 7 unexposed infants showed similar damage. Compared to unexposed infants, statistically significant mtDNA [mitochondrial DNA] depletion was observed in umbilical cord and cord blood from drug-exposed infants…Several additional factors related to mother and child health were compared to extent of mitochondrial damage to explore differences in the Combivir-exposed and unexposed groups of infants. Self-reports of maternal smoking, alcohol use, and illicit drug use during pregnancy were limited and were not correlated with mitochondrial damage in infants. Medical chart reviews did not reveal use of legal drugs/medications, other than NRTI, that are suspected or known to affect mitochondrial structure or function. There was no significant correlation between maternal age and the degree of mitochondrial damage in Combivir-exposed infants, nor was there any correlation between prematurity and mitochondrial damage in Combivir-exposed infants.”

“At term, AZT was found to be incorporated into fetal mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed mitochondrial membrane compromise, mitochondrial proliferation, and damaged sarcomeres [a type of muscle cell], while mitochondria in brain cerebrum and cerebellum were morphologically normal.”

“A 52-year-old male developed slowly progressive proximal muscle weakness of his arms and legs beginning in September of 1999. He was known to be HIV-1 positive since 1996, which was acquired through unprotected intravenous drug use. He was treated with 200 mg of AZT twice daily in 1996…He began to complain of myalgias [muscle pains] in his thighs and calves with occasional burning pain in his feet and palms in the fall of 1999. This was accompanied by weakness in his lower extremities, which progressed to involve his upper extremities and facial muscles over the next several months. By January of 2000, he was unable to climb stairs and had difficulty sitting up in bed…A muscle biopsy was performed which revealed an inflammatory myopathy…Ultrastructural examination revealed large accumulations of atypical mitochondria within muscle fibres. The mitochondria were enlarged, misshapen and contained unusual redundant cristae. Many of the abnormal mitochondria also contained irregular dense accumulations of granular osmiophilic material. Paracrystaline inclusions were not seen. Excessive lipid and focal collections of Z-band material (nemaline rod-like deposits) were also notted, particularly in severely affected fibres.”

“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.”

“To explore fetal mitochondrial consequences of this exposure [to AZT], pregnant Erythrocebus patas monkeys were given daily doses of 1.5 mg (21% of the human daily dose) and 6.0 mg (86% of the human daily dose) of AZT/kg body weight (bw), for the second half of gestation. At term, electron microscopy of fetal cardiac and skeletal muscle showed abnormal and disrupted sarcomeres with myofibrillar loss. Some abnormally shaped mitochondria with disrupted cristae were observed in skeletal muscle myocytes. Oxidative phosphorylation (OXPHOS) enzyme assays showed dose-dependent alterations. At the human-equivalent dose of AZT (6 mg of AZT/kg bw), there was an approximately 85% decrease in the specific activity of NADH dehydrogenase (complex I) and three- to six-fold increases in specific activities of succinate dehydrogenase (complex II) and cytochrome-c oxidase (complex IV). Furthermore, a dose-dependent depletion of mitochondrial DNA levels was observed in both tissues.”

“Eight children with mitochondrial dysfunction were found...the first patient presented with visual impairment...[and] died aged 13 months because of respiratory and cardiac-rhythm disorders...The second patient, from age 4 months until until death at 11 months, had refractory epilepsy and deterioration of cognitive and psychomotor abilities...At age 8 months...patient three had a seizure...At age 4 years, the child’s cardiac function was normal, but moderate muscular deficit persisted...In the fourth patient...between ages 14 and 27 months, the child had four episodes of febrile seizures...From age 7 months until 15 months, patient five had repeated seizures...at age 16 months...large necrotic lesions of the [brain]...At age 3-1/2 years the child had severe sequelae and microcephaly [abnormally small head]. Patient 6 was symptom-free until age 14 months, but persistent biochemical abnormalities were seen on standard follow-up...Patient 7 was symptom-free until age 4 months, at which time he became hypotonic [low muscle tone] [and stopped breathing]...The eighth child was symptom-free. Persistent hepatic and pancreatic abnormalities were seen from birth...At age 20 months, biological abnormalities persisted...electroretinography...was abnormal, and cerebral NMR imaging...showed abnormalities of the periventricular white matter...No child was infected with HIV-1 [but because their mothers were HIV-positive] all children were treated after birth with zidovudine [AZT] alone or with zidovudine and lamivudine [also a nucleoside analog]. Treatment continued for 6 weeks in four children and was stopped prematurely because of haematological or biochemical intolerance in four children...The observation of several cases [of mitochondrial abnormalities] in a population of about 1700 exposed children [as compared with 1/5,000 to 1/20,000 in normal populations] strongly suggests an acquired mitochondrial dysfunction...Pregnant women should be informed of the potential effects associated with these treatments during pregnancy.”

“Myopathy [muscle damage] in long-term therapy with ZDV [AZT] due to mitochondrial damage has been described by several investigators”

“Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the reference antiretroviral therapy in patients with AIDS. A toxic mitochondrial myopathy can be observed in patients treated with AZT, but not with ddI and ddC.”

“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.”

“AZT causes mitochondrial DNA chain replication termination in vitro [in lab systems], possibly by the inhibition of DNA polymerase-gamma, it has been theorized that AZT inhibits cardiac [heart] mitochondrial DNA replication in vivo [in the body]”

“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]”

“For unknown reasons, zidovudine [AZT] selectively inhibits the gamma-DNA polymerase, which is the mitochondrial DNA polymerase, in eukaryotes [higher life forms]. Patients with zidovudine myopathy [muscle damage] consistently show a selective fall in the activity of enzymes partially encoded by mtDNA [mitochondrial DNA].”

“Mhiri et al also concluded that nitochondrial myopathy is caused by AZT and not HIV…In a definitive study, Arnaudo et al demonstrated…that AZT reduces the muscle content of mitochondrial DNA (mtDNA), a condition called depletion…In a subsequent study, the depletion of mtDNA was confirmed by immunocytochemistry…The structurally abnormal mitochondria in the muscles of AZT-treated patients are impaired in oxidative metabolism…Soueidan et al found very early depletion of phosphocreatine, even in patients who had normal strength…AZT causes mitochondrial myopathy not only in HIV infection but also in normal rats and human muscle cultures…AZT is a unique muscle mitochondrial toxin, causing depletion of muscle mtDNA, which results in myopathy”

“We report 2 cases of myopathy [muscle wasting] caused by zidovudine [AZT], occurring within 16 wks of initiation of therapy, and a case of concurrent hepatic and muscle toxicity. In one case, electron microscopy demonstrated characteristic enlarged mitochondria with paracrystalline inclusions.”

“we obtained 31P magnetic resonance spectra from the calf muscles of AZT-treated patients and age-matched control subjects at rest and during an exercise protocol with a 12-second time resolution. The recovery of phosphocreatine following exercise reflects mitochondrial oxidative function and was significantly delayed in the AZT-treated patients…These findings support the hypothesis that the myopathy associated with chronic AZT results from the inhibitory effects of AZT on mitochondrial DNA synthesis and, secondarily, on the inhibition of mitochondrial oxidative metabolism…AZT is not completely specific, and micromolar concentrations of its triphosphorylated derivative inhibit the mitochondrial gamma-DNA polymerase, the enzyme responsible for the replication of the mitochondrial genome.”

“Striking differences between the AZT-treated hearts and control rat hearts were found ultrastructurally. Myocardial [heart muscle] samples from the AZT-treated group revealed widespread cardiac myocyte mitochondrial disruption and fragmentation of cristae. Some mitochondrial cristae appeared focally dissolved and poorly organized…Other zones showed mitochondrial cristae that were clumped and focally swollen. Mitochondrial findings were consistently present in multiple samples of myocytes from AZT-treated rat hearts and conspicuously absent from samples of hearts of untreated rats.”

“typical mitochondrial myopathy [muscle damage] has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy…for AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT”

“mice were treated with AZT for 35 days (10 mg/kg/day) in drinking water. Animals treated with antioxidant vitamins were fed the same diet as controls but supplemented with vitamins C (ascorbic acid, 10 g/ kg diet) and E (alpha-dl-tocopherol, 0.6 g/kg diet) for 65 days before sacrifice…Cardiac mitochondrial DNA (mtDNA) of mice treated with AZT had over 120% more oxo-dG (8-oxo-7,8-dihydro-2'-deoxyguanosine, which is a biomarker of oxidative damage to DNA) in their mitochondrial DNA than untreated controls. AZT treatment also caused an increase in mitochondrial lipid peroxidation and an oxidation of mitochondrial glutathione…The oxidative effects of AZT are probably due to an increase in production of reactive oxygen species by mitochondria of AZT-treated animals, raising the possibility that oxidative stress may play an important role in the cardiotoxicity of AZT.”

“A 52-year-old male developed slowly progressive proximal muscle weakness of his arms and legs beginning in September of 1999. He was known to be HIV-1 positive since 1996, which was acquired through unprotected intravenous drug use. He was treated with 200 mg of AZT twice daily in 1996…He began to complain of myalgias [muscle pains] in his thighs and calves with occasional burning pain in his feet and palms in the fall of 1999. This was accompanied by weakness in his lower extremities, which progressed to involve his upper extremities and facial muscles over the next several months. By January of 2000, he was unable to climb stairs and had difficulty sitting up in bed…Medications included AZT 200 mg BID [twice daily], indinavir 400 mg BID, naproxen 250 mg TID [three times a day], 3TC 150 mg BID, pyridoxine 25 mg OD [once daily], isoniazid 300mg OD, and ranitidine 150 mg BID…His AZT was discontinued. A muscle biopsy was performed which revealed an inflammatory myopathy…The patient was subsequently started on 100mg of prednisone OD for one month, which resulted in improved strength by March of 2000. He was able to ambulate with a walker…His strength continued to improve and a second muscle biopsy was performed (six months after the first biopsy) showing resolution of the inflammatory myopathy and ragged red fibre pathology. Selective type II fibre atrophy was noted, and this was felt to be secondary to his corticosteroid [prednisone] use”

“antiretroviral treatment with AZT amplified cardiac dysfunction and worsened ultrastructural features of AIDS CM [cardiomyopathy - damage to heart muscle] in TG [transgenic mice, including some genetic material believed to be from HIV]...AZT damaged cardiac mitochondria in WT [wild-type mice (not genetically engineered)], with destruction, swelling, cristae dissolution, and fragmentation. Similarly, hearts from AZT-treated TG showed increased mitochondrial damage, but with greater intensity”

“Myopathy [muscle damage] in long-term therapy with ZDV [AZT] due to mitochondrial damage has been described by several investigators”

“All [92] HIV patients suffering from an unexplained weight loss greater than 10% of body weight, seen in a tertiary university hospital [in Barcelona, Spain] were prospectively evaluated…[in patients who fulfilled the wasting syndrome definition] the final diagnosis was an AZT-related or an HIV-related myopathy in 13 patients (43%) [only two were ascribed to AZT based on muscle biopsy but without a group of untreated patients it is very difficult to say that none of the others were related to AZT]”

“AZT seemed to be the most potent inhibitor of cell proliferation [cell killer]…AZT, ddI and ddC [all nuceloside analogs] all exert cytotoxic [cell killing] effects on human muscle cells and induce functional alterations of mitochondria due to mechanisms other than the sole mtDNA [mitochondrial DNA] depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy [muscle damage] in HIV-infected patients.”

“Although the association of AZT with decreased cardiac contractility [cardiomyopathy=heart muscle damage] has been debated, our data indicates a strong correlation between treatment with AZT and the development of a decrease in left ventricular performance in children with HIV infection. The fact that 17 of the 19 patients in the study in whom cardiomyopathy developed had received AZT suggests that the observed decreases in left ventricular performance could have had clinical consequences…AZT withdrawal should be considered in any child in whom cardiomyopathy develops”

“HIV-associated myopathies [muscle diseases] include HIV-polymyositis and HIV-associated acquired nemaline myopathy. HIV-polymositis is much less frequent than zidovudine [AZT] myopathy…Zidovudine (AZT), the first-line antiretroviral therapy in patients with AIDS can induce a reversible toxic mitochondrial myopathy in patients who have received high cumulative doses of the drug…some authors are still reluctant to accept the diagnosis of zidovudine myopathy…[perhaps because] muscle biopsies from patients with muscle symptoms receiving zidovudine may show no abnormality and may lack the typical features of zidovudine myopathy. As mitochondrial dysfunction related to zidovudine is associated with impaired activity of COX [cytochrome c oxidase], we evaluated the COX histochemical reaction for the diagnosis of zidovudine myopathy…on the muscle of 10 patients with biopsy-proven zidovudine myopathy (Group 1). 10 myopathic zidovudine recipients without typical histopathological features of zidovudine myopathy (Group 2), and 10 HIV-infected patients not treated by zidovudine who had an immunhistological profile of HIV-associated myopathy or other neuromuscular disorder…partial COX deficiency was found in 10/10 patients from Group 1 and 7/10 from Group 2. No COX deficiency was observed in patients not treated by zidovudine…Most patients [but not all] with COX deficiency that could be evaluated clinically after muscle biopsy improved after withdrawal of zidovudine (5/7 in Group 1, 5/5 in Group 2).”

“The immunopathogenesis of HIV-associated PM [polymyositis - muscle wasting of unknown origin] was studied by Illa et al, Lamperth et al, and Leon-Monzon and Dalakas [interestingly all published at least 3 years after AZT was approved]…The clinical features of AZT myopathy are those of a generic myopathy, characterized by proximal limb weakness, myalgia predominantly in the thighs and calves, fatigue, myopathic changes on the electromyogram, and hyperCKemia which often worsens with exercise. In a follow-up of 30 patients with AZT-myopathy, myalgia resolved, strength improved or became normal, and spontaneous activity on the EMG decreased or disappeared 4 to 6 weeks after AZT was discontinued.”

“Cultured muscle cells exposed to zidovudine (0 to 10 to 50 to 100 to 200 kmol/I,) showed a remarkable decrease in cell proliferation [replication]. In controls, the cells number increased from one million at day 0 to about 270 million at day 25 and about 7 billion at day 45. After a 4-day exposure to zidovudine, the proliferation decreased significantly at concentrations of 50 to 200 µmol/L and also after 8 days at a zidovudine concentration of 10 µmol/L…Longer exposure to zidovudine resulted in a decrease of growth to virtually zero”

“Myopathy and hepatic toxicity are important complications of zidovudine (3'-azido-3'-deoxythymidine therapy) in patients infected with the human immunodeficiency virus (HIV) both may also occur in HIV infection in the absence of zidovudine therapy. We report 2 cases of myopathy caused by zidovudine, occurring within 16 wks of initiation of therapy, and a case of concurrent hepatic and muscle toxicity. In one case, electron microscopy demonstrated characteristic enlarged mitochondria with paracrystalline inclusions. This technique can distinguish the myopathies caused by either HIV or zidovudine. Both zidovudine-induced myopathy and hepatoxicity require discontinuation of the drug if severe.”

“we obtained 31P magnetic resonance spectra from the calf muscles of AZT-treated patients and age-matched control subjects at rest and during an exercise protocol with a 12-second time resolution. The recovery of phosphocreatine following exercise reflects mitochondrial oxidative function and was significantly delayed in the AZT-treated patients…These findings support the hypothesis that the myopathy associated with chronic AZT results from the inhibitory effects of AZT on mitochondrial DNA synthesis and, secondarily, on the inhibition of mitochondrial oxidative metabolism.”

“With light microscopy, the muscle specimens of all AZT-treated patients, but none of the five untreated patients, had unique morphologic features characterized by abundant ragged red fibers suggestive of abnormal mitochondria, as previously described. The number of ragged red fibers in the AZT-My[opathy] group…was similar to the number of ragged red fibers counted in 25 muscle biopsy specimens from patients with inflammatory myopathie…All the specimens, including those with abnormal mitochondria from the AZT-treated patients, had histologic features of inflammatory myopathy, as seen in polymyositis, characterized by varying degrees of endomvsial inflammation with necrosis and phagocytosis of muscle fibers…Necrotic [dying muscle] fibers with vacuoles were prominent in the AZT-treated patients…In patients with AZT-My, the most striking abnormality was a marked proliferation of mitochondria, especially in the subsarcolemmal regions, with extreme variations in the mitochondrial size and shape…The mitochondria ranged from 1 µm (normal) to 12 to 15 µm, with changes ranging from marked proliferation to disorganization. disruption, loss of concentric arrangement of the cristae, and occasionally small paracrystalline structures…Structurally, abnormal mitochondria such as those described above may not function normally.”

“A total of 23 patients with myopathy [muscle damage] are reported…AZT Myopathy [17 patients]…In this group of patients with necrotizing myopathy [dying muscle], all muscle biopsies were abnormal, even those obtained from clinically uninvolved muscles…Mitochondrial alterations, which were only conspicuous in degenerating fibers, included enlargement, loss of cristae with granular matrix, bizarre crystal forms, and rarely, paracrystalline arrays. Some fibers with mitochondrial abnormalities showed increased numbers of lipid globules…After stopping AZT, myalgia promptly resolved in all who had this symptom…14 patients had marked improvement…3 improved but still have substantial weakness. Improvement in strength did not begin until 4 to 6 weeks after discontinuing AZT and was slow and steady over the next few months. 2 patients stopped AZT for 3 months with resolution of myalgia and weakness, but with resumption of AZT at one-half dose, myalgia and elevated CK without weakness recurred in both.”

“Striking differences between the AZT-treated hearts and control rat hearts were found ultrastructurally. Myocardial [heart muscle] samples from the AZT-treated group revealed widespread cardiac myocyte mitochondrial disruption and fragmentation of cristae. Some mitochondrial cristae appeared focally dissolved and poorly organized…Other zones showed mitochondrial cristae that were clumped and focally swollen. Mitochondrial findings were consistently present in multiple samples of myocytes from AZT-treated rat hearts and conspicuously absent from samples of hearts of untreated rats.”

“Long term therapy with [AZT] can induce a toxic myopathy associated with mitochondrial changes”

“typical mitochondrial myopathy [muscle damage] has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy…for AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT”

“A clinically significant myopathy that precedes the development of zidovudine associated mitochondrial myopathy has been a rarity in our experience.”

“Muscle biopsies were classified into four groups on purely morphological grounds…[Most severe was] Group 4 (1 3 patients) included distinctive myopathy, with pronounced structural and mitochondrial changes…Zidovudine had been administered before performing muscle biopsy in 27 of 48 patients including all the 13 patients in group 4…There was a significant link between the evidence of structural and mitochondrial myopathy and the administration of zidovudine (Group 4, 100%; other patients, 40%)…Zidovudine therapy was not stopped in 4 patients; 3 patients rapidly died of AIDS and 1 experienced progressive deterioration of his muscular condition…Withdrawal of zidovudine was attempted in 9 of 13 patients…Partial to complete improvement of symptoms was observed in all 9 patients; myalgia resolved in a few weeks, together with a decrease of CK levels, and progressive improvement of strength was observed over the following weeks or months…mean SCR (an enzyme of the respiratory chain) activity was significantly lower in the patients with zidovudine-associated myopathy than in those in the other groups. The mean activity of CCO (the other respiratory chain enzyme tested) was decreased to a lesser extent…The present study shows that long-term zidovudine administration can cause severe myopathy in HIV-infected [HIV-antibody positive, to be correct] patients, characterized histologically by the distinctive association between structural abnormalities and mitochondrial changes. The lesions were typical in myopathic patients who had received more than 250 gm of the compound. Zidovudine myopathy has comprised about one-third of HIV-associated neuromuscular disorders we have evaluated since 1987 and has been detected in 18% of patients treated with the drug for more than 200 days”

“15 biopsy specimens were from patients who were being treated with a full dose of zidovudine (AZT) when the myopathy developed, and 6 other specimens were from patients who had myopathy before receiving AZT therapy through prior treatment with AZT may have contributed to the manifestation of myopathy, the AZT-treated patients were included because we found that their inflammatory infiltrates were identical to those occurring in patients with HIV-PM who had not been treated with AZT…Because the majority of HIV-positive patients were receiving AZT, which can also cause myopathy and affect the circulating lymphocyte subsets, the lymphocyte counts in the AZT-treated group were also analyzed separately to evaluate possible differences from the patients who were not treated with AZT…we found that the virus [HIV], although capable of infecting muscle cells in tissue culture, did not exert a cytopathic effect in the muscle and could not be detected within the muscle fibers immunocytochemically”

“In our review of our clinic patients who have received zidovudine therapy for more than 6 months, 16% (14 of 86 patients) have had persistently elevated creatine kinase values. Six percent of these patients (5 of 86) developed symptomatic myalgia and objective proximal muscle weakness. These 5 symptomatic patients had received zidovudine for an average of 45 weeks and had had creatine kinase elevations for several weeks before onset of symptoms. Of these 5 patients, 4 had creatine kinase values return to normal and symptoms resolve after zidovudine was withdrawn...Three patients were rechallenged with zidovudine: each had recurrent creatine kinase elevations at a dose of 600 mg/d. The zidovudine dose was increased to 1200 mg/d in 2 patients: after a few days, both developed recurrent muscle symptoms that again responded to dose reduction. ...Results of quadriceps muscle biopsies done on our patients who responded to zidovudine withdrawal showed severe myopathic changes without evidence of inflammatory infiltrates. Electron microscopy revealed many ultrastructural changes, including destruction of the sarcomere profile with z-band change in the form of streaming and rod bodies. Muscle mitochondria showed wide variation in size, swelling, degeneration and laminar bodies. ...There have been 40 case reports [to 1990] of patients who have developed myopathy while taking zidovudine (including our 5 symptomatic patients). Zidovudine therapy was discontinued in 34 of these patients and 26 improved.”

“Before 1986, when zidovudine (formerly called azidothymidine [AZT]) was introduced…the number of patients with HIV-associated myopathy was small, and myopathy [muscle disorders] was considered a rare complication of HIV infection. During the past two years [1988-1989], an increasing number of patients receiving long-term zidovudine therapy have had myopathic symptoms such as myalgia (in up to 8% of patients), elevated serum creatine kinase levels (in up to 15%), and muscle weakness. These symptoms generally improve when zidovudine is discontinued…We conclude that long-term therapy with Zidovudine can cause a toxic mitochondrial myopathy, which… is indistinguishable from the myopathy associated with primary HIV infection.”

“A severe proximal myopathy, predominantly affecting the legs, seems to be a significant complication of long-term zidovudine therapy, even at reduced doses; it affected 18% of our patients who had received treatment for more than 200 days. Other drugs could not be implicated. The pathogenesis is obscure; the myopathy resolves on cessation of zidovudine, but not on dose-reduction, though there is then a risk of rebound encephalitis.”

“A 24-year-old woman presented in January, 1988, with a 2-week history of progressive leg weakness and difficulty in walking. She had been found to be HIV antibody positive in April 1986, and in October, 1986, Pneumocystis carinii pneumonia developed. After the pneumonia she had been on zidovudine [AZT] 200 mg 4-hourly and had required three blood transfusion for consequent myelosuppression [white blood cell deficiency]. On examination there was proximal weakness but no wasting of the upper and lower limbs, tenderness of the shoulders and thighs, and preserved deep tendon reflexes. Her gait was waddling and she was unable to rise out of a chair without using her arms...7 days after zidovudine withdrawal, her proximal weakness and muscle tenderness had improved significantly, and muscle force was clinically normal at follow-up 2 months later.”

“All [four] patients had an insidious onset of myalgias, muscle tenderness, weakness, and severe muscle atrophy favouring the proximal muscle groups. Physical examinations revealed varying degrees of muscle weakness and grossly apparent atrophy. Weight loss due to muscle loss was uniformly noted; in one patient, the loss was a striking 18 kg…Zidovudine was discontinued in three patients, who subsequently had symptomatic improvement…The patient who continued to receive the drug had persistent [symptoms]”

“Despite many unresolved physiopathological questions, there are coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to zidovudine [AZT], alone or in combination with lamivudine [3TC]. This effect may be transitory or persistent. Although, the clinical significance of the various biological and/or histopathological mitochondrial anomalies found at birth in NA-exposed animals or children has not been formally established, the high incidence of mitochondrial neurological diseases observed in the French cohort has not been contradicted to date in other cohorts.”

“Recently, we performed a study that examined HIV-1- infected children who began a combination of one or two NRTI [Nucleoside Reverse Transcriptase Inhibitors aka Nucleoside Analogs] plus efavirenz and nelfinavir. Of note, children receiving didanosine were found to have lower mitochondrial DNA to nuclear DNA ratios than children receiving other NRTI. However, of the five NRTI drugs that we evaluated, both in vivo and in vitro, zidovudine was one of the ones that had the least effect on mitochondrial DNA and RNA levels [Note that AZT is known to have a serious effect on mitochondria so this might mean that other drugs are worse].”

“ZDV [AZT] does not usually have any serious adverse effects in women or babies or children [no citation is given for this amazing statement]”

“you are justified in sounding a warning against the long-term therapeutic use of AZT, or its use in pregnant women, because of its demonstrated toxicity and side effects. Unfortunately, the devastating effects of AZT emerged only after the final level of experiments were well underway, that is the experiments which consisted of giving AZT to large numbers of human patients over a long period of time. Your effort is a worthy one…I hope you succeed in convincing your government not to make AZT available [Anthony Brink quoting Richard Belz, the first person to synthesize the drug AZT]”

“Mitochondrial dysfunction has been reported in HIV-negative children perinatally exposed [in the womb or shortly after birth] to zidovudine [AZT]…Two expert groups conducted a systematic, retrospective review of all cerebral MR [magnetic resonance] images available in a multicentric, nationwide French prospective cohort of children born to HIV-seropositive mothers to identify imaging abnormalities…The incidence of abnormalities was determined and compared with the neurologic presentation and laboratory evidence of mitochondrial dysfunction…MR images from 49 HIV-uninfected children (mean age, 26 months) were available for study. All children were perinatally exposed to zidovudine. 22 had probable or established mitochondrial dysfunction according to their symptoms and laboratory data. 27 children without mitochondrial dysfunction presented with unexplained neurologic symptoms (n=14) or nonneurologic symptoms (n=7), and six were asymptomatic[!].”

“At term, AZT was found to be incorporated into fetal mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed mitochondrial membrane compromise, mitochondrial proliferation, and damaged sarcomeres [a type of muscle cell], while mitochondria in brain cerebrum and cerebellum were morphologically normal.”

“Zidovudine [AZT] administered during the perinatal period may result in a small but significant and durable effect on hematopoiesis [blood production] up to the age of 18 months.”

“An exhaustive study in a large prospective cohort with predetermined algorithm of the unexplained symptoms compatible with mitochondrial dysfunction. A total of 2644 of 4392 children were exposed to antiretrovirals…All the children with ‘established’ or ‘possible’ mitochondriopathy [mitochondrial damage] diagnosed in this study had been exposed to antiretroviral drugs. One of these children was treated with zidovudine [AZT] only during the prenatal period and received no treatment after birth…For the other children, the treatment was administered in the pre, per- and post-partum periods. It was zidovudine alone in five cases, a combination of zidovudine-lamivudine in 14 cases and another combination in one. 20 of the mothers received zidovudine by intravenous perfusion during labor.”

“children of HIV+ mothers are at risk for mitochondrial damage [mitochondria are the energy regulating organelles essential to every living cell, and that have their own DNA] that is further increased in infants of mothers receiving AZT during pregnancy”

“A total of 38 subjects were enrolled from June 1997 through June 1999 [1 was later excluded]…Zidovudine [AZT] was generally well tolerated in this high-risk population. The percent of patients who had selected adverse events is shown in Table II [32%-Anemia grade >=2; 11%-Neutropenia; 13%-Thrombocytopenia; 45%-Received transfusion; 26%-Received the blood production stimulator erythropoetin; 11%-HIV infection; 8%-Died] Slightly more than half of the subjects had anemia severe enough to require a transfusion [giving new meaning to the term 'well tolerated']…Three infants (8%) died at 3, 23, and 31 weeks of age. All 3 were born at <=26 weeks’ GA [gestation age] and each death was thought to be related to a complication of prematurity”

“Our results…suggested that infected infants who were perinatally exposed to ZDV [AZT] may have a more rapid early disease progression with unfavorable viral manifestations than those without exposure to antiretroviral drug [i.e. babies of mothers who took AZT did worse, but it can’t be the wonder-drug AZT, it’s got to be something else!]…The subjects were 37 infants [group C (C)] who were born to antiretroviral drug naïve HIV-1 infected mothers (MC) and 80 infants [group Z (Z)] who were born to HIV-1 infected mothers (MZ) that received a short-course ZDV [AZT] regimen…Of the whole cohort, there were 12 HIV-1 infected infants, seven in group Z [mothers were given AZT during pregnancy] and five in group C [mothers did not take AZT]…The clinical category of all 12 infants was classified as EN [without any symptoms] at the age of 1–2 months. There were 6/12 (50%) infants who developed symptoms at the age 6 months. Of these rapid disease progression, five (83.3%) were infants in group Z [whose mothers used AZT] and one was in group C. This revealed that more infants in group Z (5/7; 74%) than in group C (1/5; 20%) developed symptoms by 4–6 months (P=0.02). The clinical symptoms of these infected infants included oral thrush (4/6), dermatitis (1/6), splenomegaly [enlarged spleen] (5/6), hepatomegaly [enlarged liver] (5/6), and lymphadenopathy (3/6).”

“One potential drawback to voluntary testing [why would involuntary testing be any different?] is the unknown toxicity affect AZT use can have on infants who are born without HIV [and what about the toxicity on children who will later be found to be HIV-positive?] and the pregnant women who take it. There are no long-term studies on the efficacy of AZT use on healthy children [how could AZT be effective in HIV-negative children?]. Most clinical studies have excluded women. Moreover, a report prepared by the Institute of Medicine indicated that PCP prophylaxis or antiviral therapy for those who were HIV positive but asymptomatic had serious ramifications, especially regarding toxicity…Convincing pregnant women, especially African Americans, to use AZT or other anti-viral drugs may be difficult. One study showed that African American women hold disturbing views towards AZT use. For instance, some respondents said that AZT could harm them [shocking!], others said the drug was indiscriminately prescribed, while others were unwilling to use it because AZT had not been tested on women of color. A number of respondents indicated that AZT use was a way for pharmaceutical companies to make money”

“In univariate analysis, maternal peripartum zidovudine [AZT] had no effect on mortality up to day 230, but a negative effect beyond 8 months of age. Neonatal anaemia [quite possibly due to the maternal AZT], a diagnosis of HIV-1 infection on or before day 12 and between days 13 and 45, paediatric AIDS, a maternal CD4 lymphocyte count of less than 200/cubic mm, and a high maternal plasma viral load were risk factors for child death…The 18 month mortality rate in these HIV-1-infected children was 590 per 1000 in the zidovudine group and 510 per 1000 in the placebo group…The 18 month mortality rate in these HIV-uninfected children was 53 per 1000 in the zidovudine group and 78 per 1000 in the placebo group [meaning that AZT makes HIV-infected children sicker, but HIV-uninfected children healthier!]…11 of the 51 deaths of the HIV-1-infected children were attributed to a cause belonging to the AIDS clinical syndrome”

“In our study, we found a slightly higher risk for disease progression among ZDV[AZT]-exposed, HIV-infected children during the 18-month follow-up period [as compared to HIV-infected children whose mothers were given a placebo], although this difference was not statistically significant.”

“[Table 3 shows that congenital abnormalities occurred in 7% of infants when both mother and child had the long course of AZT (long-long), and only 1% when both had the short course (short-short). Neutropenia and leukopenia occurred in 7% of infants on the long-long course and 2% on short-short. Infections or other HIV-related events occurred in 43% on long-long and 33% on short-short. Neonatal or other obstetrical events occurred in 22% on long-long and only 14% on short-short. Number of deaths, severe anemia were similar (although severe anemia occurred significantly less (0%/1%) in the long-short and short-long treatment arms). Mothers who received the long AZT treatment had a higher rate of stillbirth (8% vs. 4%), severe anemia (7% vs 4%), infection or other HIV events (20% vs 17%), events related to pregnancy or delivery (24% vs 17%) than mothers who received the short course, although fewer died (3% vs 8%)]”

“Other factors associated with lower cumulative survival included suppressed CD4 cell counts, a history of zidovudine therapy [Table 1 shows that children who had taken AZT had a 37.5% risk of death over the study period versus 22.8% for those who had not. There was a 97% probability that this increase was not due to chance], and Pneumocystis carinii pneumonia diagnosed before the initial echocardiogram.”

“Infants with early positive HIV-1 cultures demonstrated a notable decrement in neurodevelopmental functioning within the first 30 months of life. They achieved motor developmental scores that were increasingly and significantly discrepant [worse] both from the average and from scores achieved by late HIV-1-positive children over the course of the study period. Those children with early HIV-1-positive cultures also demonstrated a trend toward a similar decline in mental functioning over time...The mothers of infants with early [HIV] positive cultures were more likely to receive ZDV [AZT] treatment during pregnancy, and their infants were more likely to receive ZDV treatment prophylactically during the first 6 weeks of life...Because antiretroviral therapy has been shown to improve neurodevelopmental function in children whose CNS has been affected by the HIV-1 virus...Infants with early HIV-1 culture positivity should be treated with multiple drugs with well-established CNS penetration to reduce the likelihood that resistance will develop in the CNS compartment [translation: this study showed that one drug may negatively affect neurological development, so multiple drugs must do the opposite!]”

“In a multicenter observational cohort study of 325 HIV-infected children born during 1986-1997, clinical progression was compared among infected children exposed or unexposed to Zdv [AZT] during prenatal and perinatal periods. Zdv exposure was associated with 1.8-fold (95% confidence interval, 1.02-3.11) increased risk of progressing to AIDS or death after adjusting for year of birth, maternal CD4 cell count, maternal AIDS diagnosis, and subsequent antiretroviral therapy of the child. Mean log10 viral copies at 712 weeks were higher among Zdv-exposed children (P = .004).”

“Children of study women who were prescribed ZDV [AZT] had increased adjusted odds of any anomaly (adjusted odds ratio [OR], 1.55; 95% CI, 1.01-2.29) [i.e. more than one-and-one-half times the risk of a birth anomaly than the HIV+ population being studied in general]...The prevalence of major anomalies in the full cohort based on definition 1 was significantly higher than that observed in the general New York State population...the SMR [Standardized Morbidity Ratio] adjusted for race, gender, and location suggests that the risk of a major anomaly in the study cohort was 2.79 times greater than the general population...the lack of data on potential adverse effects of this therapy is still a concern...we compared anomaly rates of subgroups defined by ZDV exposure history within the cohort of HIV-infected mothers. Babies whose mothers had ZDV exposure during pregnancy had a greater incidence of major malformations than those whose mothers did not.”

“The Antiretroviral Pregnancy Registry (APR), originally established in 1989 as the Zidovudine in Pregnancy Registry, was begun by the pharmaceutical industry, in conjunction with the U.S. Centers for Disease Control and Prevention, as a means of gathering sufficient data to measure incidence of structural anomalies in antiretroviral-exposed pregnancies. Despite its being an international registry, this effort had prospectively registered and closed only 392 ZDV monotherapy-exposed pregnancies by the end of 1997. Further, 20% of these were closed due to loss-to-follow-up, leaving only 317 pregnancies with data available for analyses.”

“Objective: To investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. Interventions: Elective caesarean section before labour, usually at 36–38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen).

Results: Of 179 mother–infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0– 4.7] and 12.6% (6.4–19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6–8 weeks.

Conclusion: A much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.”

“[Human Use of AZT] In the United States each year approximately 7000 pregnant women infected with the Human Immunodeficiency Virus (HIV-1) are treated with Highly Active Antiretroviral Therapy (HAART), either for their own disease or to inhibit maternal-fetal viral transmission. The HAART combinations of drugs typically include two nucleoside analogs and a protease inhibitor, and the nucleoside analogs zidovudine (AZT) and lamivudine (3TC) are used most frequently in combination in human pregnancy. Originally (1994) the CDC recommended that AZT be given orally for the last 6 months of pregnancy, by infusion to the mother during labor, and orally to the infant for the first 6 weeks, as standard-of-care for inhibition of vertical HIV-1 transmission.

[Animal Models]In 1997 AZT was reported to be a moderately-strong transplacental carcinogen in offspring of pregnant mice given the drug during the last week of gestation. Drug-induced tumor incidences in lung, liver, reproductive organs and skin from mice at 1 year of age were 2-8-fold higher than those observed in unexposed controls. Incorporation of AZT into nuclear and mitochondrial DNA (7.7-100.9 molecules AZT/106 nucleotides) of liver, lung and skin, and shortened telomeres in lung, brain and liver, were found at birth in mice exposed in utero to tumorigenic AZT doses. In addition, HPRT somatic mutation frequencies in spleen and thymus of similarly-exposed mice necropsied at 15 days of age increased in a dose-related fashion.

Subsequent modeling of human exposures in pregnant Erythrocebus patas monkeys, using human equivalent protocols for AZT or the combination AZT/3TC, demonstrated that full-term fetal monkey organs contained AZT-DNA levels higher than those found in the mouse tumor study. In addition, the combination of AZT/3TC, given for the last half of the patas monkey gestation, caused both drugs to become incorporated into fetal organ DNA and to shorten telomeres in almost every fetal organ examined. Based on animal studies and in vitro indicators of genotoxicity, the International Agency for Research on Cancer declared AZT a ‘possible human carcinogen’.

In order to explore transplacental nucleoside analog genotoxicity in human pregnancies we have examined cord blood leukocyte DNA from infants of HIV-1-infected women taking AZT or AZT/3TC. We found that 68% of infant cord blood leukocytes (n=22) were positive for AZT-DNA incorporation, with positive values ranging from 22 to 451 molecules of AZT/106 nucleotides In addition, a correlation was found between AZT-DNA incorporation and levels of intracellular AZT-triphosphorylated metabolite in cord blood leukocytes from 9 infants

Mutagenesis, presumed to be a consequence of AZT-DNA incorporation, was examined in infant cord blood leukocytes at the glycophorin A (GPA) and HPRT loci. The mean frequency of GPA N/N somatic mutant variants in umbilical cord blood erythrocytes was 2-3 fold higher in infants exposed in utero to AZT or AZT/3TC (n=27), compared to unexposed infants in the same study (n=30) or literature values for newborns (n=156). Infants exposed to AZT alone had half the induced N/N mutant frequency as infants exposed to the combination AZT/3TC (7).

The HPRT mutant frequency in cord blood lymphocytes of 66 unexposed children was half that of 37 children exposed to the combination of AZT/3TC, and sequence analysis indicated that the formation of single-base transversion substitutions was >2-fold higher in the treated group. HPRT mutant frequency increases with age in unexposed populations, and the mean mutant frequency of newborns in the AZT/3TC group was similar to that seen in adolescents, while ~30% of these infants had values comparable to adults. At 1 year of age, 30% of children exposed in utero to AZT/3TC (n=18) had HPRT mutant frequencies similar to values reported for children 6-17 years, while unexposed children (n=17) had mutant frequencies comparable to children < 6 years of age.

[Conclusions] Overall, the data indicate that children of HIV-1-infected women, exposed in utero to nucleoside analog drugs, may sustain significant genotoxic insult and should therefore be subjected to long-term surveillance”

“After adjusting for prematurity and maternal clinical characteristics, RPD [rapid disease progression] was three times more likely to occur in infants born to [mothers] treated [with AZT] compared with findings in untreated mothers (RR=2.8; p = .021).”

“Retrovir [AZT] and 3TC [Lamivudine] in children prolongs life and delays disease progression [GlaxoWellcome was the manufacturer of both drugs when this advertisement was circulated around 2000]”

“All women [in this study] received oral zidovudine [AZT] prior to delivery and/or intravenous zidovudine at delivery...Of 42 subjects...24 had a CVL [cervicovaginal lavage] taken...Of these 24 women, 7 transmitted HIV-1 to their infants and 17 did not...In the CVL samples, 41% yielded culturable HIV-1, 67% were PCR positive for proviral HIV-1 DNA, 30% were positive for cell-free HIV-1 RNA and 45% were positive for cell-associated HIV-1 RNA. Peripheral CD4 cell counts did not correlate with levels of HIV-1 in the CVL by DNA or RNA PCR or by amount of genital tract inflammation...Although all subjects in our study received zidovudine therapy in the third trimester, the high rate (29%) of HIV-1 perinatal transmission in this data set does not agree with the largest prospective, randomized study addressing this question, ACTG 076 [in fact, this rate is higher than the transmission rate in the placebo arm of ACTG 076]”

“Eight children with mitochondrial dysfunction were found...the first patient presented with visual impairment...[and] died aged 13 months because of respiratory and cardiac-rhythm disorders...The second patient, from age 4 months until until death at 11 months, had refractory epilepsy and deterioration of cognitive and psychomotor abilities...At age 8 months...patient three had a seizure...At age 4 years, the child’s cardiac function was normal, but moderate muscular deficit persisted...In the fourth patient...between ages 14 and 27 months, the child had four episodes of febrile seizures...From age 7 months until 15 months, patient five had repeated seizures...at age 16 months...large necrotic lesions of the [brain]...At age 3-1/2 years the child had severe sequelae and microcephaly [abnormally small head]. Patient 6 was symptom-free until age 14 months, but persistent biochemical abnormalities were seen on standard follow-up...Patient 7 was symptom-free until age 4 months, at which time he became hypotonic [low muscle tone] [and stopped breathing]...The eighth child was symptom-free. Persistent hepatic and pancreatic abnormalities were seen from birth...At age 20 months, biological abnormalities persisted...electroretinography...was abnormal, and cerebral NMR imaging...showed abnormalities of the periventricular white matter...No child was infected with HIV-1 [but because their mothers were HIV-positive] all children were treated after birth with zidovudine [AZT] alone or with zidovudine and lamivudine [also a nucleoside analog]. Treatment continued for 6 weeks in four children and was stopped prematurely because of haematological or biochemical intolerance in four children...The observation of several cases [of mitochondrial abnormalities] in a population of about 1700 exposed children [as compared with 1/5,000 to 1/20,000 in normal populations] strongly suggests an acquired mitochondrial dysfunction...Pregnant women should be informed of the potential effects associated with these treatments during pregnancy.”

“The UK's Committee on Safety of Medicines has issued a warning to doctors about the risk of mitochondrial dysfunction in infants born to HIV infected mothers treated with zidovudine (AZT) to prevent vertical transmission...The warning comes in advance of the publication of data from a French study in which it was discovered that 8 out of approximately 200 infants developed mitochondrial dysfunction following exposure to zidovudine, with or without 3TC treatment, for the prevention of vertical transmission of HIV infection.”

“The data show that AZT crosses the human placenta and becomes rapidly incorporated into DNA of placental tissue in a dose-dependent fashion, suggesting that even short exposures to this drug might induce fetal genotoxicity and might also inhibit maternal-fetal viral transmission…the long-term consequences of transplacental AZT exposure remain unknown. In mice, AZT is a moderate to strong transplacental carcinogen when administered during the last 37% of gestation and the same AZT exposure regimen produces AZT incorporation into the DNA of multiple newborn mouse organs”

“Incorporation of ZDV [AZT] into DNA was detected in most of the samples from ZDV-exposed adults and infants. Therefore, the biologic significance of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be further investigated in large cohorts of HIV-positive individuals.”

“Comparison of HIV-1-infected children whose mothers were treated with ZDV [AZT] with children whose mothers were not treated showed that the former group had a [1.8 times] higher probability of developing severe disease or severe immune suppression [2.4 times higher risk] and a lower survival (72.2% versus 81.0%).”

“Will my baby get HIV? Without the special drugs [”AZT” is the word they cannot say], there is a 1 in 4 chance that your baby will get HIV. The risk of HIV spread from mother to baby can be [not every paper shows less risk of developing HIV antibodies with AZT] less when the mother takes speciaL HIV drugs during pregnancy and delivery, and when the baby takes drugs [”special” drugs like AZT or just “ordinary” drugs] during the first 6 weeks of life. [The risk of side effects is not mentioned]”

“At present, data regarding the effects of ZDV use on vertical transmission rates are inconclusive and incomplete. In addition, the long-term effects of ZDV use during pregnancy and after birth on the woman and any resulting child are yet to be discovered…the possibility has not yet been ruled out that this “risk-reducing” measure may not be effective and may prove detrimental to the health of both mother and child.”

“Conclusions: In HIV-infected pregnant women treated with two RTI [nucleoside analogs, of which AZT was the most common] with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies.”

“Similar levels of AZT-DNA incorporation were detected in peripheral blood from HIV-1-positive mothers and cord blood from their infants and tissues from newborn mice exposed to tumorigenic [cancer-causing] doses of AZT in utero. Therefore, the biologically effective dose (i.e. the amount of AZT that incorporated into DNA) was similar in both species even though the mouse daily dose of AZT was much higher than that received by humans.”

“We present two cases of severe PCP [pneumocystis carinii pneumonia] in infants who were perinatally exposed to HIV [and AZT] but who were uninfected with HIV…Both children had a transient decrease in their CD4 cell counts that was concomitant with the acute PCP episode…A survey of healthy 4-year-old children showed that the seroprevalence of PCP was ~67%. Thus, children with PCP usually have asymptomatic infection. It has been suggested that immunosuppression allows P. carinii to progress to serious disease. The two children described herein were not significantly immunosuppressed, and it is unclear if any of the recognized antecedents (a mother with AIDS and severe immunosuppression, zidovudine [AZT] treatment, and concomitant herpesvirus infection) set the stage for PCP”

“Anemia occurred in 22% of the infants who received zidovudine”

“The authors selected six patients who were HIV positive and who had requested termination of pregnancy to study the passage of zidovudine through the placenta...1 gram of zidovudine [AZT] was given in five doses of 200 mg each orally...At a mean age of 17.5 weeks [into the pregnancy], samples were taken from the mothers’ blood, from the amniotic fluid and from the fetal blood...The concentrations of [AZT] in the [amniotic fluid] and in the fetal blood were higher or equaled those found in the maternal blood...The drug remains contraindicated in pregnancy”

“Treatment of HIV-infected pregnant women with anti-HIV therapeutics may, therefore, inadvertently expose many uninfected and healthy fetuses to these maternally administered and potentially toxic drugs.”

“AZT and/or its metabolites were found in every [macaque ape] fetal tissue examined, including plasma and amniotic fluid. The greatest amount of AZT-derived compound was found in the fetal kidney,”

“Initiation of ZDV [AZT] therapy during pregnancy did not result in a significant decrease in viral load at delivery when controlling for the effect of pregnancy…Mother-to-child transmission of HIV-1 occurred in one of 27 (4%) ZDV-treated women and in two of 16 (12.5%) untreated women.”

“Six women (three in each group [AZT/placebo]) discontinued their treatment [with AZT] because of toxic effects. Thirty-five women (18 in the zidovudine group and 17 in the placebo group) had anemia of more than moderate severity, neutropenia, or thrombocytopenia, and 15 women (8 in the zidovudine group and 7 in the placebo group) had abnormalities of serum electrolytes and liver function of more than moderate severity. Toxic effects were defined according to standard toxicity tables modified for pregnancy and defined in the protocol. The majority of the adverse effects were judged to be related to labor and delivery. None of the mothers died during the study. [These numbers, particularly of anemia, are suspicious, as both pairs are 1 higher in the AZT group than placebo, especially given the known association of AZT with anemia]”

“In reviewing the frequency of birth defects in this population [of HIV+ women taking AZT during pregnancy] we noted eight birth defects (10%) out of 80 live births [and 8 spontaneous fetal losses, for a total of 17% abnormal pregnancies]”

“Treatment with trimethoprim-sulfamethoxazole and zidovudine [AZT] was started earlier and was more frequent among the 16 children born to mothers with class IV disease [AIDS]. At 18 months,…13 had received zidovudine [81%], as compared with…81…of the 130 children [62%] born to mothers with class II [HIV+, without symptoms] or III disease [swollen glands].”

“Children treated with zidovudine continued to have bacterial and opportunistic infections. The effect of the drug on the frequency of these events could not be assessed because of the lack of control groups...One or more episodes of hematologic toxicity occurred in 54 children (61 percent)—anemia (hemoglobin level, <75g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, <0.75X10^9 per liter) in 42 (48 percent)”

“The concentrations of the drug [AZT] in the liquor and in the fetal blood [of 6 aborted human fetuses] were higher or equaled those found in the maternal blood...The drug remains contraindicated in pregnancy.”