By Mary Hearty

Although Pre-exposure prophylaxis (PrEP) users have a substantially reduced risk of acquiring HIV, a review  of HIV drug resistance among populations receiving PrEP for preventing HIV reported in World Health Organization’s (WHO) 2021 survey shows that they are at risk of having drug-resistant HIV.

According to the report titled: HIV Drug Resistance, this drug-resistant HIV is most likely to occur when PrEP is started in the setting of undiagnosed acute HIV infection or it could be transmitted from a partner.

This is because the same PrEP drugs and drug classes are being used for both HIV prevention and treatment, such as tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for oral PrEP and for first-line ART.

HIV drug resistance from oral PrEP could lead to failure to suppress viral loads on antiretroviral therapy (ART), whereas transmitted drug resistance from non-suppressive ART could lead to infection despite oral PrEP.

Following this, WHO has recommended taking all reasonable steps to exclude acute HIV infection before initiating or reinitiating PrEP.  This includes routine HIV drug resistance testing on all PrEP users who test positive for HIV; and also aggregate genotypic data on HIV drug resistance annually at the national level to estimate the prevalence of HIV drug resistance among PrEP users diagnosed with HIV.

WHO reported that an analysis that was done in PubMed using the search terms “HIV”, “PrEP” and “resistance” identified 37 of the 217 results having reported HIV drug resistance from individuals who seroconverted after being prescribed oral TDF + FTC for HIV prevention.

These included TDF + FTC arms from randomized clinical trials of oral PrEP and other PrEP products, open-label studies, demonstration studies and population-based cohorts.

To date, reports have been published on 348 seroconversions – transition from HIV infection to having detectable HIV antibodies in the blood-from 20 867 individuals who have been prescribed TDF + FTC PrEP. Thirty-five seroconversions have been reported among individuals who started PrEP during undiagnosed acute infection; of these, 18 of 35 (51%) had HIV-1 with mutations associated with TDF or FTC resistance.

A total of 313 individuals became HIV positive after starting PrEP; of these, 19 of 313 (6%) had TDF- and/or FTC-associated mutations.

Twelve case reports of individuals who seroconverted on PrEP despite detectable drug levels have been published. Of these 12, nine had HIV with K65R and/or M184V with or without NNRTI mutations, and three had wild-type HIV.

Again, the Global Evaluation of Microbicide Sensitivity project monitored HIV drug resistance associated with PrEP between December 2017 and July 2021 in South Africa through PrEP implementation partners, and in Eswatini, Kenya and Zimbabwe through a national protocol in which a blood sample was collected from any consenting current PrEP user (defined as having collected an initial supply or resupply of oral PrEP) who was diagnosed as HIV infected in accordance with national HIV testing algorithms.

Also, of 118 seroconversions tested for HIV drug resistance to date by Sanger sequencing, 23% had PrEP-associated resistance mutations, with the majority having TDF diphosphate levels associated with four or more doses per week.

With PrEP use outside of controlled trials, WHO stated that multiple mechanisms of resistance are possible and they need to be investigated and monitored, such as stopping or restarting PrEP without knowing HIV status, starting PrEP during acute infection and continuing PrEP after breakthrough infection.

In the DISCOVER study, there are limited data on the use of FTC + tenofovir alafenamide as PrEP. Among 2694 participants receiving FTC + tenofovir alafenamide, eight seroconversions have been reported.

Resistance was not detected among any participant by Sanger sequencing, but for one of the eight participants, sensitive next generation-sequencing detected M184V present at 2% of the viral population.

Regarding HIV drug resistance among women using the DPV vaginal ring, ASPIRE enrolled 2629 healthy HIV-negative women at 15 sites in Malawi, South Africa, Uganda and Zimbabwe, and the Ring Study enrolled 1959 women in South Africa and Uganda.

Both studies randomized participants to a monthly vaginal ring containing 25 mg of DPV or a placebo ring.

Of 71 women from the DPV ring arm who seroconverted in ASPIRE, 8 (10%) had one or more HIV non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations; of the 77 women from the DPV ring arm who seroconverted in the Ring Study, 14 (18%) had one or more HIV NNRTI resistance mutations. Similar levels of drug resistance were observed in placebo arms.

WHO also reported that the open-label studies HOPE and DREAM enrolled participants who remained HIV negative after ASPIRE and the Ring Study closed, and neither study included a placebo ring arm. The frequency of NNRTI resistance in HOPE and DREAM was 7 of 38 seroconversions (18%) and 5 of 18 seroconversions (28%) respectively.

PrEP-associated resistance is infrequent overall and should not inhibit PrEP use, but it should be better understood to minimize its occurrence.

The resistance identified in seroconversions on PrEP could be due to individuals who started PrEP during acute infection or who had inadequate drug exposure because of insufficient ARV drug levels to prevent infection.

WHO noted in the report that future consideration may be given to parallel testing of drug levels of PrEP agents among individuals who acquire HIV despite PrEP, since drug levels could help elucidate the mechanism of PrEP failure, including non-adherence, intermittent adherence or infection despite adequate PrEP drug exposure.