- Category: Pre-exposure Prophylaxis (PrEP)
- Published on Tuesday, 22 July 2014 00:00
- Written by Gus Cairns
iPrEx OLE, the open-label extension of the iPrEx study of pre-exposure prophylaxis (PrEP), reported its main findings this week at the 20th International AIDS Conference in Melbourne, Australia, published simultaneously in The Lancet Infectious Diseases. Overall PrEP effectiveness was 50% overall, but 100% in those taking 4 or more doses per week. There was a substantial early drop-out rate, especially among young people.
[Produced in collaboration with Aidsmap]
Recruitment, retention and adherence data were reported a year ago at the International AIDS Society meeting in Kuala Lumpur, but now we know how this translated into efficacy. The study recruited 1603 participants, of whom 1225 elected to take PrEP.
The group of gay men and transgender women in this study who elected to take a daily tenofovir/emtricitabine (Truvada) pill had half as many HIV infections (relative risk 0.51) as a comparator group of people who elected to stay in the study but not to take PrEP. They also had half the HIV infection rate (relative risk 0.49) of people in the placebo arm of the original iPrEx randomized controlled trial (RCT).
As has been seen in other studies of PrEP, as well as in the original iPrEx RCT, the primary determining factor when it came to the efficacy was adherence. All participants in iPrEx OLE had their level of adherence calculated from drug levels observed in blood samples.
PrEP had no significant efficacy in people who took fewer than 2 doses per week. However, the efficacy of PrEP was 84% in people who took 2-3 doses per week -- there was only 1 infection in this group -- and no infections at all were seen in people taking at least 4 doses per week. This 100% efficacy translates into a minimum efficacy of 86% if the statistical uncertainty of the result is taken into account.
More About the Study and its Participants
iPrEx OLE had a flexible design whereby men could join the trial but could elect to start PrEP at any time during the first 48 weeks of the study -- they did not have to be taking it from the start. They could also stop taking PrEP whenever they liked. Participants were followed for 72 weeks regardless of whether they were taking PrEP or not. Some 23% of people from the RCT elected to join iPrEx OLE but not to actually take PrEP, thus forming a control group. All participants received sexual health counseling, and participants taking PrEP received extra adherence counseling.
Everyone who started PrEP had a blood sample taken to assess drug levels at some point during the first 12 weeks after starting PrEP; participants did not know exactly which blood sample was used for drug level testing. In addition, a randomly selected 27% of participants had drug levels measured at every visit, and anyone who became HIV positive had drug levels at every visit assessed retrospectively. All participants were tested for HIV every 3 months and for sexually transmitted infections (STIs) including syphilis, herpes, gonorrhea, and chlamydia every 6 months.
Reflecting the make-up of the original iPrEx study, 62% of participants came from Peru or Ecuador, 18% from the U.S., 13% from Brazil, and smaller numbers from South Africa and Thailand. The proportion actually allocated to PrEP ranged from 67% of participants in Peru to 95% of participants in Ecuador. Their average age was 31, with 20% being under 24 and 22% over 40. A total of 70 individuals (4%) were transgender women -- a higher proportion than in the original study.
At the start of the open-label extension study, one-third of participants reported recent receptive anal sex without a condom, 11% had a partner known to have HIV, 16% were diagnosed with syphilis, and 13% had herpes.
As reported previously, less than half of the men who had been in the iPrEx study (44%) went on to participate in iPrEx OLE. A few of these (5%) became HIV positive in the gap between studies, but most elected not to continue, with concern about side effects being the biggest reason cited for not continuing. There were 2 people found to have acute HIV infection at the time they started iPrEx OLE.
Also as noted previously, drug levels varied by site: the proportion of participants with detectable drug in their blood varied from 83% in the U.S. to 62% in Ecuador, and in every country except the U.S., adherence was better than it had been in the original iPrEx RCT.
Efficacy, Adherence, and Risk Behavior
Overall, 41 people out of 1603 participants (2.6%) became HIV positive during the study. 13 of these were in the group that had elected not to take PrEP (annual incidence rate 2.6%) while 28 were in the majority who had elected to receive PrEP (annual incidence rate 1.8%). However, 7 of these participants had actually stopped taking PrEP more than 2 months before they became HIV positive, in 5 cases because of side effects.
This meant that HIV infection rates in people on PrEP were 36% lower than in people not on PrEP. However, people who chose not to take PrEP had -- as one might expect -- lower rates of HIV risk behavior at the start of the study than those who elected to take PrEP. Adjusting for the higher risk of HIV acquisition in people taking PrEP resulted in an effectiveness of 49%.
As noted above, there were no infections in participants with drug levels consonant with taking PrEP at least 4 times per week. However, only one-third of participants actually achieved this level of adherence, underlining the fact that the biggest challenge for the usefulness of PrEP will be adherence.
Adherence was higher in people with higher levels of education. It was 69% higher in participants reporting receptive anal sex without a condom, 57% higher in participants reporting more than 5 sexual partners in the previous 3 months, and 40% higher in participants with a known HIV positive partner, indicating that people were adjusting their PrEP use according to their perceived risk of acquiring HIV.
Principal investigator Robert Grant, commenting on this, said: "If people were at higher risk they took more PrEP and adhered to it better. I think this contradicts previous assumptions that people [who have it] together enough to use PrEP would already be managing risk in other ways; it shows that people who are at risk can take reasonable and appropriate decisions on their own behalf."
Age, however, was the strongest determent of adherence: participants in their 30s were twice as likely to have detectable drug levels in their blood as participants under 25, and over-40s were 3 times as likely. Rates of adherence were not associated with recreational drug or alcohol use.
Adherence tailed off gradually over time, and adherence that tailed off faster was associated with becoming infected with HIV.
The researchers noted a "PrEP cascade' effect whereby 75% of those whose risk behavior indicated a need for PrEP actually chose to start taking it, 93% of them returned 3 months later, 93% of them were still being dispensed PrEP, but only 70% were actually taking it in significant amounts. Adding in planned discontinuations for side effects or by patient choice (during the study 16% of participants were in a planned discontinuation at one time or another), this meant that only 39% of participants who were at high risk of HIV infection at the start of the study were taking clinically meaningful doses of PrEP 3 months later.
If people stopped, they tended to do so early, after what the researchers called "a brief period of engagement with PrEP." People were much less likely to discontinue PrEP later on in the study.
Interestingly, although taking PrEP was related to sexual risk, receiving it was not, indicating that a lot of people were stockpiling it at home, possibly for times they did feel at risk, though a pattern of intermittent use was rarer than simply stopping taking it.
One other big influence on adherence was whether people believed PrEP would work or not. News of the efficacy of PrEP from iPrEx and other RCTs was released about halfway through the follow-up period in iPrEx OLE, and after this there was a substantial improvement in adherence seen in the men in Peru, who also tended to be younger than the other groups.
Self-reported sexual risk behavior declined during the study. At the start 34% of those allocated PrEP reported receptive anal sex without a condom, and this dropped to 25% during the study. Among those not allocated PrEP, it started at 27% and ended at 20% -- in other words being allocated PrEP made no difference with regard to risk behavior. As an independent measure of risk exposure, syphilis incidence was 7.2% per year for participants allocated PrEP and 5.4% for those not allocated it, not a statistically significant difference.
This study provides the first efficacy results from a large, open-label study of PrEP where participants knew they were not taking a placebo. As such, the results are mixed: on the one hand, it confirms that if PrEP is taken with even moderate consistency it is extremely effective; that those at highest risk have the highest levels of adherence; that there appeared to be no risk compensation, at least in this cohort; that factors like recreational drug use did not impact adherence; and that belief that PrEP was effective appeared to be a motivating factor.
On the other hand, it shows evidence of a substantial drop-out rate, especially among young participants, which occurred early on, was not related to obvious adherence risks, and occurred despite people being at continued risk of HIV infection. This may show that PrEP is not a usable prevention option for some at-risk gay men, or it may indicate that more sophisticated support and better motivational incentives need to be devised for would-be PrEP users.
Asked about this, Grant commented: "The important thing may be choice. Some at risk of HIV may use condoms, others PrEP, others will rely on viral suppression in an HIV positive partner, others a negotiated safety agreement with their partner. In addition, we have up until now been very conservative in public statements about how well these things will work when used, and we have imagined that the drugs are toxic when in fact toxicity is very rare."
The findings lend further support to the World Health Organization's recent recommendation of PrEPas an additional prevention option for all HIV negative men who have sex with men who are at high risk of acquiring HIV. The guidance emphasizes that PrEP should be provided within a "comprehensive prevention package" that also includes condoms and lubricants, STI screening and treatment, HIV testing and counseling, and interventions for harmful substance use. PrEP should also be offered to serodiscordant couples as an additional prevention measure.
Keletso Mokefane of the Global Forum for MSM and HIV stressed that the challenge now would be to ensure that men who have sex with men and other key populations had access to prevention resources such as PrEP globally, and the findings of MSMGF's last survey, which showed that the attitudes of healthcare staff, violence in the community against gay men, and the strength of men's own social networks were all key to the degree to which they accessed prevention resources.
"We need to talk about what we need to put in place to support these interventions," Mokefane said.
RM Grant, PL Anderson, V McMahan, et al. Results of the iPrEx open-label extension (iPrEx OLE) in men and transgender women who have sex with men: PrEP uptake, sexual practices, and HIV incidence. 20th International AIDS Conference (AIDS 2014). Melbourne, July 20-25, 2014. Abstract TUAC0105LB.
RM Grant, PL Anderson, V McMahan, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. The Lancet Infectious Diseases. July 22, 2014 (Epub ahead of print).
iPrEx News. Data from iPrEx Open-Label Extension (OLE) Demonstrate High Interest in PrEP, Longer-term Evidence of Safety and Efficacy, and No Sign of Increased Risk Behavior Among PrEP Users. Press release. July 22, 2014.