AZT: Unsafe at Any Dose?

“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.”

“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.”

“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).”

“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”

“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”

“nearly one half of patients treated with AZT for [HIV]-associated disease develop transfusion-dependent anaemia due to bone marrow depression”

Harmful Side Effects, General

AZT has a wide range of side effects. Those that have not been reported widely enough to deserve their own section are reported here.

“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.”

“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.”

“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”

“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.”

Warnings from Experiments with Animals

Experiments have been performed on animals that would be unethical in humans (whether they are really ethical on animals is another question). The information that they have produced about AZT is very worrying. It is generally ignored by AIDS doctors and researchers.

“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.”

“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.”

“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.”

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

“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, macocytic 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]”

AZT and Cancer

AZT has a strong association with cancer, not surprising for a drug that interferes with DNA replication, and therefore cell division. Note that uncontrolled cell division is the definition of 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]”

“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.”

“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”

Increased Risk of Sickness and Death with AZT

AZT, the 'life saving' drug, may actually accelerate illness and death.

“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”

“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.”

“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.”

“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 manufactures AZT] 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”

Lack of Effectiveness and Toxicity

Although AZT is commonly described as a 'life saving' drug, there are some papers that show that it might be strikingly ineffective in at least some cases.

“[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.”

“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”

“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.”

“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].”

“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.”

“[in these clinical trials] it was often difficult to distinguish adverse events possibly associated with administration of Retrovir from underlying signs of HIV disease or intercurrent illnesses [i.e. AZT can cause AIDS-defining illnesses]”

AZT and Mitochondria

Mitochondria are the energy regulating organelles in every living cell. Because they are self-replicating and therefore have their own DNA they are susceptible to damage from drugs (such as AZT) that interfere with DNA replication (mitosis). In fact, they are more susceptible, because they don't have the same repair mechanisms as the DNA in the cell's nucleus. Symptoms of mitochondrial damage are varied, but often include muscle damage, as the ability of the cells to obtain energy is diminished.

“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.”

“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 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]”

“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.”

“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”

Muscle Disorders (including Heart)

AZT causes muscle damage, which often shows up as muscle wasting or pain. It is believed that this is largely through damage to mitochondria, the energy regulating organelles in every animal cell. AZT may interfere with the replication of mitochondria (which have their own DNA) or with their supply of phosphates, the energy currency of cells.

“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: Unsafe at Any Dose?

The quotes are categorized as:

Harmful Effects on Blood and Bone Marrow

AZT is known to suppress the ability of the body to produce red blood cells (anemia) and white blood cells (*-penia, e.g. neutropenia -- deficiency of neutrophils or pancytopenia -- deficiency of all types of cells).

Harmful Side Effects, General

AZT has a wide range of side effects. Those that have not been reported widely enough to deserve their own section are reported here.

Warnings from Experiments with Animals

Experiments have been performed on animals that would be unethical in humans (whether they are really ethical on animals is another question). The information that they have produced about AZT is very worrying. It is generally ignored by AIDS doctors and researchers.

AZT and Cancer

AZT has a strong association with cancer, not surprising for a drug that interferes with DNA replication, and therefore cell division. Note that uncontrolled cell division is the definition of cancer.

Increased Risk of Sickness and Death with AZT

AZT, the 'life saving' drug, may actually accelerate illness and death.

Lack of Effectiveness and Toxicity

Although AZT is commonly described as a 'life saving' drug, there are some papers that show that it might be strikingly ineffective in at least some cases.

AZT and Mitochondria

Muscle Disorders (including Heart)