Unbelieveably High Adherence Doesn't Guarantee Effectivenss of Truvada

A less well publicized trial of Truvada for pre-exposure prophylaxis has finished early. Not only is it less well publicized, but the results are not being released in full until further notice.

Family Health International's (FHI) press release said "the Independent Data Monitoring Committee (IDMC) advised that the FEM-PrEP study will be highly unlikely to be able to demonstrate the effectiveness of Truvada in preventing HIV infection in the study population."

This trial was like the iPrEx study except that it was testing the use of Truvada to prevent HIV infection in women. The release of preliminary data only contrasts strongly with the way iPrEx data was released, even though the latter data was not particularly impressive.

Adherence appears to have been extremely high, higher than in the iPrEx study. But the rate of new infections was very high, at 5% per year, and there was not difference in rate between those on Truvada and those on a placebo.

Interestingly, 66% of women were using injectible contraceptives. This a popular contraception method in many African countries. Unsafe injection rates, which are extremely high in developing countries, might explain at least some of the transmissions.

Higher pregnancy rates were found among women who were taking Truvada and this was quite unexpected. It's good to hear that researchers and other commentators are being cautious, unlike with the iPrEx trial results.

PrEP Should Never Be First Line of Defence Against HIV

There's an interesting exchange that I heard about through JournalWatch. Readers of HIV/AIDS Clinical Care journal were asked if they would prescribe PrEP for a high-risk patient. Remarkably, 45% said they would not. More surprisingly, 35% said they would prescribe PrEP intermittently, surprising because this is not a currently recommended use. Only 20% said they would prescribe daily PrEP, the only use that is  currently available.

But two detailed responses outline what the practitioner would do, step by step. And it is these steps that makes me wonder what form PrEP prescription would take in developing countries, where most people are unlikely ever to see a doctor.

Those with only vague notions of what PrEP is, anyone who has been informed by following the mainstream press, might think it is a pill that you can take to prevent yourself from being infected with HIV. In fact, it's a pill that may play some small part in reducing the probability of infection if you also take other precautions, such as always wearing a condom, reducing your number of partners, etc.

As one of the practitioners says, PrEP "should never be the first line of defense against HIV infection". The same practitioner says "the healthcare system [in the US] currently lacks the infrastructure to support PrEP care in the manner recommended by the CDC". Whatever Western health infrastructures lack, they sure as hell will not be found in developing countries.

But there is a sort of paradox about behavioral interventions that aim to reduce HIV transmission: PrEP depends on strict adherence, which is a behavioral matter. Whether someone is considered to be at high or low risk of HIV infection is based on their behavior. If their behavior is tractable, their risk can be reduced. If their behavior is not tractable, their risk can not be reduced.

So, if someone is the sort of person who would adhere strictly to a PrEP prescription, they would be likely to benefit from PrEP. But then they would be unlikely to be at high risk of infection. But then a person would be unlikely to be able to benefit from PrEP if they are genuinely at high risk of infection because of their behavior.

Perhaps a partner of someone whose sexual behavior puts them at high risk of HIV infection could benefit. They would need to take other precautions aside from PrEP, otherwise it is unlikely to give them much protection. But penile-vaginal sex is not particularly high risk, so PrEP is unlikely to be the intervention of choice anyway.

Will Profits From the HIV Pandemic Ever Be Accompanied By Progress?

The answer to the question 'will Africans most in need of PrEP be able to access it?' is not a straightforward yes or no. If the question were 'will Africans in need of the most common and effective drugs for the most common, treatable, preventable and deadly diseases have access to them?', the answer is 'they certainly don't have access right now'. So why should we believe they will ever have access to PrEP?

But the question is harder to answer than that. Even if the HIV industry were to wave a magic wand and grant PrEP to whoever needed it most, they have no idea who those people would be. They don't know who is at most risk of HIV infection or of transmitting HIV and they have never known. Or they have never been quite frank about it.

There are Modes of Transmission Surveys, but these are figures cobbled together from a disparate collection of assumption, guesswork, prejudice, overactive imagination and devotion to the tooth fairy. In the end, some Africans are more likely to be infected than others, but those the industry says are most likely to be infected are not the most likely, or they are not likely to be infected for the reasons the industry says.

The majority of infections in East African countries are in married couples and those in long term relationships. Many of these people are not promiscuous, many only have sex with their partner, they don't have sex very often and many of them even take precautions to prevent infection with HIV, other sexually transmitted infections and unplanned pregnancies. In other words, a disease that is difficult to transmit through any kind penile/vaginal sex is commonly transmitted through low-risk heterosexual sex.

An update from a recent conference doesn't mention the above issues. It is accepted that effectiveness is only moderate. But there is a tendency to believe that adherence will, almost miraculously, become better than anything every seen in the history of healthcare that focuses on technical fixes.

One only need look at the number of HIV positive people who die without treatment, the number who die on treatment, the number whose treatment has failed and they are seriously ill, the levels of resistance that are mounting up over the years, etc, to wonder where all the optimism about PrEP comes from. It may be great, but will it have a great impact, or any impact, where it is most needed?

Maximizing Profits from a Drug that Doesn't Work

Advocates of PrEP are probably as aware as anyone else that it hasn't yet shown much promise for men who have sex with men (MSM). It may not even be of much use in combination with other strategies (that also haven't shown much promise). But no one really wants to be the first to say that there is still a lot left to do, or admit that PrEP may end up in the broom cupboard.

Advocates still go back to their tack of 'sub-group analysis', taking the group that shows the best level of adherence to the drug and pointing out how effective it was for them. But high levels of adherence to PrEP could indicate other protective and risk avoidence practices, so care needs to be taken in interpreting this.

More importantly, levels of adherence in the group that shows the lowest levels of adherence could indicate that they engage in other risk behaviors and fail to take protective measures, adhering to PrEP just being one. Dr Joseph Sonnabend has discussed the folly of such analyses.

So these advocates of PrEP gathered around the ashes to figure out what to do and one of the questions they came up with was "what subset of men would be the most appropriate candidates for this new prevention tool?" Sonnabend's warning against sub-group analysis recommends an 'intention to treat analysis' as an alternative.

However, PrEP on an intention to treat basis would mean they would aim to put all MSM on the drugs. And then you have the problem that you will spend a lot of money for a miniscule return (if any). Even UNAIDS will start to notice if the effectiveness of PrEP doesn't improve considerably.

The group of advocates conclude that "PrEP is not a “magic bullet” and that it should not be viewed as the sole approach to reducing new HIV infections among MSM".

Exactly; they've also got a brand new roll of sticky tape, a stapler, a needle and some thread, a pot of glue and some thumb tacks, otherwise known as 'treatment 2.0'. So maybe they won't need the PrEP after all.

If You Need PrEP, You Probably Won't Receive It

Although not yet approved for use as a pre-exposure prophylaxis for men who have sex with men, CDC has issued guidelines for its use, a sort of de facto approval. But the guidelines make it clear that this is an expensive drug, intended for recreational use among those who can afford it. It's certainly not for people who live in the handful of African countries where HIV prevalence rates are the highest in the world.

For example, confirming that someone is at "substantial, ongoing, high risk for acquiring HIV infection" is going to be a bit of a challenge for the UNAIDS dominated prevention strategies in developing countries. As far as they are concerned, if someone is African and has sex, they are at high risk. The majority of infections occur among those engaging in what is essentially low risk sex. The contradiction doesn't bother UNAIDS.

Regular testing for those on PrEP is out of the question for most people in countries where most people are never tested and HIV positive people usually find out their status by the time their problem is AIDS rather than HIV. Similar remarks apply to regular sexually transmitted infection testing; poor countries don't have the health infrastructure to do this sort of work on large sectors of the population, even if they could identify which sectors those happen to be.

And so on. The measures recommended by CDC are pie in the sky for developing countries, where HIV prevalence wouldn't be nearly as high if they had such strong health services. And as for the remarks about adherence, the trial results cited completely fudge this issue. The overall 44% lower likelihood of acquiring HIV is constantly qualified by the higher figure achieved by those with high levels of adherence.

How about the lower figure for those who achieved the lowest level of adherence? People who fail to adhere to drug regimes or other measures that are intended to reduce risk of contracting HIV and other diseases are the very people who are at the highest risk. In other words, those least likely to adhere, and therefore to benefit from Truvada PrEP, are the ones who should be targeted. That's according to the guidelines, anyhow.

African populations are handy for testing out HIV drugs because there are very high levels of HIV transmission in many areas. But this drug is not intended for them. It is intended for those who wish to continue having risky sex but to minimize the risk of contracting HIV. The less risk they take, the better Truvada will work, but the less they will need it. The more risk they take, the worse Truvada will work and the more they will need it.

Mixed Messages From CDC for Men Who Have Sex with Men

Apparently only 'high-risk' men who have sex with men should use Truvada as pre-exposure prophylaxis. Who are these high-risk men but those who tend not to take precautions? PrEP, if it works, is a precaution. Therefore, the only people likely to take PrEP as recommended would be considered to be low-risk.

But is Truvada really intended for those men who have sex with men who are at highest risk of HIV infection? I don't really believe that. I would suggest that Gilead, the manufacturers of Truvada, intend to break into the recreational drug market. I'd say they want people who don't wish to use condoms to use PrEP instead. I think that's what the whole pharmaceutical industry wants.

The US Center for Disease Control (CDC) has not approved the drug for preventive use. Yet they issue guidelines for its use as PrEP. Anyone can use Truvada if they can get hold of it and any doctor can prescribe it. I think we can be fairly certain that it will be prescribed and used as PrEP, as a recreational drug.

After all, people who are at high-risk of becoming infected, well, take risks. CDC not approving it as PrEP, but issuing guidelines, is not going to make people think twice. And whether Truvada results in "78% fewer cases of HIV infection" or reduces "infection by 44%" will make little difference to those who may already be engaging in have unprotected anal sex.

CDC and others are giving mixed messages and they seem to be doing so knowingly. If people listened to advice, they wouldn't be at high risk of being infected with HIV. Therefore, I suspect this whole scenario is calculated to maximize profits and minimize risk for the pharmaceutical industry and has little to do with the risk of contracting or transmitting HIV.

Is PrEP Destined to Be a Recreational Drug for Westerners?

There's a lot of excitement, not so surprising, about the results of a PrEP trial which took place among gay men and transgender women; it can cut new infections by at least 44%, those carrying out the research say. Thankfully, there are also cautioning voices, suggesting that there is a long way to go and that 44% in ideal conditions may not translate into 44% in non-trial conditions, the above article being one of the cautioning voices.

Presumably timed to coincide with World Aids Day on the 1st of December, this good news is likely to dominate the headlines for some time to come. I needn't go through the ins and outs of the trial, they are widely available. And there are even some good critiques that raise questions that need to be asked about an approach to a disease that depends entirely on some drugs.

Technologies such as antiretroviral treatment (ART) are great when they are used to prevent and treat a virus like HIV.But something that bothers me about HIV drugs is that the, arguably more important, objective of preventing HIV transmission by finding out what its determinants are and mitigating them has long gone out the window.

I have argued elsewhere that a significant amount of HIV transmission comes from unsafe medical practices. The WHO estimates a figure of 260,000, likely to be on the low side. No drug is required to prevent this so-called nosocomial (or iatrogenic) transmission of HIV. All that is required is good, affordable healthcare.

But there doesn't seem to be much appetite for providing people with what they really need. Single diseases have always had greater appeal and the exaggerated association of HIV transmission with sex continues to make it the biggest single recipient of health funding ever.

Sean Strub has an interesting article on post-exposure prophylaxis (PEP), antiretroviral drugs used after a suspected exposure to HIV has occurred. He has found that many people who should know about PEP don't. Although it has been widely available to healthcare workers in wealthier countries, and ostensibly in poor countries, it is not promoted widely enough among the many people who may face similar or even higher risks.

[For more information about PEP, have a look at the PEPnow site.]

I have talked to a lot of people in Kenya and Tanzania who should know about PEP but don't. This is inexcusable because PEP has been available for many years. But the fact that it is nowhere near as well known as it should be suggests to me that the current enthusiasm for PrEP is not because it could reduce and perhaps eventually eradicate the virus.

The fact that 'we' or 'science' or 'technology' can do something does not mean it will be done. 20% of deaths in under fives could be prevented by provision of clean water and sanitation, another 20% are caused by easily preventable and treatable respiratory infections. The vast majority of maternal deaths are also preventable.

Dare I suggest that developers of PrEP are more interested in the 'recreational' drug market? Something to reduce the risk of contracting HIV without the need for condoms or other precautions, perhaps?