on-demand PrEP works if fewer meds; and HIV self-testing
Details:
-- overall the IPERGAY trial had an 86% relative risk reduction in HIV transmission compared to placebo, and was 100% effective in those actually taking the medications, see http://gmodestmedblogs.blogspot.com/2015/12/on-demand-hiv-pre-exposure-prophylaxis.html . Of note, the median intake was 15 pills per month of TDF/FTC (tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg)
-- in IPERGAY, 400 MSM or transgender women who had sex with men were randomly assigned to on-demand PrEP versus placebo
-- 270 people (136 in the PrEP group, 134 on placebo) had at least one period of less frequent sex but high PrEP adherence (defined as <=15 pills/month) during the study, representing 134 person-years of follow-up and 31% of the total study follow-up. The percentage of plasma samples with unquantifiable tenofovir was 38%
-- during these times, people took a median of 9.5 (6.0-13.0) pills per month and had a median of 5.0 (2.0-10.0) episodes of sex per month in the active treatment group, with essentially equal numbers in the placebo group
-- this post-hoc analysis assessed incident HIV infections, comparing those having less sex but regularly taking reduced level of PrEP in the active treatment group versus placebo
-- there was no statistically significant difference between the groups in terms of age, ethnicity, relationship status, post-secondary education, use of recreational drugs, drinking more than four alcoholic drinks per day, number of sexual partners in the prior two months, episodes of sex in the past four weeks, circumcision rate, or rate of syphilis, gonorrhea, or chlamydia at screening
Results:
-- new HIV infections:
-- placebo: 6 HIV-1 infections, incidence of 9.2 per 100 person-years (3.4-20.1)
-- PrEP: NO HIV-1 infections (0-5.4), a statistically significant difference with p=0.013
-- sensitivity analysis looking at those taking 10 pills or fewer per month was not statistically significant, likely because of a lower number of infections overall, with zero incident HIV infections in the PrEP group and 3 in the placebo group
-- the two incident HIV infections in those in the PrEP group taking <15 pills/month occurred in one patient who took 2.5 pills/month and reported 6 episodes of sex; the other took 1 pill/month and reported 12 episodes of sex
Commentary:
-- as a result of the initial IPERGAY trial, on-demand PrEP is considered appropriate in Europe in MSM and was included in the new WHO recommendations in 2019, but has not been endorsed by the CDC at this point
-- the iPrEx study also found that those taking at least four pills per week had no associated incident HIV infections
-- animal studies, particularly in macaques, confirm protection with event-driven PrEP
-- this post-hoc analysis revealed a few things:
-- during periods of less frequent sex, where participants averaged 2.2 pills per week, there was documented HIV protection
-- around two thirds of the participants in the larger IPERGAY study had at least one period of less frequent sex, suggesting that aligning medication testing with amounts of sexual activity makes sense
-- limitations of the study include:
-- the fact that this was a post-hoc analysis: we do not know how effective medication taking in this randomized controlled trial might have changed in the different subgroups during the study (eg, perhaps there were different adverse events in the different groups leading to differing sexual behaviors or pill-taking)
-- we do not have specific information regarding the lengths of time people had more versus less sex, or the timing of actual med taking with sexual events (eg, the results might have been different if people had prolonged periods of reduced sexual activity versus perhaps several brief periods, in terms of residual tenofovir concentrations and PrEP effectiveness)
-- the number of incident HIV infections was relatively low, limiting the generalizability of the results to higher risk groups
-- there are no data on people having fewer than five episodes of sex per month, limiting the generalizability to those who might have only one or two encounters
-- but, it probably would be difficult to have a randomized controlled trial, where participants were randomized to different sex frequencies for a prolonged period of time….
-- and, this trial does not include men who have sex with women; so results should not be generalized to that situation
-- one caveat: the FDA recently approved TAF/FTC (with tenofovir alafenamide) for daily PrEP, based on a single study in MSM and transgender women only. as per http://gmodestmedblogs.blogspot.com/2019/10/new-recs-to-prevent-hiv-transmission.html , i have real concern about using TAF as a main component, since studies have suggested that tenofovir levels in mononuclear cells in rectal tissue are about 10x lower than with TDF (also reduced in the vagina, fyi). so, we should not consider TAF/FTC for on-demand treatment. and, as per the blog, i would be wary about even prescribing TAF/FTC as a daily med in those who are not clearly going to take the meds regularly (and, by the way, in the IPERGAY trial as well as others, medication adherence was a very real problem; and is perhaps moreso in a non-study, community setting)
-- on a related issue, a recent study found that internet-distributed HIV self-tests significantly improved identification of new HIV infections (see hiv selftesting inc hiv identif jamaintmed2020 in dropbox or doi:10.1001/jamainternmed.2019.5222), this going hand-in-hand with PrEP in preventing new HIV infections (directly by PrEP, and indirectly in this study by finding more HIV infections, hopefully getting people into care sooner, and decreasing their further HIV transmission)
--2665 MSM individuals, mean age 30, either without or having had negative prior HIV testing, were randomized to self-testing vs control groups. all were given access the link AIDSvu.org, and the intervention group were mailed oral and fingerstick HIV self-tests with the option to order more as needed
--retention rate in the study was 54%, and 75% responded to 1 or more surveys
--more people in the self-test group reported testing 3 or more times (done in 77% of the self-test group)
--overall there was a 56% increase in annual HIV testing, from 61% to 96% by the end of the trial
--the cumulative number of new HIV infections detected was twice as high in the intervention group: 25 of 1325 (1.9%) vs 11 of 1340 (0.8%), half of which were found in the first 3 months
--and the self-test group reported 34 newly identified infections among social network members (33% of the self-tests were distributed by the self-test individuals to their social network members)
--of the 36 new HIV infections identified overall, 72% had initiated linkage to care (a not statistically significant difference of 64% in the self-test group vs 91% in usual care, the latter having mostly gotten their testing done in a health care facility so more likely to link to care directly)
--and, one big plus of this study is that it was not health center-oriented, but with easy anonymous access over the internet (ie, reaching some people who were not seeking out health care or testing: 17% had never been tested). and half of the newly diagnosed HIV infections were found in men who had not tested in the prior year (as recommended by the CDC), and 9 patients had never been HIV tested before the study
So, this analysis of the IPERGAY study does suggest benefit in contouring PrEP pill taking to specific sexual encounters and that this is likely as effective as prescribing and reinforcing regular medications even for those people with infrequent sexual encounters. this approach would expose people to fewer adverse events from these meds. One concern with the on-demand approach is that the protocol is a bit complex and involves taking two pills 2-24 hours before sex, a third pill 24 hours later, and a fourth pill 24 hours after that (though we do not have granular data on exactly how the meds were taken in IPERGAY participants). However, this on-demand PrEP does seem to be a reasonable option for some at-risk MSM who have less frequent sex.
And the national study of supplying free HIV self-tests reached many people who had never had prior HIV testing. seems like a great idea that should be systematized...
other related blogs:
--see http://gmodestmedblogs.blogspot.com/2018/10/prep-mostly-given-to-white-men-and.html , reviews a very successful Australian study with PrEP, and a CDC report that prescriptions for PrEP were shockingly low in non-white men and in all women
--for a review of the USPSTF guidelines, see http://gmodestmedblogs.blogspot.com/2019/06/uspstf-guidelines-on-hiv-testing-and.html
--for a review of HIV control in the US (slowly improving) and the new FDA program "Ready, Set, PrEP", see http://gmodestmedblogs.blogspot.com/2019/12/hiv-control-in-us-and-accessible-prep.html
--for a review of the British PROUD trial on PrEP, see http://gmodestmedblogs.blogspot.com/2015/09/hiv-pre-exposure-prophylaxis.html
geoff
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