PrEParing the way
HIV Australia | Vol. 9 No. 3 | November 2011
In a little over a year we have seen the results of several trials of different antiretroviral (ARV)-based HIV prevention strategies, most of which have shown the potential of these interventions to reduce the risk of HIV acquisition. However, concerns about the impact of pre-exposure prophylaxis (PrEP) on condom use has hampered discussion about rolling out this strategy.
Evidence and controversy
There is now a growing body of evidence indicating the potential of ARV drugs in preventing sexual transmission of HIV. This includes the recent results from a study examining the impact of ARV therapy on transmission (‘treatment as prevention’), as well as several studies of pre-exposure prophylaxis and one study of a vaginal microbicide. (See Table below)
The greatest overall efficacy was demonstrated by the HPTN 052 trial, in which early initiation of ARV treatment by the HIV-positive partner showed a 96% reduction in HIV transmission.
Although these studies provide a great deal of hope for ARV-based prevention, only one of the recent trials – a Phase III clinical trial (called iPrEx) of daily oral dosing of ARVs to prevent HIV acquisition – was conducted among men who have sex with men, and potentially has an immediate and direct impact on the Australian epidemic.
In November 2010, the results of this study were released showing that Truvada (tenofovir plus emtricitabine) is effective in reducing sexual acquisition of HIV by 44% among men who have sex with men.
A post hoc analysis showed that among those participants in the PrEP arm of the trial who were most adherent to the daily dosing regimen, the risk of contracting HIV was even lower – 73% lower than the placebo group. All participants in the study who remain HIV-negative have been invited to take part in a rollover study called iPrEx OLE (which stands for open label extension).
Everyone in this study will be receiving Truvada and the study will be looking at longer term efficacy and safety, adherence, drug resistance, bone mineral density and fat distribution,impact on hepatitis infection, and changes in sexual behaviour.
TIME Magazine pronounced the iPrEx study as the top medical breakthrough of 2010.1 However, there has also been a backlash against the idea of gay men using PrEP instead of condoms to prevent HIV (see campaign by AIDS Healthcare Foundation below). Also,in Australia, the responses from the media and from HIV organisations have been very cautious; even though the iPrEx trial results show that PrEP is an intervention that reduces HIV risk, PrEP is also continually positioned as undermining prevention.
While it is true that any particular prevention strategy could be undermined by other changes in the external environment,what is odd in this debate is the positioning of PrEP as likely to cause more infections. This argument hinges on three different aspects:
- condom migration (or risk compensation)
- assumptions about adherence and efficacy in a post-trial or ‘real life’ context, and
- concerns about informal use and the extrapolation of results of a daily dosing study to intermittent or event-based dosing.
Mathematical models have been constructed to look at various scenarios, including the implementation of PrEP in Australia. This modelling has suggested that if all gay men take PrEP with an overall individual level of efficacy similar to that reported in the iPrEX trial, then there would be a 50% reduction in cumulative infections over the next 10 years.2
Other scenarios with only those men at highest risk of HIV taking PrEP – even if condom use and other risk reduction strategies decrease – suggest that PrEP can still have an impact if coverage and adherence are sufficiently high. Also, these more targeted strategies may make PrEP cost effective, although this would not likely be the case if it was a broad-based intervention.
In the United States, there has been a campaign against PrEP – and more particularly against the manufacturer,Gilead – by the AIDS Healthcare Foundation, a healthcare and advocacy organisation, which has campaigned against FDA (Food and Drugs Administration) approval of this drug for HIV prevention. The organisation has taken out full-page advertisements in gay print media in the United States claiming that gay and bisexual men will act recklessly and will spread HIV if they are allowed to use PrEP.
Guidelines for PrEP use
As a result of the iPrEx study results,the Centers for Disease Control and Prevention (CDC) issued interim guidance for the use of PrEP among men who have sex with men in the United States at high risk of HIV infection.
(Note: FDA only regulates the marketing of drugs in the United States – not prescribing practice – so a licensed physician may prescribe off-label use of the drug regardless of FDA approval for this purpose.) However, as there are no immediate plans to make PrEP available in Australia for this purpose, there will be no benefit to Australian gay men as a result of the first randomised controlled trial shown to reduce HIV transmissions among this group.
Potential subgroups for targeting of PrEP in Australia have been identified by Poynten et al.3 These groups – men who have unprotected anal intercourse (UAI) with a known HIV-positive partner, receptive UAI with casual partners, and report use of both oral erectile dysfunction medication and methamphetamines – account for more than 70% of seroconversions (and have an HIV incidence of greater than 2%).4
At the time the iPrEx study results were released, AFAO noted the appropriateness of PrEP for some individuals or groups at very high-risk of HIV infection. Such individuals have yet to be specifically identified,but the article by Poynten et al., cited above should be a starting point for such consideration. More specifically, men at high risk may be identified through clinicians – for example HIV-negative partners in serodiscordant couples where the other partner does not have suppressed viral load (and do not consistently use condoms), and men who have used PEP on a number of occasions after unprotected receptive anal intercourse.
There has been a general tendency to frame biomedical prevention as a threat to existing ‘behavioural’ prevention instead of a supplement to it. Given that there are no plans to make PrEP available in Australia, FDA approval for marketing of Truvada as prevention in the US may lead to more informal use of PrEP in this country. Currently, use of ARVs as PrEP is very low; recent research suggests that although HIV-negative men are somewhat interested in PrEP they are still worried about taking ARVs on an ongoing basis and the possible side effects of the drugs.5
Given these concerns by gay men – and the likelihood that PrEP would only be accessed by a small number of men – as is the case in the US – serious attention needs to be paid to PrEP so that the only option is not an informal one.
In Australia, the majority of gay men surveyed in early 2011 indicated they would be willing to take PrEP.6 Only about half the men believed they would never need to take it. Less than one-quarter said they are going to use it as soon as it becomes available. More analysis will need to be undertaken to examine whether those who are most enthusiastic about PrEP are those men who are also those at highest risk for HIV, but it seem likely there is not going to be a rush to replace other HIV prevention strategies with PrEP except among those who are probably not currently (or consistently) using other strategies, including condoms.
A qualitative arm of the Australian study referred to above is currently interviewing gay men about the acceptability of PrEP, including issues such as the use of existing HIV treatment drugs for preventing HIV acquisition, and possible stigma associated with PrEP use, both of which may have an impact on how PrEP is understood and taken up by gay men.
Other PrEP study results
The results of two studies were released in July 2011 demonstrating that taking ARVs as pre-exposure prophylaxis (PrEP) reduces sexual transmission of HIV among heterosexual couples.The Partners PrEP study of 4,758 men and women in serodiscordant couples in Kenya and Uganda released results early because of the overwhelming outcome. The participants in the study were couples in which one partner was HIV positive and the other was HIV negative.
The HIV-negative partners were assigned to one of three groups: tenofovir; Truvada; or placebo.There were 47 infections in people on placebo, compared to only 18 in those taking tenofovir (a 62% reduction) and 13 in those taking Truvada (a 73% reduction). Women and men were equally protected. The study will now continue. All participants receiving tenofovir only or Truvada will remain on those medications, and those receiving placebo will start receiving tenofovir or Truvada.
In the other study (CDC TDF2) in Botswana, 1,219 men and women were assigned to take either Truvada or placebo. Nine people taking Truvada became infected compared to 24 taking placebo – a 63% reduction. The results from these studies are in contrast to the FEM-PrEP study of 2,000 women in Kenya, Zimbabwe, South Africa, which was stopped earlier this year because Truvada provided no protection for the women in this study arm. More research and analysis needs to be conducted to understand why these studies had different results. It is likely that adherence plays a major role, as already indicated by detailed analyses of the iPrEx study results.
Adherence in the Partners PrEP study was reported to be 97%, which may be attributed to the fact that participants were more motivated to take the medication because they were in a known serodiscordant relationship.
In September 2011, researchers from the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study announced that one of the study arms would be closed.
An interim analysis had found that even if it continued to its scheduled completion date, the study would not be able to show whether oral tenofovir tablets were any better than a placebo for preventing HIV in the women assigned to that study group.This study involves 5,029 women at 15 trial sites in Uganda, South Africa and Zimbabwe.
The study was designed with five study groups: tenofovir gel, a placebo gel, oral tenofovir, oral Truvada and a placebo tablet. All the other study arms will continue to the schedule’s trial completion date. VOICE is an important study because it is the only trial evaluating a daily oral pre-exposure prophylaxis and a vaginal gel in the same study. This design will determine how each product works compared to its control (placebo gel or placebo tablet) and which approach women prefer.
These results from several trials of antiretroviral-based HIV prevention strategies show that pre-exposure prophylaxis is efficacious among gay men and heterosexual couples. Concerns about cost-effectiveness and the impact of pre-exposure prophylaxis (PrEP) on condom use have hampered discussion about implementing PrEP in Australia. Even though the iPrEx trial results show that PrEP is an intervention that reduces HIV risk, PrEP is also continually positioned as undermining prevention.
Recent research suggests that although the majority of gay men are open to the concept of PrEP, most do not believe that they would ever need to use it and most also indicate they would be unlikely to give up condoms even if they were using an ARV-based prevention strategy. However, for the minority of men who are at high risk of HIV infection and are willing to use ARVs, PrEP may be an important intervention.
|Study name||Results released||Population||Design||Result|
|Partners PrEP||July 2011||Heterosexual serodiscordant couples Kenya, Uganda) 4,578 couples||Oral daily tenofovir vs. Truvada vs. placebo||Tenofovir reduced HIV risk by 62%; Truvada reduced risk by 73%. (No statistical difference between Groups.)|
|CDC TDF2||July 2011||Heterosexuals (Botswana) 1,219 men and women||Oral daily Truvada vs. placebo||Truvada reduced HIV risk by 62.6%|
|HPTN 052||May 2011||Serodiscordant couples (Africa, Asia, Americas) 1,763 couples||Immediate or deferred antiretroviral therapy for HIV-positive partner||96% reduction in HIV transmission|
|FEM-PrEP||April 2011||Women (Kenya, Zimbabwe, South Africa) 2,000 women||Oral daily Truvada vs. placebo||Truvada provided no protection (Trial closed early due to futility)|
|iPrEx||Nov 2010||MSM (Peru, Ecuador, Brazil, USA, Thailand, South Africa) 2,499 men||Oral daily Truvada vs. placebo||Truvada reduced risk by 44%|
|CAPRISA 004||July 2010||Women (South Africa) 889 women||1% tenofovir gel vs. placebo||39% reduction in HIV risk|
2 Gray, R., Prestage, G., Down, I. et al. (2011, September). HIV Pre-exposure prophylaxis for Australian gay men is effective but too expensive. Paper presented at 23rd Australasian HIV/AIDS Conference, Canberra. Paper no. 466.
3 Poynten, I., Jin, F., Prestage, G. et al. (2010). Defining High HIV Incidence Subgroups of Australian Homosexual Men: Implications for Conducting HIV Prevention trials in Low HIV Prevalence Settings. HIV Medicine, 11: 635–641.
5 Murphy, D., Holt, M., Callander, D. et al. (2011, September). Measuring attitudes towards HIV pre-exposure prophylaxis (PrEP): findings from the PrEPARE Project. Paper presented at 23rd Australasian HIV/AIDS Conference, Canberra. Paper no. 304.
Dean Murphy works at AFAO in the areas of HIV education and biomedical prevention.
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