AIDS Drug Effectiveness: "Best Evidence" Debunked

DeeTee6 said at http://forums.about.com/innocuous/messages?msg=90.18

"Perhaps you will accept a study of 1142 children from Italy as evidence for the efficacy of therapy? Somehow I doubt it, but here it is anyway:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10889592&dopt=Abstract

To point out the crucial finding, it states that the risk of death in children when receiving monotherapy, double, or triple combination therapy was 23%, 30%, and 71% lower, respectively, compared to no antiretroviral therapy at all."

Perhaps you will accept it as evidence for the inefficacy of therapy?

"To point out the crucial finding, it states that the risk of death in children when receiving monotherapy, double, or triple combination therapy was 23%, 30%, and 71% lower, respectively, compared to no antiretroviral therapy at all."

My first impression here was that you were confusing the phrases "crucial finding" and "bullshit statistical analysis". Having now read the whole paper I am confirmed in my opinion that you have indeed sacrificed your critical faculties to your profound faith in HIV and the gloss-over techno-twaddle it generates.

The first thing that strikes me about this study is that although the data collected purports to represent all HIV positive Italian children born from 1980 to 1997 it cannot do so, if only because data collection did not start until 1985:

"Data were provided by the Italian Register for HIV Infection in Children, which is involved with a nationwide multicenter study, instituted in 1985 by the Italian Association of Pediatrics, of children perinatally exposed to HIV. Data collection started on June 1, 1985;"

By 1992 60% were on monotherapy by which time 76% of the total 1142 were involved in the study. Only 10% of the total 1142 were retrospectively included in the study by 1985 and 3 years later 20% were on monotherapy. The antiretroviral-free numbers and time periods are not sufficient to draw conclusions.

There is no drug-free control group in this study. It does not present us with any actual survival times or relate these times to drug-free and drug using periods. It does not tell us how many healthy children were put on the antiretrovirals purely because of technological measures such as CD4 count or "hit hard, hit early". What we have instead of tangible survival times are statistical estimates called "cumulative survival probability" and "relative hazard of death" the latter calculated by including pre-existing data on the survival-related effects of AIDS drugs! The possible importance of non-HIV dependent factors in this study is of course not entertained at all. Note that, while antiretroviral free and presumably healthy, the children were given Septrin as PCP prophylaxis. This would not of course be done to HIV negative children.

Rather than proclaim any "crucial findings" the authors are a little more tempered:

"Compared with nontreated children, the adjusted RH for those who had received monotherapy and double combination therapy was lower than 1.0, but the difference was not statistically significant"

"The incremental protective effect of therapy was also evident, in that the risk of death decreased by 30% for double combination therapy (although statistically nonsignificant)"

Despite their phrasing, the authors admit their statistical data has no significance.

"it is possible that the insufficient period of observation (the introduction of the double combination therapy was rapidly followed by that of triple combination therapy) led to our study having limited statistical power."

My personal preference leans towards "useless" rather than "limited statistical power".

"Finally, the estimated decrease in the risk of death since 1996 disappeared after adjusting for type of therapy, suggesting a causal relationship between decreased risk of death and use of combination therapy."

This is meaningless to any rational person but an article of faith to you. The adjustment here is from a comparison of drugs with drugs not drugs with no drugs.

The authors fail to justify why their reference data should be data from the particular years 1980 to 1989. By 1989 30% were on monotherapy.

By the way, here is another abstract based on the same Italian registry of HIV infected children:

http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10371173

"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);"

Only in the mind of an AIDS Inc. drone is there no incompatability between this and the study you cite.


Dr David Rasnick's comments on this same study:

http://bmj.com/cgi/eletters/326/7381/126/e#29889

Dear Editor,

Peter Flegg says that I fail "to understand what is an appropriate study to demonstrate clinical efficacy of a drug. I will say again, a phase I/II safety/tolerability study is not designed to look at efficacy. The fact that Rasnick fails to acknowledge this fact, and that he persists in misrepresenting the trial data speaks volumes." I understand completely the purposes of the three phases of clinical trials. However, I can only work with what has been published. I could not find (nor has Flegg cited) a completed or even partial phase III clinical trial on the efficacy of anti-HIV drugs in children. I ask Flegg: Where is that study? Where is the phase III clinical trial that demonstrated that children taking the anti-HIV drugs live longer or at least healthier lives than a similar group of HIV-positive children not taking the drugs?

Failing to take his own advice, Flegg offers not a phase III, nor even a phase I/II study, to argue for the life-saving benefits of the anti-HIV drugs for children. Instead, the best he has come up with is an observational study that spans 17 years (1980-1997) of the AIDS epidemic in Italy [1]. Flegg says that, "This longitudinal cohort study of HIV in 1142 children demonstrated clearly that survival improved with HIV therapy. In fact, the more drugs in combination that children took, the better their prognosis (a finding that drives a horse and cart through the dissidents' assertions that the drugs do harm). The relative hazard of death declined with each extra drug added into the combination as compared with no therapy (RH 0.29 for triple therapy)."

I have already provided ample evidence in the literature that the anti-HIV drugs do considerable harm. The task now is to show, if possible, that there are life-saving and other real clinical benefits of the drugs that out weigh their well documented risks. With that in mind, let's take a closer look at the de Martino et al. observational study that spans a period that spawned four definitions of AIDS.

A decisive argument against this study proving any clinical benefit whatever is that it was not a clinical trial designed to detect potential clinical benefits of the drugs. A crucial point is that the authors did not compare during the same period similar groups of children taking the drugs and placebo. Instead, the authors used the trick commonly employed by an AIDS establishment desperate to justify claims that the anti-HIV drugs do more good than harm. They compared the outcomes of three arbitrary groupings of patients from different periods of the epidemic. This approach is highly deceptive and is at best bad science. The authors state that, "The [survival] estimates were calculated for birth cohort and calendar period and grouped according to the distribution of predominant type of antiretroviral therapy administered over time (in part reflecting availability): 1980-1989 (reference group), 1990- 1995, and 1996-1998 (1996-1997 only for birth cohort because those born later were excluded from this analysis)" [1]. I use the following parable to make clear the fallacy in the approach taken by de Martino et al.

By arbitrarily comparing different periods of the epidemic one could propose all sorts of nonsensical explanations for observed correlations. For example, from 1980 to 1992, Republicans held the presidency in the USA. This was the same period when AIDS began in the USA and slowly increased to its peak in 1992 (see cover of reference [2]). But, in 1992, a Democrat was elected president and the AIDS epidemic immediately began to decline and continued to do so through 2000, the end of Clinton's last term in office. Ominously for this scenario, a Republican now occupies the Whitehouse. It is still too soon to tell if there will be a rebound in AIDS as a consequence.

Even though this farcical scenario is completely consistent with the data, and shows a perfect correlation between political party and direction of the AIDS epidemic, one would be foolish to conclude, without further, more compelling evidence, that Republican presidents promote AIDS while Democrats retard the epidemic. Yet, in an analogous scenario we are encouraged to accept a shaky (certainly unproved) explanation for a much poorer correlation (almost no correlation, as shown below) between survival of HIV-positive children and various periods in which different antiretroviral drugs and combinations were in fashion.

Table 1 from the de Martino study shows that the number of HIV- positive children reached a plateau from 1985 to 1992 and has since declined steadily. This trend reflects the peaks in the various AIDS epidemics for adults and children that were seen between the late 1980s up to about 1995 all across Europe and the USA (see especially Fig. 3 on page 43 of reference [3]).

In contrast with Flegg's assertions about what the de Martino et al. study showed, the authors state that, "The probability of survival did not significantly differ between the 1980-1989 and 1990-1995 birth cohorts (P=.15), whereas it was significantly higher for the 1996-1997 birth cohort... In evaluation of the calendar period effect..., the cumulative probability of survival did not significantly differ between children at risk in 1980-1989 and 1990-1995 (P= .75), whereas probability of survival was significantly higher for 1996-1998...". The authors attributed the reduction in the mortality of the 1996-1997 cohort and the 1996-1998 calendar period to the introduction of triple combination antiretroviral cocktails, some of which included the protease inhibitors or a nonnucleoside reverse transcriptase inhibitor. But, Table 2 of the same paper seems to erase the prospect that triple combination therapy prolonged the lives of the Italian children. It shows that there was no significant reduction in the adjusted relative hazards of death of the children regardless of birth cohort or calendar period. Such shaky evidence is not nearly as convincing to me as it apparently is to Flegg.

Even if one uncritically accepts the validity of the seriously flawed de Martino et al. study, its own results clearly do not show any beneficial effect on survival of the children who went from no drugs to one anti-HIV drug, then two DNA-chain terminators, followed by multiple combinations of two antiretroviral drugs. Yet we are somehow expected to accept the magic number of three life- saving antiretroviral drugs even though the evidence for them is only two to three years old, compared to 9 years of evidence of no life-saving benefits for one or various combinations of two drugs.

The authors conclude that, "Our study shows that although the survival of HIV-infected children in Italy remained unchanged up to 1995, it has significantly improved since 1996, with a more than 30% reduction in the adjusted risk of death for children at risk in the period 1996-1998 vs those at risk in the period 1980-1989." But, since the authors state that, "57% of children were born to a mother who was an injecting drug user or sexual partner of an injecting drug user", there may be another explanation that the authors did not consider. Were the children born to iv drug using mothers equally distributed over the 17-year period under consideration? Perhaps there were more such children in the 1980-1989 and 1990-1995 periods compared to the 1996-1998 period. If so, this could explain the reduced mortality in 1996-1998. Almost any explanation is possible with an observational study that spans 17 years, 4 definitions of AIDS, numerous changes in therapies and heads of state.

Referring almost in passing to another study, Flegg says that McSherry et al. showed that "26% of placebo-children progress[ed] to AIDS compared with 14% of zidovudine-exposed children. The actual numbers are small and immaterial in the context of this discussion (even though they support my contention) [4]." Then why bring it up? Nevertheless, here's how McSherry et al. summed up their results that Flegg says support his contention. "In this limited study, zidovudine therapy during pregnancy and labor and in the neonatal period for 6 weeks failed to have a major effect on rapid progression of disease, timing of transmission, and viral replication in HIV-infected infants." Given that conclusion, I say that the results of the McSherry et al. study better support my contention than his.

David Rasnick

References

1. de Martino, M., et al. (2000) Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. Italian Register for HIV Infection in Children and the Italian National AIDS Registry, Jama 284, 190-197

2. Centers for Disease Control and Prevention. (1997) U.S. HIV and AIDS cases reported through December 1997; Year-end edition, 9, 1-43

3. European Centre for the Epidemiological Monitoring of AIDS. (2002) HIV/AIDS Surveillance in Europe: End-year report 2001, No. 66, Saint-Maurice: Institut de Veille Sanitaire

4. McSherry, G. D., et al. (1999) The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type- 1 (Pediatric AIDS Clinical Trials Group Protocol 076), J Pediatr 134, 717-724