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What's so Bad
About AZT ?
Referenced Citations on the Adverse effects of AZT on Expectant Mothers and Children, Harmful side effects in general, Damage to Blood and Bone Marrow, Muscle Disorders, Toxicity and Lack of Effectiveness, Increased Risk of Sickness and Death and warnings from Animal Studies.
Adverse effects on Mothers and Children
"We analysed observations of a trial of tolerance of combined zidovudine [AZT] and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France....Findings: Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1...Interpretation: Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained[!]. Further assessment of the toxic effects of these drugs is required."
Blanche S, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet. 1999 Sep 25.
"Comparison of HIV-1-infected children whose mothers were treated with ZDV with children whose mothers were not treated showed that the former group had a higher probability of developing severe disease [57.3% (95% CI 40.9-74.3) versus 37.2% (95% CI 30.0-45.4); log-rank test 7.83, P = 0.005; adjusted hazard ratio 1.8 (95% CI 1.1-3.1)] or severe immune suppression [53.9% (95% CI 36.3-73.5) versus 37.5% (95% CI 30.0-46.2); log-rank test 5.58, P = 0.018; adjusted hazard ratio 2.4, (95% CI: 1.3-4.3)]" The Italian Register for HIV Infection in Children. Rapid disease progression in HIV-1 perinatally infected children born to mothers receiving zidovudine monotherapy during pregnancy. AIDS. 1999 May 28;13:927-33.
"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." and "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."
Perinatal AZT: New warning on potential risk to infants. www.aidsmap.com. 1999 Jul 21
"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."
Olivero OA et al. 3'-azido-3'-deoxythymidine (AZT) transplacental perfusion kinetics and DNA incorporation in normal human placentas perfused with AZT. Mutat Res Fundam Mol Mech Mutagen. 1999 Jul 16;428(1-2):41-7.
".these two [HIV+ babies taking AZT+3TC] died of an extremely rare disease caused by genetic damage to the mitochondrial DNA < which is found in the cell body rather than in the nucleus with the genes. One died at 11 months and one died at 13 months, both from severe brain damage. Blanche [of the French medical research institute INSERM] told the meeting that there was no proof the drugs caused the damage. But he said there was also no evidence the babies had inherited abnormalities, and HIV drugs are known to cause mitochondrial damage."
HIV drugs may show adverse effects in babies. Reuters. 1999 Feb 2.
"transplacental exposure studies demonstrated that AZT is a moderate to strong transplacental carcinogen in mice...Since AZT-DNA incorporation in human placenta occurs rapidly by 2 hr of AZT perfusion, infants exposed to AZT even for short periods of time during gestation may sustain genotoxic damage. In previous studies AZT has
been shown to produce both, large scale DNA damage and point mutations...the consequences of any fetal exposure to a nucleoside analog, in utero, remain unknown"
Olivero OA et al. 3'-azido-3'-deoxythymidine (AZT) transplacental perfusion kinetics and DNA incorporation in normal human placentas perfused with AZT. Third Conference on Environmental Mutagens in Human Populations. 1999 Feb 18.
"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 ³risk-reducing² measure may not be effective and may prove detrimental to the health of both mother and child."
Bennett R, Foster G. Mandatory testing of pregnant women and newborns: a necessary evil? and Realistic alternatives to breastfeeding in the HIV/AIDS era. AIDS Information Exchange. 1998.
"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."
Lorenzi P et al. Antiretroviral therapies in pregnancy: maternal fetal and neonatal effects. AIDS. 1998;12:F241-247.
"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."
Melvin AJ et al. Effect of pregnancy and zidovudine therapy on viral load in HIV-1-infected women. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Mar 1;14(3):232-6.
"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+ but no symptoms] or III disease [swollen glands]."
Blanche S. Relation Of The Course Of HIV Infection In Children To The Severity Of The Disease In Their Mothers At Delivery. NEJM. 1994 Feb 3;330(5):308-12.
"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."
Kumar RM et al. Zidovudine Use in Pregnancy: A Report on 104 Cases and the Occurrence of Birth Defects. J Acquir Immun Defic Syndr. 1994;7:1034-9.
"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 contra-indicated in pregnancy."
Gillet JY et al. Preliminary study on the transport of AZT (Retrovir-zidovudine) through the placenta. J Gynecol Obstet Biol Reprod. 1990;19(2):177-180.
Warnings from Experiments with Animals
"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 sixfold 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."
Gerschenson M et al. Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3'-azido-3'-deoxythymidine. . AIDS Res Hum Retroviruses. 2000 May 1;16(7):645-44.
"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"
Ha JC et al. Fetal, infant, and maternal toxicity of zidovudine (azidothymidine) administered throughout pregnancy in Macaca nemestrina. J Acquir Immun Defic Syndr Hum Retro. 1998 May 1;18(1):27-38.
"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 is genotoxic in fetal mice and monkeys and is a moderately strong transplacental carcinogen in mice examined at 1 year of age."
Olivero OA et al. Transplacental effects of 3'-azido-2',3'-dideoxythymidine (AZT): tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst. 1997 Nov 5;89(21):1602-8.
".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]"
Olivero OA et al. AZT is a Genotoxic Transplacental Carcinogen in Animal Models. JAIDS-J Acquir Immun Defic Syndr Hum Retro. 1997 Apr 1;14(4):A29.
"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"
Ha JC et al. Fetal toxicity of zidovudine (azidothymidine) in Macaca nemestrina: preliminary observations. J Acquir Immune Defic Syndr. 1994;7(2):154-7.
"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."
Olivero OA et al. Vaginal epithelial DNA damage and expression of preneoplastic markers in mice during chronic dosing with tumorigenic levels of 3'-azido-2',3'-dideoxythymidine (AZT). Cancer Res. 1994;54:6235-42.
"Mice receiving AZT during gestation yielded fewer fetuses.and greater numbers of resorptions.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."
Toltzis P et al. Zidovudine-associated embryonic toxicity in mice. J Infect Dis. 1991;163:1212-8.
"[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"
Mansuri MM et al. Comparison of In Vitro Biological Properties and Mouse Toxicities of Three Thymidine Analogs Active against Human Immunodeficiency Virus. Antimicrobial Agents and Chemotherapy. 1990;34(4):637-641.
Harmful Side Effects, General
"Recently, we observed an unusual cluster of cases of rapidly progressing multicentric Castleman's disease. Fever, weakness, generalized enlargement of lymph nodes, and marked polyclonal gammopathy developed in three patients with AIDS...Two of these patients died within one week after the diagnosis, with generalized involvement of the lymphatic system, liver, and bone marrow at autopsy. A fourth patient with AIDS who died equally rapidly after the diagnosis of multicentric Castleman's disease had been seen in our hospital 14 months earlier... symptoms of multicentric Castleman's disease started after the initiation of highly active antiretroviral therapy in these three patients."
Zietz C et al. An unusual cluster of cases of Castleman's disease during highly active antiretroviral therapy for AIDS. NEJM. 1999 Jun 17;340:1923-4.
"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."
Agarwal RP, Olivero OA. Genotoxicity and mitochondrial damage in human lymphocytic cells chronically exposed to 3'-azido-2',3'-dideoxythymidine. Mutat Res. 1997 May 23;390(3):223-231.
"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]"
Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995 May;1(5):417-22.
"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."
Neurology. 1994;44:1982-1900.
"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" Don PC, et al. Nail dyschromia associated with zidovudine. Ann Intern Med. 1990;112(2):145-6.
"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."
Swanson CE, Cooper DA. Factors influencing outcome of treatment with zidovudine of patients with AIDS in Australia. AIDS. 1990;4(8):749-57.
"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."
Dubin G, Braffmann MN. Zidovudine-induced hepatotixicity. Ann Intern Med. 1989;110(1):85-6.
"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."
Fischl MA, et al. Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. JAMA. 1989;262(17):2405-10.
"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"
Dournon E, et al. Effects of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet. 1988 Dec 3;2:1297-1302.
Harmful Effects on Blood and Bone Marrow
"We found that 78.2% of the patients with mild or severe anaemia at baseline had received zidovudine [AZT]"
Mocroft A, et al. Anaemia is an independent predictive marker for clinical prognosis of HIV-infected patients from across Europe. AIDS. 1999;13:943-50.
"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."
Hymes KB et al. The Effect of Azidothymidine on HIV-related Thrombocytopenia. NEJM. 1998 Feb 25;318(8):516-7.
"While effective drug therapy is continued in zidovudine[AZT]-treated HIV-infected patients.PROCRIT Reduces Transfusion Requirements and Helps Lift the Burden of Anemia."
Advertisement for PROCRIT. 1997.
"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."
Mir N, Costello C. Zidovudine and Bone Marrow. Lancet. 1988 Nov 19;1195-6.
"nearly one half of patients treated with AZT for [HIV]-associated disease develop transfusion-dependent anaemia due to bone marrow depression"
Dainiak N et al. 3'-Azido-3'-deoxythymidine (AZT) inhibits proliferation in vitro of human haematopoietic progenitor cells. British Journal of Haematology. 1988;69:299-304.
"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."
Costello C. Haematological abnormalities in human immunodeficiency virus (HIV) disease. J Clin Pathol. 1988;41:711-5.
"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."
Walker RE, et al. Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome (AiDS) and Kaposi sarcoma treated with zidovudine. Ann Intern Med. 1988;108:372-6.
"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)."
Richman DD et al. The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex. NEJM. 1987;317:192-197.
"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."
Gill PS et al. Azidothymidine Associated with Bone Marrow Failure in the Acquired Immunodeficiency Syndrome (AIDS). Annals of Internal Medicine. 1987;107:502-505.
Muscle Disorders (including Heart)
"Long term therapy with [AZT] can induce a toxic myopathy associated with mitochondrial changes"
Chariot P, Gherardi R. Partial cytochrome c oxidase deficiency and cytoplasmic bodies in patients with zidovudine myopathy. Neuro muscul Disorders. 1991;1:357-363.
"typical mitochondrial myopathy has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy" and "for AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT"
Hayakawa M et al. Massive conversion of guanosine to 8-hydroxy-guanosine in mouse liver mitochondrial DNA by administration of azidothymidine. Biochem Biophys Res Commun. 1991;176:87-93.
"A clinically significant myopathy that precedes the development of zidovudine associated mitochondrial myopathy has been a rarity in our experience."
Coker R et al. Exacerbation of HIV-associated myopathy by zidovudine. AIDS. 1991;5(2):229-31.
"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 percent of patients), elevated serum creatine kinase levels (in up to 15 percent), 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."
Dalakas MC et al. Mitochondrial myopathy caused by long-term zidovudine therapy. NEJM. 1990;322(16):1098-1105.
"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."
Till M, MacDonnell KB. Myopathy with Human Immunodeficiency Virus type 1 (HIV-1) infection: HIV-1 or zidovudine?. Ann Intern Med. 1990;113(7):492-4.
"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."
Helbert M, et al. Zidovudine-associated myopathy. Lancet. 1988 Sep 17;2:689-90 .
"A 24-year-old woman presented in JanA 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 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."
Gorard DA, Henry K, Guilodd RJ. Necrotising myopathy and zidovudine. Lancet. 1988 May 7;1:1050.
"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 "
Bessen L. Severe Polymyositis-like Syndrome Associated with Zidovudine Therapy of AIDS and ARC. NEJM. 1988 Mar 17;708.
Lack of Effectiveness.and Toxicity
"Antiretroviral therapy may be initiated early during antituberculosis therapy in HIV-infected patients with tuberculosis. After initial clinical improvement, paradoxical worsening of disease developed in up to 36 percent of these patients, characterized by fever, worsening chest infiltrates on radiograph, and peripheral and mediastinal lymphadenopathy...In contrast, only 7 percent of patients who received antituberculosis therapy but not antiretroviral therapy had paradoxical reactions."
Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. NEJM. 1999 Feb 4;340:367-73.
"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]"
Lavie A et al. The bottleneck in AZT activation. Nature Medicine. 1997 Aug;3(8):922-4.
"[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]."
Kelleher AD et al. Immunological effects of antiretroviral and immune therapies for HIV. AIDS. 1997;Vol 11 (suppl A):S149-155.
"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]"
Retrovir. Canadian Pharmaceutical Association Compendium of Pharmaceuticals & Specialities. 1997;1357-61.
"[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]"
Retrovir. Physicians Desk Reference, Mosby-Year Book Inc.. 1996
"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"
Scott WF. The Delta Trial. Lancet. 1996;348(9036):1238.
"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."
Cohen J. Fulfilling Koch's Postulates. Science. 1994 Dec 9;266:1647.
"the efficacy of zidovudine in preventing HIV infection after initial exposure remains unproven"
Gostin LO, et al. HIV testing, counseling, and prophylaxis after sexual assault. JAMA. 1994;271(18):1436-44.
"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 cyomegalovirus disease, cytomegalovirus retinitis, candida esophagitis, and wasting syndrome"
Bacellar H, et al. Incidence of clinical AIDS conditions in a cohort of homosexual men with CD4+ cell counts < 100/cubic mm. JID. 1994;170:1284-7.
"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."
Sheppard HW et al. Viral burden and HIV disease. Nature. 1993 Jul 22;364(6435):291-2.
"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. The1749 participants were followed up for an average of 3 years. "
Press Release: Results from Concorde Trial of AZT vs. Placebo. Medical Research Council. 1993 Apr 2.
"Some HIV-infected individuals have remained healthy for more than 15 years following seroconversion. Lower numbers of CD4+ peripheral blood lymphoctyes 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."
National Institute of Allergy and Infectious Diseases State-of-the-Art Panel on Anti-Retroviral Therapy for Adult HIV-Infected Patients. Anti-retroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art conference. JAMA. 1993;270:2583-9.
"Doubts may be raised about the long-term beneficial effects of zidovudine treatment on AIDS-related cognitive impairments"
Reinvang I et al. Only temporary improvement in impaired neuropsychological function in AIDS patients treated with zidovudine. AIDS. 1991;5(2):228-9.
Increased Risk of Sickness and Death with AZT
"A total of 172 (96 Imm, 76 Def) participants died [169 while taking AZT, 3 while on 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 who were also members of the Coordinating Committee have declined to endorse this report."
Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet. April 9, 1994;343:871-881.
"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."
Phillips, et al. NEJM. 1997 Mar 27.
"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."
White IR et al. Impact of treatment changes on the interpretation of the Concorde trial. AIDS. 1997;11:999-1006.
"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."
Hogervorst E et al. Predictors for non- and slow progression in HIV type-1 infection: low viral RNA copy numbers in serum and maintenance of high HIV-1 p24-specific antibody levels. JID. 1995;171:811-21.
"Only 38% of the HLP [Healthy long-term positives] had ever used zidovudine [AZT] or other nucleoside analogues, compared with 94% of the progressors.
" Buchbinder S, et al. Long-term HIV-1 infection without immunologic progression. AIDS. 1994;8:1123.
"
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 can act as a mutagen"
Pluda , et al. Development of Non-Hodgkin Lymphoma in a Cohort of Patients with Severe Human Immunodeficiency Virus (HIV) Infection on Long-Term Antiretroviral Therapy. Ann Int Med. 1990;113:276-282.
Afterword
"Trevor Jones, director general of the Association of British Pharmaceutical Industries...remembers the dramatic identification of the virus that causes AIDS...'We weren't looking for AIDS drugs, we were looking for compounds that would hit the DNA of bacteria, and we had made hundreds of these compounds. When Luc Montagnier and Robert Gallo discovered that AIDS was due to this virus, we just opened up our store cupboards and said: these should work, because they will hit the RNA of the virus. And they did,' he said. 'Since DNA is a ubiquitous part of life, compounds that act against it can potentially stop life forms like bacteria, like viruses, like humans. Of course, they can cause cancer as well, so balancing the risks is an essential part of the fascination.' They settled on an anti cancer drug which had proved too toxic to use against cancer: it was AZT. It is now part of the cocktail of treatments that has changed life utterly for huge numbers of HIV positive people in the US and Europe.² [So, AZT was too toxic for short term use as chemotherapy, but perfectly acceptable for long term use against HIV!]"
Radford T. Tomorrow's pharmaceutical scientists will be part of the revolution. The Guardian. 2000 Mar 30;5.
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