HAART is toxic: Mainstream concedes it, in backhanded ways

Just as it’s rare to find “HIV” mentioned without the add-on of “AIDS” or “the virus that causes AIDS”, so it’s rare to see antiretroviral drugs mentioned without the adjective “life-saving”. Yet the technical mainstream literature is replete with backhanded admissions that antiretroviral drugs are highly toxic.
What do I mean by backhanded? Making the admission in such a way that it seems like not an admission.
For example, in what the Journal of Infectious Diseases  labeled a “Major Article”, Walensky et al. calculated “The survival benefits of AIDS treatment in the United States” (194 [2006] 11-19) without claiming any survival benefit for the use of AZT from its introduction up to its approval in 1994 for prevention of mother-to-child transmission. Yet when mainstream researchers are confronted with dissident statements about the lack of life-saving benefit of AZT and its toxicity, they resist ferociously by every conceivable evasive maneuver.

I’ve just come across another choice example of admitting in one context what in other contexts is not admitted. The activist gurus of the Treatment Action Campaign (TAC) have long castigated President Mbeki and others for not providing the life-saving benefits of antiretroviral drugs to South Africans. But now the very same self-appointed experts, in collaboration with Médecins Sans Frontières (MSF) have asked the Gates Foundation  not to support a clinical trial in which the relative benefits of tenofovir are to be compared with stavudine at 20 mg dosage — because stavudine is so toxic!
Mbeki was President of South Africa from 1999 to 2008. Had he bowed to TAC activists, he would have been providing this highly toxic stavudine to his fellow country-people, because stavudine has been one of the staples of antiretroviral treatment since the mid-1990s. It was approved for adults in the middle of 1994, and for children in the latter part of 1996. In 1998 it was recommended for antiretroviral treatment at dosage of  40 mg for body weights > 60 kg and 30 mg for <60 kg (MMWR 47, RR-5, 24 April). The Treatment Guidelines issued by the National Institutes of Health have sanctioned use of stavudine as first-line or alternative ever since, despite the pleas by the World Health Organization cited  in the TAC/MSF letter to the Gates Foundation.
The letter says, “In 2004, stavudine was removed from the list of preferred first-line antiretroviral drugs recommended by the US Department of Health and Human Services”. That might mislead unwary readers into thinking that stavudine had been removed from all recommended uses, whereas in fact it continues to be listed in the Treatment Guidelines as an available alternative. Thus the Guidelines of 1 December 2009 include the following:
“The 2NN trial compared efavirenz and nevirapine, both given with stavudine and lamivudine, in treatment-naïve  patients. Virologic responses were similar for both drugs, although nevirapine was associated with greater toxicity and  did not meet criteria for noninferiority compared with efavirenz”, illustrating that stavudine was by no means regarded as beyond the pale.
Note too the mention of toxicity of nevirapine. Dissidents have long protested the use of nevirapine and AZT as the standard procedure recommended to avoid mother-to-child prevention of transmission of “HIV”, whereas vigilantes like the TAC gurus have consistently supported these uses of these drugs — see for example “Nevirapine, TB, and HIV/AIDS”  and “Nevirapine — P.S.”
Of course the Treatment Guidelines do acknowledge the toxicity of stavudine:

— at least in combination with lamivudine. But “Not recommended as initial therapy [emphasis added]” is not at all the same as “Should not be used”.
The 2009 Guidelines also warn that “combined use of didanosine and stavudine as a dual-NRTI backbone can result in a  high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis . . . . This  combination has been implicated in several deaths of HIV-infected pregnant women secondary to severe lactic acidosis  with or without hepatic steatosis and pancreatitis . . . . Therefore, the combined use of didanosine and stavudine is not recommended”. Again, “not recommended” is not synonymous with “should not be used”.
Furthermore, “NRTI Substitutions (e.g., changing from zidovudine or stavudine to tenofovir or abacavir): This may be considered for a patient who has no history of viral resistance on an NRTI-containing regimen” (p. 74) illustrates that both zidovudine (= AZT) and stavudine continued, in 2009, to be standard components of antiretroviral cocktails.
Beyond that, the dangerous combination of didanosine and stavudine continues to be recommended as a possible last resort:

or if patients already have renal or hepatic insufficiency (= kidney or liver disease):

Perhaps the reasoning is that they’re dying anyway, maybe the stavudine will help them along?

So by 2009 there were certain caveats to the use of stavudine, by contrast to the “strong recommendations” for its use in earlier years, even in the deadly combination with didanosine:
In February 2001, the Treatment Guidelines “strongly recommended” stavudine “for initial treatment of established HIV infection”, in combination with “didanosine or lamivudine plus efavirenz or indinavir”.
Again in July 2003, The “Recommended Combination  Antiretroviral Regimens” included  “Efavirenz + (zidovudine or tenofovir or stavudine)  + lamivudine as preferred initial NNRTI-based  regimens (except for pregnant women)”.
In  October 2005, it was downgraded to ordinary, not strongly recommended:
“NNRTI-Based Regimens —  Efavirenz + (didanosine or abacavir or stavudine) + (lamivudine or emtricitabine) (except during pregnancy, particularly the first trimester, or in women  with high pregnancy potential)”. However, it was still lauded for efficacy: “The most experience with efavirenz, demonstrating  good virologic responses, has been shown in  combination with 2-NRTI backbones of lamivudine plus zidovudine, tenofovir, stavudine, abacavir, or  didanosine”. “Alternative PI-based regimens may include: . . . all used in  combination with zidovudine or stavudine or  tenofovir . . .”.
For “Selection of Dual Nucleoside ‘Backbone’  as Part of Initial Combination Therapy” the recommendation was “(Zidovudine or tenofovir) + (lamivudine or emtricitabine) as the 2-NRTI backbone of choice  as part of some combination regimens. . . . (Stavudine or didanosine or abacavir) + (lamivudine or emtricitabine) may be used as  alternative 2-NRTI backbone combinations”.
“It may be necessary to prescribe alternative NRTIs for some patients because of side effects of these agents, such as bone marrow  suppression with zidovudine and the increasingly reported toxicities including lipoatrophy and  symptomatic lactic acidosis with stavudine”.
A backhanded admission that AZT/ZDV suppresses the bone marrow — an admission that was not made, of course, when Duesberg said it and pointed out that this kills the immune system, so that the drugs produce the very disease they are supposed to treat.
Given the acknowledged toxicities, why are antiretroviral drugs continuing to be administered?
Because of  their supposed effectiveness — effective in lowering “viral load”, that is: “Both the tenofovir + lamivudine combination and stavudine + lamivudine combination  are highly and durably effective when used in  combination with efavirenz, with data up to 144 weeks . . . .  In this study, patients randomized to the stavudine + lamivudine arm experienced more adverse effects including peripheral neuropathy and  hyperlipidemia”.  “The combined use of didanosine and stavudine as a 2-NRTI backbone can  result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis . . . .This combination has been implicated in  several deaths in HIV-1 infected pregnant women  secondary to severe lactic acidosis with or without hepatic steatosis and pancreatitis . . . . In general, a  combination containing didanosine and stavudine should be avoided unless other 2-NRTI combinations have failed or have caused unacceptable toxicities, and where potential benefits outweigh the risks of toxicities”.
“Avoided unless” once again falls far short of condemning the use.
Evidently the “operation” is a success if it kills “HIV”, even if the patient also dies in the process.
Note the shameless evasion or disclaiming of responsibility in weasel-expressions like “where potential benefits outweigh the risks of toxicities”. How might one practice that? By spelling out what the risks actually are and what the benefits are supposed to be — what are the odds ratios? For absolute risk and absolute benefit? Does anyone do that for patients?
Note too that “not recommended” is the Treatment Guidelines’ backhanded way of acknowledging dangerous toxicity. Stavudine went from “strongly recommended” merely to “not recommended” and “alternative” when other things don’t seem to work. Yet the TAC/MSF letter cites copious evidence that stavudine is so toxic that it shouldn’t be used even at half the original dosage, even in a clinical trial where incipient adverse events would be closely monitored. That’s because “For good reason, tenofovir has become the gold standard for today’s first-line antiretroviral  therapy”.
That surprised me, since I had blogged about the toxicity of tenofovir already 4 years ago: “To avoid HIV later, damage your kidneys and liver now”; “Tenofovir and the ethics of clinical trials”; “Kidney-disease denialism (a special case of HAART denialism)”: “increasing exposure to tenofovir was associated with a higher incidence of CKD [chronic kidney disease] . . . . Nephrolithiasis was seen in up to 27% of patients treated with indinavir . . . and there are numerous studies . . . demonstrating that tenofovir is associated with impaired kidney function”.

Not that I claim to have discovered the toxicity of tenofovir — it’s noted in government sources:

as well as by the manufacturers:

To summarize:
Stavudine was highly recommended for antiretroviral treatment for about a decade and is still in use, though it was soon found to be so toxic that TAC/MSF describes it as unacceptably toxic — by comparison to tenofovir, which has been known for years to cause serious liver damage  and lactic acidosis, both potentially fatal. But then, as noted in the manufacturer’s warning above, these toxicities are associated with all nucleoside analogues (NRTIs).

How many people were killed or maimed by stavudine during the decade or so when it was strongly recommended and used routinely?

TAC/MSF are correct: “There is therefore no good reason why a properly  informed patient should want to enrol in this study” [of tenofovir vs. 20 mg stavudine]. But they ought to have made that more general:

A properly informed “HIV-positive” patient
would refuse antiretroviral drugs altogether.

The TAC/MSF letter stretches over 4 pages and is a cornucopia of other deficiencies. To support their claim of tenofovir’s superiority, for instance, they cite an article just published “ahead of print” — when anyone who understands science knows that no just-published claim is to be taken seriously until others have confirmed it. The letter refers to the “Serious adverse event” of mitochondrial toxicity, without acknowledging that this serious adverse event is characteristic of ALL antiretroviral drugs. That’s been known for a long time: “Hidden in plain sight: The damage done by antiretroviral drugs”.

I’m left with a curiosity about the social psychology of all this. What could stimulate this group of people to compose so pompous and unwieldy a petition whose only purpose is to give preference to one highly toxic drug over another highly toxic drug?
I think this illustrates how addled brains become when they have been so indoctrinated as to lose the ability to weigh the actual evidence.
Or, as I’ve mused before, behold what cognitive dissonance does to true believers.

Tenofovir and the ethics of clinical trials

It seems to me hare-brained, or worse, to attempt to prevent “HIV infection” with the same drugs with the same dangerous “side”-effects as would be used to treat the actual illness IF one ever became “infected”; and being “infected”, IF illness actually ensued after an average of 10 years of symptom-free existence. So the clinical trials of tenofovir for “PreP (pre-exposure prophylaxis for HIV prevention)” appear to me to be thoroughly misguided. After all, over the years there have been various initiatives for treatments to be interrupted periodically precisely because of those “side” effects that many patients simply can’t tolerate; and, for that reason, every now and again the mainstream view has swung back to deferring treatment as long as possible.

Nevertheless, the obsession with antiretroviral drugs continues. In how many clinical trials, would you guess, does tenofovir feature, for treatment or for prophylaxis?

The information is on-line. For tenofovir, there are listed 118 clinical trials (including not yet recruiting, recruiting, active & not recruiting, completed, and one each withdrawn and enrolling by invitation only)  .

The most troubling aspect of clinical trials, of course, is that they are experiments on human beings. Therefore common sense and decency suggest that the conceivable benefits from the knowledge possibly gained should outweigh indisputably the dangers to which the human guinea-pigs are exposed. A seemingly obvious corollary is that all potential human guinea-pigs should be informed in the most complete and honest possible manner about the dangers they would expose themselves to, as well as the possible benefits to them and to humankind at large.

In First-World countries, these considerations have led to regulations that make clinical trials increasingly onerous and expensive, and clinical trials are more and more frequently carried out in places where the regulations are not quite so protective of the potential guinea-pigs. Thus it becomes possible in Africa to do experiments to find out whether the tiny cost of feeding malnourished people is a useful adjunct to very expensive antiretroviral treatment [Drugs or food?, 25 December 2007 ; Food is good for children, 8 January 2008 ], or whether the minimal cost of de-worming children helps to slow the spread of “HIV infection” or progression to AIDS better than just those very expensive antiretroviral drugs[Are intestinal worms good for us? Are they good for Africans? For African children?, 30 December 2007 ; Parasitic worms are *not* good for you!, 24 July 2008 ].

Occasionally, though, some troublemakers who are not even AIDS Rethinkers or HIV Skeptics draw attention to rather unsatisfactory circumstances in clinical trials outside First-World countries. Thus certain proposed trials of tenofovir for PreP among prostitutes had been called off :
“activist groups, including Act Up-Paris have ‘halted the progress of at least two important clinical trials of tenofovir as PREP and brought negative attention to tenofovir, somewhat similar to that visited on thalidomide more than four decades ago,’ say two researchers in an essay in the open access global health journal PLoS Medicine” [that essay is Singh JA, Mills EJ (2005). The abandoned trials of pre-exposure prophylaxis for HIV: What went wrong? PLoS Med 2(9): e234].
“But Jerome Singh, of the Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, and Edward Mills of the Department of Clinical Epidemiology and Biostatistics, McMaster University, Canada, argue that ‘if tenofovir is someday proven to be clinically efficacious as a PREP, today’s irresponsible reporting and activism surrounding tenofovir could cause those in need to snub the drug if, or when, it becomes licensed for use as a PREP.’”

That concern was underscored by “Joep Lange, who was the President of the International AIDS Society at the time . . . . ‘Activist groups have now managed to derail several PREP trials, arguably the most important studies for those at high risk of acquiring HIV infection around the globe.’ Lange is highly critical of the tactics used by those who have managed to shut down the PREP trials. ‘The methods of these specific activist groups,’ he says, ‘are uninformed demagogy, intimidation, and ‘AIDS Exceptionalism’, the last in the sense that they exploit their HIV-positive status to get away with behavior that would not be accepted from others.’”

What was that “uninformed demagogy” and “intimidation” displayed by, for example, Act-UP Paris? Here it is:

“the end justifies the means?

The trial conducted by FHI in Cameroon, Nigeria and Ghana, financed by BBG with the logistic support of Gilead does not seem to us to provide a satisfactory response to all our questions. Provision for psychosocial support and the means implemented to promote condom use are clearly insufficient, even ridiculous: only 5 counselors and one doctor for 400 prostitutes, no access to the female condom, despite it being much easier for the prostitutes to use in negotiating with their clients. However, scientifically speaking, cases of contamination are ‘needed’ for the trial results to be ‘interesting’.
If all precautions were taken with regard to prevention and supervision, it is certain that the trial would have to recruit a much larger study population so that a difference in contamination rates between the placebo and tenofovir groups would be statistically significant. . . .
The heart of the dossier is not so much an ethical/scientific conflict, as an ethical/economic duel. In this sense also, if recruitment for the trial did not target a population already ‘forced’ to take risks, it would be necessary to considerably increase the number of participants and consequently the cost of the trial… By holding this trial in Africa, Gilead and the BBG Foundation know that they will find a population that is vulnerable both materially and in terms of practices, women willing to let them carry out a trial at minimal cost. It is then, really a question of money . . . .

when hypocrisy rhyme with economy

The tenofovir DF trial expects to provide follow-up and access to treatment for sexually transmitted diseases (STD). This plan may appear generous. In fact, it is nothing more than a means of building the prostitutes’ loyalty and minimizing the risks of their dropping out. Moreover, it so happens that follow-up tests are required for the scientific validation of the trial. Setting the amount allowed for expenses at 2,750 Fcfa shows an extraordinary level of cynicism. In fact, a rapid calculation shows us that this amount was figured to cover transportation expenses on the one hand (500 F for the taxi) and the prostitutes’ lost income on the other hand (2,150 F for two tricks, minimal fee in Douala).
What will happen to prostitutes who are found to HIV-positive during pre-enrolment testing? We don’t know, but we can imagine. In Cameroon, the promoter plans to refer women who become HIV-positive during the trial to the system of access to care and treatments set up in this country by NGOs and the government. While it is true that in Cameroon, treatment access is less difficult than in other African countries, it remains uncertain. It is estimated that one million people are infected with HIV, i.e. a prevalence of 15% (according to all of our interlocutors, this figure is an underestimate), and that 40,000 people are in urgent need of antiretrovirals (currently only 10, 000 are under treatment). It is therefore particularly shameful that Gilead; which is donating the tenofovir and placebo for the trial has not also arranged to provide free antiretrovirals to participants who need them.
. . .
In the future; the design of this type of trial must be discussed with the patient associations in the host country. We hold Gilead and the BBG Foundation responsible for the lives of the women included in the trial.”

Those words from Act-UP Paris may be strong, but they are hardly “uninformed demagogy” or “intimidation”. And it isn’t only in Africa, and it’s not only AIDS activists who object; similar ventures in Thailand brought criticism from Doctors Without Frontiers, who also contradict Joep Lange’s assertions [Chua et al., The Tenofovir Pre-Exposure Prophylaxis Trial in Thailand: Researchers Should Show More Openness in Their Engagement with the Community, PLoS Med. 2005 October; 2(10): e346]:

“The key community groups that have expressed concerns about the tenofovir trial in Thailand are the Thai Drug Users Network (TDN) and the Thai AIDS Treatment Advocacy Group (TTAG)  . . . . These community groups, which can justifiably claim to represent Thai drug users, are well informed about the trial, but their objective concerns have been ignored by the trial investigators. Contrary to the assertion of Joep Lange [2] “that the investigators did consult intensely with community groups concerned”, TDN and TTAG were not consulted about the trial design and conduct until a very late stage, after several attempts to engage with the investigators had been rebutted. TDN and TTAG had attempted to constructively engage with the investigators since October 2004; they confined their statements of concern to private letters and meetings with the investigators, until the matter was made public in a Lancet editorial in March 2005 [3].
. . . .
We believe that the disagreements surrounding the tenofovir trial in Thailand would have been avoided if the investigators had set out to engage the community more openly, and if the wealth of established knowledge among community members could have contributed enormously to the success of the trial design and implementation. TDN and TTAG have made recommendations . . .  that represent a constructive way for this trial to move forward. Mechanisms that ensure systematic involvement of legitimate representatives of the affected community as partners in research are the only way to ensure that future trials will proceed in a more productive way.”

[2] Lange, J. We must not let protestors derail trials of pre-exposure prophylaxis for HIV. PLoS Med. 2005;2:e248
[3] [Anonymous] The trials of tenofovir trials. Lancet. 2005;365:1111.

(In Thailand, the trial was to enroll drug abusers. A central issue concerned providing drug abusers with clean needles. That would be required under the spirit of the Helsinki Declaration, but the US Government bans funding for such a procedure; and the penalties in Thailand against drug abuse are so severe that participants in any such trial would need specific protection against prosecution under those laws.)