Pre-exposure prophylaxis: A flawed clinical trial that no one should take seriously
Posted by Henry Bauer on 2010/11/29
“Daily AIDS drug lowers risk of HIV, study finds” (David Brown, Washington Post, 24 November, 2010), is how the media ballyhooed a study that is not worth the paper it was printed on (or will be printed on, since it had only been released on-line).
“When gay men at high risk of becoming infected with HIV through sex take a daily dose of antiretroviral drugs, their chance of catching the virus drops by at least 40 percent, according to a new study. The protective benefit could be as high as 95 percent if a person is extremely attentive about not missing a dose, the research on nearly 2,500 men on four continents found.”
But the protective effect could also be as little as zero, even if no dose is ever missed, because the details of this study inspire no confidence at all. The on-line publication was available as of 28 November 2010 at http://www.nejm.org, together with a Supplementary Appendix that contains further details.
As usual, there are general reasons for skepticism: No single publication or study should ever be accepted at face value (“Real science isn’t news”); and the statistical criteria used, p<0.05, may greatly overstate the significance of the results (Matthews, “Significance Levels for the Assessment of Anomalous Phenomena”). But there are also some very specific reasons for not taking this work seriously: the subjects of the study were rather sick people leading highly unhealthy life-styles.
The median age of these men (including some transgendered former men) was about 25 (data in Figure 3). A little over half of them had more than 5 drinks in any given day on which they drank. 1 in every 7 or 8 reacted positive on a syphilis test, and more than a third did so for herpes. Unprotected anal intercourse in the last 3 months was acknowledged by 60% of them, and in the last 6 months by 80%. And 40% reported “transactional sex” during the last 6 months. It is unconscionable to suggest, as the report does, that this group might be representative of “men who have sex with men”. It is representative only of people who work at least occasionally as male prostitutes and who behave in ways conducive to poor health and high risk of all sorts of infection.
Furthermore, a few exceptionally promiscuous subjects might well have had a disproportionate influence on the overall results: Table 1 reports the number of partners in the last 12 weeks as 18±35 and 18±43 for treated and placebo groups respectively, indicating that a few individuals are clear outliers. The same is suggested by Figure S2, where for most of the study period the mean number of partners with whom subjects had receptive anal intercourse was between 4 and 6 while the median was only 1; in anything approaching a normal distribution, mean and median are close to one another (in a truly normal distribution they are identical).
The poor state of health is illustrated by the fact that in both placebo and treated arms more than 1 in 20 of these young men, median age 25, suffered a “serious adverse event” during the median follow-up time of 1.2 years: “Serious adverse events (SAEs) were defined in accordance with the ICH, as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity”. This is anything but representative of 25-year-old gay men.
Nor were these “Serious” adverse events the only signs of a sick population. Table 2 has about 1 in 8, again in both placebo and treated arms, suffering a grade 3 or 4 event, defined by the Division of AIDS as:
Grade 3 — Severe — Symptoms causing inability to perform usual social & functional activities
Grade 4 — potentially life-threatening — Symptoms causing inability to perform basic self-care functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death.
My attempts to determine whether “serious” adverse events in Table 2 included the Grade 4 events was unsuccessful because the detailed information in the Supplement delivered numbers that do not match those in Table 2, presumably because the former omitted events experienced by no more than 25 subjects. Since they are reported separately here, it seems that 17-18% of these young men fell seriously ill in not much more than a year. This is not typical of 25-year-old gay men.
Testing for “HIV-positive” involved two positive rapid tests plus a “confirming” Western Blot or “HIV” RNA. Please recall that Weiss & Cowan have stated, and explained why, neither Western Blot nor PCR nor any other “HIV” test “confirms” infection (“HIV” tests are self-fulfilling prophecies, 10 May 2009).
Even on its own terms, this article contradicts HIV/AIDS theory: Figure S4 shows “HIV RNA level” declining slightly during the first month after seroconversion and then remaining unchanged for as much as 60 months in both placebo and the group treated with ARVs; and the CD4 counts were also essentially the same for those 60 months in both treated and untreated groups. Moreover, “Plasma RNA level was not lower in those reporting higher pill use or in the 3 seroconverters with detectable drug levels” (Supplement, p. 18) — no antiretroviral effect of the antiretroviral drugs, in other words.
So there are ample specific grounds for distrusting the conclusions offered by the authors of this study. Beyond that, there are ample general grounds for never recommending any existing antiretroviral drugs for “pre-exposure prophylaxis”, because that involves administering highly toxic agents to perfectly healthy people. Even this study notes that “Side effects may have contributed to low pill use among some subjects” and “TDF [tenofovir disoproxil fumarate] treatment is known to cause decreases in renal function” — yes indeed, see “Kidney-disease denialism (a special case of HAART denialism)”, 2010/11/20.
The mainstream promulgates such shibboleths as condoms and circumcision being effective in prevention, and HAART being life-saving, even as the actual data in published studies offer as much evidence against these beliefs as for them. One finds acknowledgment that the shibboleths are baseless only when it suits the mainstream to tout some new approach or to repeat the need for more research. Thus here it is admitted, in the context of hyping the present study, that prevention approaches have been singularly unsuccessful:
“Few concepts for the prevention of sexual HIV transmission have been rigorously proven: of 37 late-phase trials, only 6 have demonstrated a significant protective benefit. [1,2] Tenofovir 1% vaginal gel had 39% efficacy in heterosexual women.  All other successful prevention interventions were clinic-based and directly observed, including enhanced services for sexually transmitted infections (STIs),  male circumcision, [4-6] and a vaccine candidate.  None of the successful interventions are known to be effective in men and transgender women who have sex with men (MSM), who carry a major burden of the global epidemic. [8,9]” (Supplement, p. 6).
This entry was posted on 2010/11/29 at 11:31 am and is filed under antiretroviral drugs, clinical trials, HIV risk groups, uncritical media. Tagged: pre-exposure prophylaxis against HIV. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.