PrEP failures in African programs are rare, but some do occur in people with good adherence
A study in the 11th The International AIDS Society Conference on the Science of HIV (IAS 2021) is the first to study drug levels and drug resistance in people with HIV infection despite taking PrEP in the real world of HIV programs. Rapidly expanding PrEP from four African countries.
Dr Urvi Parikh of the University of Pittsburgh told the conference that the GEMS (Global Microbicide Susceptibility Assessment) The project found 229 cases of HIV infection among approximately 104,000 people taking PrEP in South Africa, Kenya, Zimbabwe and Eswatini. This may not be the total number of infections, as some may not have been reported, but it does suggest that HIV infections on PrEP are rare.
The GEMS study has been described as an ‘observational cross-sectional study’, meaning that it only examines the characteristics of the cases – people who have contracted HIV – rather than controls, the vast majority who do not. have not.
This has important limitations, including that although drug resistance mutations to the PrEP drugs, emtricitabine and tenofovir, have been detected in people who seroconverted after starting PrEP, researchers cannot. not be sure if they happened as a result of taking PrEP or in some cases may have already been there in the HIV that people have contracted.
The rates of drug resistance found were higher than those seen in general among locals, but so were the rates of resistance to another class of drugs, NNRTIs, which are do not included in PrEP.
Of 229 seroconverted people who were notified to GEMS, 208 (91%) provided a sample of dried blood drops (DBS). Intracellular tenofovir levels in the samples were measured, and in 118 (57%) of them, drug resistance genotyping was performed. (The main reason this was not done in the others was that in 30% of the samples the viral load was too low.)
Of the 208 people tested for drug levels, 38% were from South Africa, 31% from Kenya, 17% from Zimbabwe and 13% from Eswatini.
Three quarters of them were women and the same proportion was between 16 and 24 years old. In terms of key populations, the group included 21% partners of HIV-positive people, 10% female sex workers, 9% men who have sex with men, and 6% transgender women or men.
The majority of HIV infections have been in people who have been taking PrEP for some time: 35% got HIV in the first three months on PrEP, 40% between three months and one year, and 18% in people who have it. had taken for over a year.
Of the 118 people tested for drug resistance, 55% had no HIV drug resistance mutations. Another 22% had resistance mutations to drugs other than emtricitabine or tenofovir. These were the NNRTI drugs nevirapine, efavirenz, rilpivirine and etravirine.
This left 23% (27 people) who had resistance mutations to emtricitabine or tenofovir. All but one of the people had the M184V / I resistance mutation to emtricitabine. It happens easily and is most common in people who get HIV while taking PrEP. Thirteen people had M184V / I alone and ten people had it with various NNRTI mutations.
The other four, including the person without M184V / I, had the characteristic tenofovir resistance mutation, K65R. Three were also resistant to NNRTIs; one who also did not have another tenofovir mutation called K70E.
Perhaps the biggest surprise of the study was that if people who caught HIV while taking PrEP and had do not tend to have low levels of tenofovir in the blood – indicating poor adhesion – those with drug resistance appear to have good adhesion.
Eighty-two percent of those without resistance had tenofovir levels consistent with taking two or less PrEP pills per week, as did 60% of those who had only resistance. NNRTI. But 78% of people who were drug resistant to PrEP had tenofovir levels consistent with four to seven doses per week, which should be enough to prevent HIV.
What was the explanation? First, resistance only arises when HIV tries to reproduce in a situation where drug levels are high, so people with very low adherence will tend to get HIV, but not acquire resistance.
Second, while the samples for the GEMS study were taken on or near the day of diagnosis, we do not know how long people were infected before diagnosis, so some may have contracted HIV over a period of time. poor adherence or interruption of drug supply, but once diagnosed had good adherence. Dr Parikh said that in the absence of incidence testing, the study will assess viral load in seroconverters; very high viral loads would tend to indicate recent infection.
“So as long as PrEP remains effective overall, it is unlikely to contribute more than a small proportion to resistance to circulating HIV drugs. “
There may also have been a few people who received ART on the day they were diagnosed and drug level tests detected this, not PrEP. But that still does not fully explain as almost all drug-resistant people had strong adhesions.
One question asked was whether the study showed that women on PrEP needed near-perfect adhesion to prevent HIV infection, unlike gay and bisexual men. However, Dr Parikh said if this were the case, an even higher proportion of people with resistance to PrEP drugs would be expected to be women than the 75% in the overall study. In fact, the proportion of women was a little lower – 69%. However, she agreed that the effectiveness of PrEP in the general population in women needed further study.
The proportion of seroconverters on PrEP that were resistant (23%) was considerably higher than the rate of this type of resistance reported in other people newly diagnosed with HIV (about 10%); but so was the rate of resistance to NNRTIs. NNRTI resistance could only be transmitted in response to PrEP, so data on resistance in southern Africa may be out of date.
Does this higher level of resistance matter? First, it is important to remember that of the estimated number of people taking PrEP, the 229 infections represent only 0.22% of the estimated 104,000 people taking PrEP. As long as PrEP remains effective overall, it is unlikely to contribute more than a small proportion to resistance to circulating anti-HIV drugs.
Second, Dr Parikh commented, with dolutegravir-based regimens becoming increasingly common in Africa, the elevated levels of M184V / I observed may not have a clinically significant impact on the effectiveness of the regimens. Even with the rarer tenofovir mutations, which eliminate most NRTI drugs, effective and available treatment regimens may replace this class.
The GEMS study is ongoing; Dr Parikh commented that even since his presentation was finalized, 13 new cases of people who contracted HIV while taking PrEP have been detected and will be evaluated.