MSM PrEP Clinical Trials for Beginners
Introduction
The recent announcement by the MCC approving a combination of two anti-HIV medications, tenofovir and emtricitabine, taken daily in a single combination pill to prevent HIV infection is a huge step forward in our efforts to turn the tide of the HIV epidemic. Dr Yogan Pillay, Deputy Director General in the Department of Health, has indicated that the South African Government will include pre-exposure prophylaxix (PrEP) in their health policy plans and activities from next year. These developments have not occurred in a vacuum; they represent the culmination of years of research and activism to get to this point.
Before any intervention can be rolled out as a public health policy, there needs to be robust, reliable and reproducible proof that the intervention is safe and effective. This has occurred for PrEP, which makes the Anova Health Institute very confident in this intervention. Here is why.
A large number of clinical trials on PrEP have been completed for men who have sex with men (MSM). They have some interesting names. Some of the trials are quite complex for the newbie reader but it is important to understand where the proof that PrEP works comes from. This section will explain these studies in easy to understand terms. The following studies are the ones that are most relevant to gay and other MSM.
[gdlr_box_icon icon=”icon-cog” icon_type=”circle” icon_color=”#ffffff” icon_background=”#1b79ba” icon_position=”top” title=”How Do Clinical Trials Work?” ]Most of the trials that have been used to prove that PrEP works follow two groups of participants. One group gets a placebo, something that looks just like PrEP but actually doesn’t contain anything. The other group gets PrEP. Each group also gets a host of other ways to prevent getting HIV – counseling, STI treatment, condoms and lube, and meeting regularly with a doctor. They are treated the same in every other way. Each group is then followed over time and the number of HIV infections in each group is counted at the end of the study. Since the groups are treated identically any difference in HIV infections must be due to PrEP. A lot of people question if these studies asked people to go out to have sex without condoms to see whether PrEP works. That would be very unethical and did not occur. Every study mentioned here provided all their participants with the highest standard of care and were monitored by multiple international regulatory groups.[/gdlr_box_icon]
2010 The Global iPreX Study
2014 The iPreX OLE Study
2015 The PROUD Study
2016 The IPERGAY Study
The Global iPrEX Study
Full study title:
iPrEX – Investigations for the Pre-Exposure Initiative
Where was it done:
This was a multisite study which recruited gay men and other MSM in many countries which included the USA, Brazil and South Africa. 88 South Africans took part in the study
What was done:
2499 men who have sex with men (MSM) took part. These men were all HIV negative and were sexually active with other men. They had quite a lot of sex, didn’t always use condoms and suffered some sexually transmitted infections (STIs). Half the men were given a placebo and half received Truvada ® (tenofovir + emtricitabine). All of them received counselling and support, STI treatment, plus condom and lubricant supplies. The men were followed up for more than a year and were monitored for HIV infection and PrEP side effects
What were the important results:
- Overall, PrEP use reduced the risk of contracting HIV by 44%. This sounds very low but the statistical analysis was done on all men in the study who were given PrEP, whether they actually took the meds or not. If one looks only at the men who actually used PrEP correctly, the protection rate was much higher, above 70%. This shows the vital importance of correct use of PrEP. If you don’t take the pill, it doesn’t work!
- Side effects were rare. When they did occur, they were mainly gastrointestinal side effects such as mild nausea, bloating and loss of appetite. Most side effects were self-limiting, meaning they stopped or ended on their own and did not require stopping PrEP. A very small number of men had kidney side effects which highlights the importance of checking kidney function in those who want to use PrEP.
- While a small number of people did still contract HIV despite Truvada® (this was predictable as the effect of PrEP is close to, but not 100%), resistance was not a problem and these men could still receive excellent management for HIV. Resistance only occurs if PrEP is started in someone who is already HIV positive, or is in the window period for HIV.
The Bottom Line
- PrEP is effective in preventing HIV infection. This study proved the concept!
- PrEP is safe
- PrEP only works if you take it correctly
- PrEP should only be started when HIV negativity has been confirmed.
The iPrEX OLE Study
Full study title:
Investigations for the Pre-exposure Initiative Open Label Extension
Where was it done:
This study was done in multiple sites (USA, Brazil, South Africa and Thailand). Men who have sex with men (MSM) who had enrolled in one of three prior PrEP studies were offered the chance to continue taking PrEP if they were HIV negative and interested in continuing. Some participants in PrEP OLE were South Africans.
What was done:
1603 MSM entered the study and 1225 of those decided to actually take PrEP. MSM received Truvada®(tenofovir + emtricitabine). There was no placebo in this study so unlike the iPrEX study, all the men who chose PrEP knew that they were getting active PrEP medication. They were followed up for a maximum of 72 months. All of them received counselling and support, STI treatment, condom and lubricant supplies. The men were followed up for more than a year and were monitored for HIV infection and PrEP side effects
What were the important results:
- Overall, PrEP reduced the number of HIV infections by about 50%. This sounds low but the analysis included people who didn’t actually take the medication they’d received and therefore could not benefit. Rates were much higher in those with correct use of PrEP.
- PrEP provided protection rates of about 84% in people who took 2-3 doses per week and almost 100% in those who took 4 or more doses per week. The suggestion therefore is that 4 pills per week was the lowest number of doses that could be taken, while still providing extremely high levels of protection against HIV. Nobody who took more than 4 doses per week became infected with HIV.
- Risk compensation did not occur. This means that men did not engage in more condom-free anal sex because they thought they were protected by PrEP.
- PrEP will fail as a prevention intervention if it is stopped while HIV risk remains ongoing.
- PrEP was safe with predictable and self-limiting side effects.
- PrEP uptake in this study was highest in those with the most risk of HIV acquisition. In other words, MSM were able to recognize that they were at significant risk of HIV and were able to initiate and maintain PrEP to mitigate that risk.
The Bottom Line
- PrEP is effective in preventing HIV infection
- PrEP is safe
- PrEP only works if you take it correctly but is more forgiving than HIV treatment regimens (4 or more doses per week worked well)
- PrEP is effective in people with relatively highest risk of HIV infection
- PrEP had a psychological benefit of reducing anxiety around sex
- The study provided some indications of why some people who might benefit, chose not to take PrEP. (See table below.)
| Reason Given for Declining PrEP | % |
|---|---|
| I am concerned about side effects from the pills | 50% |
| I don’t want to take a pill every day | 16% |
| I don’t like taking pills | 13% |
| I can avoid HIV in other ways | 14% |
| I am concerned that people will think that I am HIV positive because I am taking Truvada |
7% |
| I am concerned that people will know that I have sex with men and/or trans people because I am taking Truvada |
3% |
| Grant Melbourne 2014; Grant et al, Lancet Infectious Diseases, published online July 22, 2014 |
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The PROUD Study
Full study title:
Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection
Where was it done:
This study was done in the United Kingdom only. 13 clinics in the National Health Service of the UK recruited participants.
What was done:
544 HIV negative MSM were recruited into this study. All of these men reported unprotected (condom free) receptive anal sex within the past 90 days prior to joining the study. About half the men (275) were given immediate Truvada® (tenofovir + emtricitabine) PrEP. The other half were requested to delay starting PrEP for one year. In other words, this was a study that looked at the difference between immediate versus delayed PrEP. All of them received counselling and support, STI treatment, condom and lubricant supplies. The men were followed up for more than a year and were monitored for HIV infection and PrEP side effects
What were the important results:
- This study was stopped early when it became apparent that PrEP was very effective in the immediate use group. It was considered unethical to continue the study which delayed PrEP use in the “delayed group” as 20 people in this group become HIV positive while awaiting their PrEP. This study therefore added to the evidence base that PrEP is effective in preventing HIV among high risk MSM.
- PrEP use reduced the overall risk of contracting HIV by 86%. In this study, PrEP prevented 17 out of 20 HIV infections that otherwise would have occurred.
- Side effects were uncommon; only about 5% of MSM reported any side effects. When side effects did occur, they were mainly gastrointestinal, were self-limiting and did not require stopping PrEP.
- Rates of STIs did not increase in men who used PrEP. This has always been a concern: if men stop using condoms because PrEP provides excellent HIV prevention, they are likely to get STIs because PrEP does not protect against these. This did not occur in the study.
- PrEP needed to be given to 13 high risk men for 1 year to prevent a case of HIV infection. This is known in medical terms as the “Number needed to treat”. The lower the number needed to treat, the more likely it is that an intervention will have an impact while remaining cost effective and feasible to implement. 13 is a very low “number needed to treat” and highlights the potential benefit that PrEP may offer to our MSM communities.
The Bottom Line
- PrEP is effective in preventing HIV infection. This study again added to the growing evidence base for PrEP
- PrEP is safe and minimal side effects were reported
- Delaying PrEP is a poor strategy for high risk MSM
- Risk compensation did not occur in a clinical trial setting
- The results of this study agreed with the results of prior studies and strengthened the resolve of European scientists and activists to push for PrEP.
The IPERGAY Study
Full study title:
Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (IPERGAY)
Where was it done:
This was a multisite study which recruited gay men in France. It was conducted by the France Recherche Nord et Sud Sida- HIV et Hépatites (ANRS) group.
What was done:
400 men who have sex with men (MSM) took part in this study. The design of this study differed significantly from iPrEX, iPrEX OLE and PROUD. Men were randomized into two groups. One group got a placebo (fake) drug as in the other studies. The other group were assigned PrEP but this was not taken daily as in other studies.
PrEP was taken only when sex occurred (i.e. sex-based or event-driven dosing). Men were asked to take doses of Truvada before and after sex. The men took two Truvada pills (double dose) 2-24 hours before sex occurred, a third pill 24 hours later and a fourth pill after another 24 hours. One additional pill was added per day if there were consecutive episodes of sex (i.e. at least 4 doses were taken for each episode of sex). These men were all HIV negative and were sexually active with other men. They had quite a lot of sex, didn’t always use condoms and suffered some STI infections. All of then received counselling and support, STI treatment, condom and lubricant supplies. The men were followed up for more than a year and were monitored for HIV infection and PrEP side effects.
Figure 1: Graphic of IPERGAY PrEP Doses
The use of a placebo (fake) pill in this study was seen by some as controversial because we already had good evidence that PrEP worked from the iPrEx study and that men in this group were therefore being denied an evidence-based therapy.
[/gdlr_box_icon]What were the important results:
- PrEP was effective in preventing HIV when used in an event-based dosing strategy. This is the first study to investigate an alternative way of providing PrEP doses. Intermittent dosing might be appropriate for MSM who have infrequent (but risky) sex and do not require ongoing high level protection at all times. Intermittent dosing would allow such individuals to avoid unnecessary exposure to PrEP when they don’t need it and hopefully reduce side effects by lowering the total cumulative amount of tenofovir and emtricitabine over time. One concern is that the men in this study were highly sexually active and took a lot of PrEP; in fact they took an average of 15 doses per month (i.e. about the 4 doses per week that we know from iPrEX OLE is enough for protection). One could argue that since the men took (almost) continuous PrEP, we need further evidence for event based dosing. We cannot be certain that this strategy would be effective for men who have infrequent sex.
- The men in the study were sexually active (about 8 sex partners in two months), had a high rate of recreational substance use and reported high rates of condomless sex. Their behaviour risk did not increase once they started PrEP.
- Side effects were generally uncommon and minor. Only 14% reported any side effects with only one study participant having to stop PrEP due to a drug-drug interaction. PrEP was therefore well tolerated.
The Bottom Line
- PrEP is effective in preventing HIV infection. This study agreed with all prior reports and attempted to explore a new dosing strategy
- PrEP is safe and side effects are predictable and minimal
- PrEP only works if you take it correctly
- Event-based dosing is an interesting and attractive option for some men, however further data is needed to support this
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Despite the results of the IPERGAY study, the Anova Health Institute supports the use of daily tenofovir + emtricitabine (Truvada®) as PrEP for HIV prevention, based on all the current evidence.
