Blinded by Bigotry: Why Researchers May Have Been the Only Ones Surprised by VOICE Trial Failure

The failure of the VOICE pre-exposure prophylaxis trial, daily treatment of HIV negative people with antiretroviral drugs via a vaginal ring, was guaranteed by the long and widely held assumption that almost all HIV transmission in African countries is a result of 'unsafe' sexual behavior.

Participants were deemed to be at risk of being infected with HIV by researchers who had no evidence for this risk. In fact, sexual risk was low, with only one fifth reporting more than one sex partner in the previous three months, relatively low rates of sexual intercourse, very high rates of condom use and fairly low rates of anal sex (which may or may not have involved condoms).

During this trial HIV incidence was very high, more than 6 cases per 100 person years. Yet, researchers made no effort to find out how the several hundred seroconverting women were infected. There were high rates of certain sexually transmitted infections (though low rates of others); could some women have been infected with HIV as a result of unsafe treatment at an STI clinic?

A whopping 71% of the participants use injectible Depo-provera (DMPA), which is known to double HIV transmission risk from women to men and from men to women. Two thirds of participants were from Durban, in South Africa's highest prevalence province, Kwa-Zulu Natal. To what extent could this have contributed to these high HIV transmission levels?

It is to be wondered if taking part in this trial could have exposed many women to the risk of being infected with HIV, given that they were selected on the basis that they were currently uninfected and had low sexual risk at baseline.

Whatever the answer to these questions, the unwarranted but ubiquitous assumption that HIV is almost always transmitted through heterosexual intercourse in African countries (but not elsewhere) remains in urgent need of revision. But where does it come from?

UNAIDS, effectively a UN funded lobby for the rich and powerful pharmaceutical industry, bandies the figure about at every opportunity. The claim had been made before this lobby was spawned, but it seems impossible now to identify any body of evidence to support it. Indeed, evidence claimed to support it often suggests the opposite, such as the baseline figures collected by the VOICE study.

Until the HIV industry establish how people are being infected with HIV and employ appropriate (and effective) prevention interventions, high rates of transmission will not stop in African countries. The continued recruitment of vulnerable people in high HIV prevalence areas for trials adminsitrated by researchers who are so entirely blinded by bigotry is inexcusable.

To make matters worse, some are calling for types of monitoring that no longer require them to rely on answers given by participants themselves. This is yet another instance of a 'veterinarian' approach to Africans, similar to the insistence on the utility of injectable Depo-provera (DMPA) in developing countries, despite evidence of harm that even those promoting the drug do not deny.

There is a supremely patronizing article on the trial in the New York Times which, like the researchers, can't accept the possibility that it failed for any other reason than the "elaborate deceptions employed by the women in it". Nothing is said about the elaborate deception of the HIV industry and the researchers eagerly looking for any way of giving pharmaceutical companies the green light to sell ever growing quantities of their grossly overpriced products.

Instead of admitting to any of their obvious failures, researchers are finding ways to get around trial conditions specifically designed to ensure that such trials do not depend entirely on lies and subterfuge in their efforts to find positive results for the various sub-sectors of the HIV industry that stand to benefit most.

Viewed from a different angle, the many rumors that the NY Times article refers to are not surprising, given the experiences of African people countries of unethical practices, harmful procedures, fudged figures for adverse events (or a failure to report them), outright lies told to participants and cover-ups of evident harm to people taking part in trials, and even to people taking various medications.

The issue of payments to participants is briefly discussed (after all, if there's sex there must also be money, right?). One 'global health specialist' says “I’ve never been concerned that money is the factor driving participation or is corrupting the results”. He may like to revise that view during future trials, rather than by further eroding the already weak protection from abuse that participants currently receive.

When a trial fails as miserably as the VOICE trial, researchers need to re-examine some of their most unsupported assumptions, particularly their most bigoted ones. Then they might think twice (or even once) before accusing participants of deception, in addition to promiscuity, lack of understanding, and indifference to the risk of transmitting a deadly disease to their partner and their children.

HIV Drug Regimes: the Good the Bad and the African

The reactionary (or 'mainstream', if you prefer) view of HIV transmission in African countries is that it is predominantly a result of 'unsafe' sexual behavior. Early interventions to reduce transmission included exhortations to 'abstain' from sex, to be 'faithful to one faithful partner' (or something like that) and to use condoms (an approach that later became known as ABC). Most people didn't know what words like 'abstain' and 'faithful' meant, but they became very good at repeating them until other interventions were dreamed up.

Like 'ABC', more recently touted interventions such as mass male circumcision and pre-exposure prophylaxis (or PrEP; the use of antiretroviral drugs by HIV negative people with the expectation of reducing the risk of infection), also depend on replacing some kind of 'unsafe' behavior with some other kind of behavior, deemed to be safe, or safer, or fervently hoped to be safer. Both circumcision and PrEP require that people also adhere to the strictures of the ABC approach (and if the name sounds paternalistic, that's exactly what it is).

Ever-paternalistic when writing about Africa, the BBC has heard that "some sex workers are having unprotected sex - and taking antiretroviral drugs afterwards to cut the infection risk". This is called post-exposure prophylaxis, or PEP. It has long been available in developed countries to people who are accidentally exposed to HIV, through their occupation, as a result of sexual assault, etc, although it is probably not as widely available in high HIV prevalence countries with inadequate health services, low levels of education and poor drug supply systems.

The BBC article is claiming that sex workers should be using condoms, but sex workers themselves are pointing out that they can make more money if they don't use condoms; clients are often willing to pay more. Most sex workers don't have the massive number of clients that media outlets such as the BBC have reported in the past, so they need to get as much money as they can each time they do get a client. The BBC is also 'concerned' that sex workers are using PEP too often; some say the drugs should only be used a maximum of once a year, otherwise they may cease to be effective.

In contrast, those touting PrEP can't speak highly enough of the use of drugs to reduce the risk of HIV transmission (as a look back through previous posts on this blog will show). Trials of such drugs are promoted in frequent press releases, perhaps in the hope of receiving the customary spontaneous standing ovation that some announcement must receive at every AIDS conference. The media generally picks up the press releases and spreads them far and wide, sometimes embellishing them with an extra layer of gilding.

PrEP and PEP are different. In general, PEP is taken after exposure. PrEP is taken before exposure by a person who faces a high risk of infection, or who is thought to face a high risk (which is just about every sexually active person in high HIV prevalence countries). But there are different versions of PrEP, daily and intermittent. The daily version involves taking the drug every day; but the intermittent version is taken just before sexual intercourse, or even just after.

Both versions require strict adherence to the regime, but it's clearly a lot easier to take a drug just before or just after a specific event than to take a drug every day because you or someone else considers you to face high risks of infection. Intermittent PrEP is still being studied, but the general tone of Big Pharma press releases about PrEP is that it is a great thing, that trials are doing very well, and that if people (and governments) will just pay their exorbitant prices, everything will be great. Strangely, the tone used about PEP is usually far more measured; perhaps PEP is just not lucrative enough as a market?

But the BBC can't resist the temptation to point (or at least wag) their finger. If people in African countries are infected, it's because of their behavior. If interventions don't work it's because of people's behavior. If drugs don't work it's because of lack of adherence. If people don't appear to be following instructions it's because they are failing to 'adhere to the regime'. If people are infected and know it wasn't because of their sexual behavior they are said to be 'under-reporting', or simply lying. Etc.

You get the picture. We are clever and they are not. Some people writing on the subject are even happy to use the word 'stupid', because the 'good AIDS/bad AIDS' dichotomy didn't disappear in the 1980s, as it should have. It lives on in the media, in popular books about AIDS and various other sources. There are also different drug regimes available for the good and the bad, those who were infected 'by accident' and those who are 'reckless'.

Could PrEP be in Competition with Mass Male Circumcision Programs?

After years of trying to create a market for pre-exposure prophylaxis (PrEP) pills, such as Truvada, Big Pharma has turned to their favorite mass marketing ploy: dumping their products in African countries that are starved of health funding. Of course, why wouldn't they dump them in Africa, won't they be paid for with donor funding?

An article in Kenya's The Star entitled "Kenya: 'Wonder Pill' for Risky Sex On the Way" takes the unusual step of raising some difficult questions about PrEP, rather than repeating the Big Pharma press release, despite a shaky introduction. The article continues "Kenyans involved in risky sex behaviours will soon get a 'wonder pill' that can prevent HIV infections. Experts say Truvada, which some call the 'new condom', can reduce chances of catching HIV but there are fears the drug may be misused by the youth".

What, exactly, would constitute misuse of the drug? If it can cut the risk of infection by "up to 75 per cent if one faithfully swallows it daily", what could go wrong? Well, as the article eventually reveals, most people don't swallow drugs daily and most people can not expect 'up to 75%' reduction in risk. That figure is not even from a randomized controlled trial, but from a 'sub-group' study, where the best results are used to exaggerate the level of protection people, in (comparatively) strict trial conditions, may expect. Outside of that sub-group, and outside of drug trial conditions, risk reduction is far lower.

It's odd that such reports talk about studies and proofs for something that they then refer to as a 'wonder pill', a 'new condom' and talk of 'up to 75% protection' (although that's a bit weak compared to the term 'invisible condom' used by those marketing mass male circumcision), and the like. These are PR buzzwords, not scientific findings.

It is said that PrEP programs intend identifying those most at risk of being infected, such as sex workers, intravenous drug users and men who have sex with men. This will be a departure from vilifying these already stigmatized and criminalized groups; it remains to be seen how much donor funding will actually be spent on these groups to provide them with PrEP, given that it has been so difficult in the past to provide them with condoms, injecting equipment and even basic sex and sexuality education.

As the article says, Truvada is expensive, and it has made billions of dollars for Gilead. So it's worth their while pushing as much of the stuff as possible in countries with high HIV prevalence while the patent guarantees that their product will face little competition. By the time the patent expires the likes of Bills Clinton and Gates will surely have set up some program whereby the drugs can continue to be purchased at inflated prices.

The article makes the important point that nearly 1 million HIV positive Kenyans currently need antiroviral drugs just to keep them alive. So why would donors want to provide these same drugs to people who are not yet infected with HIV (aside from an obvious desire to enrich big pharma)?

Oddly enough, a cost effectiveness study makes its estimates using existing levels of male circumcision and antiretroviral therapy. This means that the three multi-billion dollar programs will be in direct competition with each other for funding, and each one will be trying to claim that any drop in HIV incidence is a result of their work. The study also seems to assume far higher levels of success than have been achieved so far. But that's big pharma for you.

While Gilead and other pharmaceuticals can gain a lot from any increase in antiretroviral therapy and PrEP programs, they may not stand to gain from mass male circumcision programs. Their assumption that their PrEP programs will be cost effective only in countries where circumcision levels are low suggests that by the time their product may be approved, the circumcision programs will already need to have failed, some time around 2015.

Worries that people may use PrEP as a kind of recreational drug, so they can dispense with the use of condoms when they are engaging in sex with people who may face a high risk of being HIV positive are not very convincingly addressed; nor are worries that overuse and misuse of antiretrovirals, either for HIV positive people or as PrEP, are brushed aside, with remarks about "government policy" and making the drug available "in form of a package that probably includes HIV testing and other prevention methods".

I seem to remember condoms, circumcision, ABC and various other programs being made available in the form of a package, without that leading to extraordinary results. But it will be interesting to see if PrEP will erode some of the funding currently being made available to, or earmarked for, mass male circumcision programs.

Circumcision programs stand to rake in billions for the big providers, but widespread use of PrEP would be worth far more. It's unlikely that a full scale version of both programs could co-exist; they are not mutually exclusive, but their cost effectiveness is predicated on their being the only or the main program in high HIV prevalence countries.

Whether one program displaces another, or whether they all get funded, the losers will be people in high HIV prevalence African countries, which will continue to suffer from under-funded health and education sectors. They will continue to be a mere 'territory' for sales reps, who will continue to carve things up in ways that should be very familiar to us by now.

Treatment Action Group Raises Concerns About Thai PrEP Trial

The media reacted predictably when it was announced that a pre-exposure prophylaxis trial in Thailand showed some promise in reducing HIV transmission among intravenous drug users (IDU). However, many raised concerns throughout the course of the trial about how it was being conducted. One concern was that clean needles were not provided to trial participants, even though these are known to be the best means of reducing transmission among IDUs. But there were other serious issues that put a question mark over the value of the trial.

Another observation is that "the extent to which tenofovir protected against parenteral versus sexual exposure is unknown". The extent to which sexual versus parenteral exposure may have been involved was never questioned in many other PrEP trials, in mass male circumcision trials and in trials of numerous other HIV prevention interventions. Many HIV related trials fail to account adequately for modes of transmission, assuming that the virus is almost always transmitted sexually, often despite evidence to the contrary.

I'm just curious to know why these concerns have been raised by the Treatment Action Group about this trial in particular, when serious concerns about some other HIV prevention trials don't seem to be heard much, at least, not without attracting accusations of 'denialism' and similar ad hominem responses.

Give ARVs To Those Who Need Them; PrEP Can Wait

It's been a while since I've written anything about PrEP and it's hard to keep up with two blogs. But there have been a few articles on the subject. One, and I've only seen the abstract, finds that PrEP has high acceptability but that adherence and use are more challenging. This may be a reflection of the sheer idiocy of throwing drugs at a disease that is treated in almost complete isolation from all other diseases, from the conditions in which people live, from their overall health status, etc.

Interestingly, people on PrEP ran the risk of being perceived as HIV positive, giving rise to stigma, rumors and relationship difficulties. A paper about lymphatic filariasis reports that people have difficulty understanding why they should take pills for a condition for which they have no symptoms, and also why they should take the same pills for what they see as two different conditions (swollen legs and swollen testicles).

The authors of the PrEP article note that "adherence was challenged by complexities of daily life, in particular post-coital dosing adherence suffered from alcohol use around time of sex, mobile populations, and transactional sex work". The research into giving antiretroviral drugs to HIV negative people took place in Kenya, a country where many HIV positive people with a critical need for the drugs are not receiving them, and where many babies are still being infected by their mothers (or perhaps through some other route that antiretroviral drugs will not be able to address, such as through unsafe healthcare).

A review of a mathematical modelling study of PrEP mentions the ethical problems of rolling out such a program in a country where many HIV positive people are not yet on antiretrovirals. The article finds that the strategy would be cost effective in a middle income country, such as Peru, but only if it was highly targeted. However, this is where PrEP and most other HIV interventions come unstuck in African countries. HIV in high prevalence African countries is characterized by not disproportionately affecting just a few easily identifiable groups. While prevalence is high in certain groups, the largest groups of HIV positive people don't have obvious sexual risks that could easily be targeted. Also, these groups are far too large for any African country to afford.

What I don't really understand about PrEP though, is why it is necessary at all. Proponents of the use of antiretroviral drugs in as many scenarios as possible (early treatment, lifetime treatment for women receiving prevention of mother to child treatment, etc) tell us that someone on ARVs is not very infectious. If PrEP could be targeted at people who are thought to be at risk, targeting those who put them at risk would seem like a much better prospect; that is, targeting people who are already HIV positive. They are a far smaller group, for a start, and this would be a good reason for putting all HIV positive people on ARVs as soon as they have a clear clinical need for them.

PrEP is Win-Win for Big Pharma, Lose-Lose for Ordinary People

When a PrEP trial produces poor results, the reaction is often to point the finger at the patient: they didn't take the drugs regularly, 'adherence' was low, etc. The irony of this is that people thought of as good candidates for PrEP are often those who have not successfully modified their sexual behavior, or have shown themselves unwilling to do so. If they will not or can not modify their sexual behavior, why would they be more willing or able to modify their drug taking behavior?

Some drug trial reports parcel up the high achievers and exclude the low and medium achievers and call it a 'sub-study' or something similar. But the point of a randomized controlled trial is to make it clear what kind of result can be expected of people taking part, not what kind of result can be expected if everyone behaved as drug manufacturers would wish them to. Given that people don't behave in real life as they do during drug trials, the results for strategies such as PrEP so far have been somewhat encouraging, but not good enough to roll out the strategy.

Even with PrEP, people are encouraged to engage in safe sex, to limit their number of partners, to use condoms, etc. If they can't or won't do some or all of those things, PrEP will not be very effective; but it may not have any positive impact at all. Those behind the trials and those producing the drugs are anxious to portray the strategy as tested and proven, but it is most definitely not, not yet anyhow. One of the main exponents of the strategy tries to persuade us that PrEP is the way to go, but some of his readers are clearly not convinced. And the opposing case raises additional concerns about PrEP, referring to the strategy as 'grasping at straws'.

In countries where HIV prevalence is very high and transmission is highest among low (sexual) risk groups, those engaging in heterosexual sex with one HIV negative partner, PrEP is not going to be feasible. Those who face the lowest risk, but are paradoxically the highest risk group in Modes of Transmission Surveys, are unlikely to be targeted by a PrEP campaign.

And given that the majority of HIV positive people in need of treatment are still not receiving it due to cost, infrastructure, political and other reasons, it would be odd to offer the same drugs to people who are still HIV negative. It would seem far better to establish what exactly the risks are and address those risks before throwing yet more drugs at the problem. But PrEP is the way to go if you want to sell lots of drugs to healthy people; if that doesn't work, you'll then have lots of sick people to sell even more drugs to.

Truvada Manufacturer Gilead Stops Funding to Critics

The Aids Healthcare Foundation (AHF) provides healthcare for HIV positive people and advocacy in the broader field of HIV health. In that capacity, the AHF has criticized the pharmaceutical company Gilead Sciences on a number of issues, including drug pricing policies.

But in addition, AHF has questioned the use of Gilead's Truvada as a pre-exposure prophylaxis (PrEP), a pill to be taken by HIV negative people to give them some protection from HIV infection. It could be taken, for example, by someone whose sexual partner is HIV positive. However, PrEP is not as effective as using a condom and it doesn't protect against other sexually transmitted infections.

More importantly, using a drug like Truvada can give rise to the development of drug resistant strains of HIV, especially in users who are unknowingly infected when they start taking the drug or who unknowingly become infected while taking it. AHF have argued that every time someone gets a prescription for Truvada, they should also be able to show that they have been tested for HIV and the result is negative.

Drug manufacturers are not known for their tolerance of public accountability; as a result of AHFs actions, Gilead have stopped their funding to AHF. This is particularly unfortunate right now because approval for Truvada as PrEP, which was expected to be rushed through the usual regulatory procedures, has now been delayed so that the requirement for a negative HIV test be stipulated. But it's likely that Gilead will continue to lobby for the right to aggressively pursue their own ends at the expense of public health.

The increasing dependence on drugs with outrageously high prices is worrying even in a wealthy country like the US. But as the country has the highest HIV prevalence in the Western world, it would be an even bigger threat to the country's public health systems if widespread resistance to Truvada were to develop. As well as resistance developing in an individual taking the drug, resistant strains of HIV can also be transmitted to others.

Also of concern is that, up until now, HIV drugs have been used by HIV positive people. The use of the same drugs by people who are HIV negative should be raising questions in people's minds about how far public health should go with what is effectively medical treatment for perfectly healthy people.

They may even ask how far it is possible for public health to go; the number of healthy people should, hopefully, far outnumber the number of sick people; it's undoubtedly a great market. But some level of drug resistance is inevitable. So are companies like Gilead stealthily creating new markets for even more costly second line drugs by vastly increasing the number of healthy people taking Truvada?