Truvada: holy grail or poisoned chalice?

Guest post by Leigh Johnson

On Tuesday, 8 December 2015, South Africa’s Medicines Control Council approved the use of Truvada for HIV prevention. Truvada, a combination of two antiretroviral agents, has been shown to be effective in preventing acquisition of HIV in people who take the drug regularly. It is one of two drugs commonly used in ‘pre-exposure prophylaxis’ (PrEP), which refers to HIV-negative people taking antiretroviral drugs prior to sex in order to reduce their risk of HIV infection (the other drug that is often used in PrEP is tenofovir alone). Here we consider a few of the key questions relating to this new HIV prevention method.

What evidence is there that Truvada protects against HIV acquisition?

There is overwhelming evidence that Truvada substantially reduces HIV risk in gay men. In the recent PROUD study, conducted in the UK, the rate of HIV acquisition in gay men who were randomly assigned to take tenofovir was 86% lower than that in men who were not. The IPERGAY trial in France also found an 86% reduction in HIV acquisition in gay men who were taking Truvada. In the OLE trial, no HIV acquisition was documented in men who took four or more tablets per week, and even in men who took the drug 2-3 times per week, efficacy was estimated to be around 77%.

In studies of heterosexuals, the evidence is a bit more mixed. The most promising trials, conducted in Botswana, Kenya and Uganda, have found levels of effectiveness comparable to those found in gay men. But there have also been a few trials that found poor effectiveness. The VOICE and FEM-PrEP trials, both conducted in South Africa, found that HIV incidence rates were no lower in women taking PrEP than in women who were taking placebos.

Why are these trial results so inconsistent? The answer lies in the disappointingly low levels of drug adherence found in the VOICE and FEM-PrEP trials. Very few of the women in these two trials took the drugs consistently, so it is not surprising that there was no observable benefit. This of course raises the question of whether we would not face the same adherence challenges in the real world, outside of the carefully-controlled setting of a drug trial. We don’t know the answer to this question, but it is possible that women in the VOICE and FEM-PrEP trials might have been less motivated to take the drug because (a) its efficacy was unknown at the time of the trial, and (b) they didn’t know whether they had been randomized to take the placebo or the drug. The PROUD, IPERGAY and OLE trials, in contrast, were conducted in men who knew that PrEP was effective, and who knew whether or not they were receiving the drug.

What are the side effects of taking Truvada?

The knee-jerk reaction against the notion of PrEP often stems from the perception that antiretroviral drugs are toxic and have terrible side effects, and that they should be reserved for HIV-positive people who need them for therapeutic purposes. However, many of the newer antiretroviral drugs – Truvada and tenofovir among them – are relatively well tolerated. Some people experience nausea when they start taking the drug, but this usually passes once the person’s system has adjusted to taking the drug regularly. There is also concern that people who take tenofovir and Truvada may experience a loss of bone mineral density, which is one of the reasons why clinicians are reluctant to prescribe these drugs in children and adolescents, who are in a critical phase of bone growth.

Are there other dangers associated with Truvada?

HIV rapidly becomes drug resistant when it faces a single antiretroviral drug, but it is less likely to become drug resistant when it is faced with a combination of three or more antiretroviral drugs. A concern is therefore that if people taking PrEP acquire HIV, the continued exposure to a single antiretroviral drug while they are HIV-positive may lead to the virus becoming drug-resistant. This would indeed be a problem, as resistance to tenofovir or Truvada would complicate things when they later start a triple-therapy combination for therapeutic purposes. However, evidence suggests that very few people who acquire HIV while taking PrEP go on to develop drug-resistant strains. In most cases, they acquire HIV because they haven’t been taking the drug often enough for it to exert a selection pressure on the virus, which means that the virus doesn’t need to mutate into a drug-resistant form. Nevertheless, it is important for people taking PrEP to get tested for HIV regularly, so that they can stop PrEP if they become HIV-positive and avoid any risk of drug resistance.

Another concern is that PrEP doesn’t protect against other sexually transmitted infections (STIs) or pregnancy, in the way that condoms do. Tenofovir and Truvada have been shown to be partially protective against the acquisition of herpes, but there is no evidence to suggest that they are effective against other STIs.

There is some evidence to suggest that people taking PrEP may use condoms less frequently and have more sexual partners, as a result of the perception of reduced HIV risk. From an individual perspective, that is not necessarily a bad thing, though moralistic commentators may argue otherwise. From a public health perspective, on the other hand, it could have negative consequences, particularly in terms of increased transmission of other STIs, such as gonorrhoea and chlamydia. There is also some anxiety that even though this ‘risk compensation’ is unlikely to be big enough to negate the HIV prevention benefit completely, it may mean that we get less HIV prevention benefit than we would otherwise have expected.

Is Truvada likely to be funded by the South Africa government?

Antiretroviral drugs are expensive. This is probably the biggest obstacle to PrEP becoming widely used in the South African setting. Relative to other prevention options, PrEP does not rank very highly in terms of cost-effectiveness – at least not when considered as a strategy for the general population. However, there is definite interest – from government as well as local HIV prevention experts – in promoting PrEP to specific high risk groups, such as sex workers, gay men, youth and people who have HIV-positive partners. In such groups, PrEP could be relatively more cost-effective. Various pilot studies are either being conducted or are being planned, to explore the feasibility of PrEP in the South African population, among these high risk groups. Although there is not yet any official government funding for nationwide PrEP availability, this may well change in the near future.

Would South Africans want to use Truvada?

This is the most difficult question to answer. Even if the drugs were freely available, many people may shun them because of the perception that they are only used by people who are ‘promiscuous’. Indeed, this was the case when PrEP was first adopted in the American gay community, with many men who chose to use PrEP being labelled as ‘Truvada whores’. But perceptions can change. Condoms were once seen as being associated with promiscuity, but with intensive social marketing and activism programmes, they have gained greater acceptance. Ironically, the very fact that they are freely available in so many government facilities has become a sticking point, with many people reporting that the idea of using government-issued condoms is just not sexy – in contrast to privately-purchased condoms, which are regarded almost as a status symbol. PrEP could gain traction as something that is ‘sexy’ if it was sold on the private market, perhaps with some degree of government subsidization in order to make it affordable. If people could buy Truvada pills and HIV self-testing kits at their local pharmacy – in the same way that they buy oral contraceptive pills and pregnancy self-testing kits – this could avoid some of the embarrassment that they may feel about having to receive PrEP from a healthworker. There are many variables that remain unknown, and it is too soon to say whether PrEP will take off as the next big thing or end up being the next big disappointment.