AZT: Unsafe at Any Dose?

html. file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (2 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? “1 patient [out of a grand total of 10 in this clinical trial] suffered from severe anemia resulting from ZDV [AZT] therapy” Lafeuillade A et al. Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission. J Acquir Immune Defic Syndr. 2001 Jan 1;26(1):44-55. “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 [!] ” Levine AM et al. Prevalence and correlates of anemia in a large cohort of HIVinfected women: Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2001 Jan 1;26(1):28-35 . “Of variables related to HIV infection, low CD4+ cell count, AIDS diagnosis and receiving zidovudine [AZT] therapy were predictive for prevalent anemia ” van der Werf MJ et al. Prevalence, incidence and risk factors of anaemia in HIVpositive and HIV-negative drug users. Addiction. 2000 Mar;95(3):383-92. “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 May 28;13 (8):943-50. “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. “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] ” Moore RD et al. Long-term safety and efficacy of zidovudine in patients with file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (3 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? advanced human immunodeficiency virus disease. Zidovudine Epidemiology Study Group. Arch Intern Med. 1991 May;151(5):981-6. “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 lowdose 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. ” Fischl MA et al. A randomized controlled trial of a reduced daily dose of Zidovudine in patients with the Acquired Immunodeficiency Syndrome. N Engl J Med. 1990;323(15):1009-14. “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%).” Volberding PA et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med. 1990 Apr 5;322(14):941-9. “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. ” Creagh-Kirk T et al. Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program. JAMA. 1988 Nov 25;260(20):3009-15. “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;2 (8621):1195-6. “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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (4 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. ” Richman DD, Andrews J. Results of continued monitoring of participants in the placebo-controlled trial of zidovudine for serious human immunodeficiency virus infection. Am J Med. 1988 Aug 29;85(2A):208-13. “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 Jul;69(3):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 Jul;41(7):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. “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. N Engl J Med. 1988 Feb 25;318(8):516-7. “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). Ann Intern Med. 1987 Oct;107 (4):502-505 . file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (5 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? “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. N Engl J Med. 1987 Jul 23;317 (4):192-197. “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 ” Kolata G. Imminent marketing of AZT raises problems; marrow suppression hampers AZT use in AIDS victims. Science. 1987 Mar 20;235:1462-3. 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. “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. ” Sussman HE et al. Mutagenicity of AZT in the human lymphoblastoid cell line, TK6. 2nd National AIDS Malignancy Conference. 1998 Apr;94. “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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (6 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. “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 ” Meng TC et al. Combination therapy with recombinant human soluble CD4immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. J Acquir Immune Defic Syndr. 1995 Feb 1;8(2):152-60. “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 dosedependent manner ” Bacellar A et al. Temporal trends in the incidence of HIV-1 related neurological diseases: Multicenter AIDS cohort study. Neurology. 1994 Oct;44:1892-1900. “[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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (7 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. ” Tokars JI et al. Surveillance of HIV infection and zidovudine use among health care workers after occupational exposure to HIV-infected blood. The CDC Cooperative Needlestick Surveillance Group. Ann Intern Med. 1993 Jun 15;118 (12):913-9. “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 ” Van Leeuwen R et al. Failure to maintain high-dose treatment regimens during long-term use of zidovudine in patients with symptomatic Human Immunodeficiency Virus type 1 infection. Genitourin Med. 1990 Dec;66(6):418-22. “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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (8 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. “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 lowdose 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” Fischl MA et al. A randomized controlled trial of a reduced daily dose of Zidovudine in patients with the Acquired Immunodeficiency Syndrome. N Engl J Med. 1990;323(15):1009-14. “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.” Volberding PA et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med. 1990 Apr 5;322(14):941-9. “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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (9 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? inhibition results predominantly from termination of DNA chain elongation. ” Herzlich BC et al. Synergy of inhibition of DNA synthesis in human bone marrow by azidothymidine plus deficiency of folate and/or vitamin B12?. Am J Hematol. 1990 Mar;33(3):177-83. “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 Nov 3;262(17):2405-10. “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. “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. file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (10 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? “[adverse reactions] reported were one case of Stevens-Johnson syndrome in a severely atopic [allergic] patient and 32 reports of seizures. ” Creagh-Kirk T et al. Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program. JAMA. 1988 Nov 25;260(20):3009-15. “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 ” Ayers KM. Preclinical toxicology of zidovudine. An overview. Am J Med. 1988 Aug 29;85(2A):186-8. 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. “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 ” Lewis W et al. Cardiac Dysfunction occurs in the HIV-1 transgenic mouse treated with Zidovudine. Lab Invest. 2000 Feb;80(2):187-97. “Myopathy [muscle damage] in long-term therapy with ZDV [AZT] due to mitochondrial damage has been described by several investigators” Brinkman K et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as a common pathway. AIDS. 1998 Oct 1;12(14):1735-44. “AZT seemed to be the most potent inhibitor of cell proliferation [cell killer]...AZT, ddi and ddC [all nuceloside analogs] all exert cytotoxic [cell killing] effects on human muscle cells and induce functional alterations of mitochondria due to mechanisms other than the sole mtDNA [mitochondrial DNA] depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy [muscle damage] in HIVinfected patients.” file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (11 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? Benbrik E et al. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC) on cultured human muscle cells. J Neurol Sci. 1997 Jul;149(1):19-25. “Although the association of AZT with decreased cardiac contractility [cardiomyopathy=heart muscle damage] has been debated, our data indicates a strong correlation between treatment with AZT and the development of a decrease in left ventricular performance in children with HIV infection. The fact that 17 of the 19 patients in the study in whom cardiomyopathy developed had received AZT suggests that the observed decreases in left ventricular performance could have had clinical consequences...AZT withdrawal should be considered in any child in whom cardiomyopathy develops” Domanski MJ et al. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus. J Pediatr. 1995 Jul;127(1):137-46 . “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 [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 ” 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% of patients), elevated serum creatine kinase levels (in up to 15%), and muscle weakness. These file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (12 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. N Engl J Med. 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 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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (13 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. N Engl J Med. 1988 Mar 17;708. 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. “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 humanequivalent 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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (14 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. ” Olivero OA et al. Transplacental Genotoxicity of Combined Antiretroviral Nucleoside Analogue Therapy in Erythrocebus patas Monkeys. J Acquir Immune Defic Syndr. 2002 Apr 1;29(4):323-9. “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 threeto 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. ” 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 Retro. 2000 May 1;16(7):645-44. “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 2to 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 ” Diwan BA et al. Transplacental carcinogenicity of 3'-azido-3'-deoxythmidine (AZT) in mice. Proc Am Assoc Cancer Res. 1998;39:21. file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (15 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? “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 Immune Defic Syndr. 1998 May 1;18(1):27-38. “At 1 year of age, the offspring of AZT-treated mice exhibited statistically significant, dosedependent 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 ” 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. “At 1 year of age, the offspring of AZT-treated mice exhibited statistically significant, dosedependent 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. ” 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. J Acquir Immune Defic Syndr. 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 file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (16 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? 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. “It previously has been demonstrated that zidovudine (AZT) is lethal to early murine [mouse] embryos. The effect of the drug on preand 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 lowconcentration (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. ” Toltzis P et al. Effect of zidovudine on preimplantation murine embryos. Antimicrob Agents Chemother. 1993 Aug;37(8):1610-3. “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. file:///Users/dad/Documents/Green/AIDS/ARAS/aras.ab.ca ƒ/test/azt-integrated.html (17 of 45)3/27/2006 6:16:14 PM AZT: Unsafe at Any Dose? “The most consistent hematologic effect from treatment with AZT [in mice] was a poorly regenerative, macrocytic anemia ” Luster MI et al. Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection. Int J Immunopharmacol. 1991;13 Suppl 1(Suppl 1):99-107. “[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. Antimicrob Agents Chemother. 1990 Apr;34(4):637-641. “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] ” Ayers KM. Preclinical toxicology of zidovudine. An overview. Am J Med. 1988 Aug 29;85(2A):186-8.