Lack of Effectiveness and Toxicity of AZT

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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