No significant risk of resistance if HIV infection occurs during use of Truvada PrEP

Treatment with pre-exposure prophylaxis (PrEP) does not involve a significant risk of HIV drug resistance should seroconversion occur, results from the iPrEx study published in the online edition of the Journal of Infectious Diseases demonstrate.

The only cases of drug resistance among people who had taken PrEP involved individuals with unrecognised acute HIV infection when they started therapy.

“Detection of PrEP-selected DR [drug resistance] mutations was infrequent,” comment the authors.

PrEP is a promising HIV prevention technology. Results of the iPrEx study showed that PrEP with FTC/tenofovir (Truvada) reduced the risk of infection with HIV by 44% for men/transgender women who have sex with men. The risk was reduced by 99% for those with blood levels of Truvada that were sufficient to suggest they took the treatment as instructed.

Poor adherence to antiretroviral drugs can lead to the emergence of drug-resistant strains of HIV. Therefore, infection with HIV when adherence to PrEP is inadequate could mean resistance to FTC and/or tenofovir develops. This is a major concern, given that both of these agents are key first-line drugs in HIV therapy.

Investigators from the iPrEX study therefore used phenotypic and genotypic resistance assays to test for drug-resistant HIV in people who seroconverted during the study. Samples of virus with minor FTC/tenofovir resistance mutations were analysed using deep sequencing and an allele-specific PCR-based assay.

The total iPrEx study population comprised 2451 individuals who were equally randomised into treatment and placebo arms.

There were 141 HIV infections. These included ten patients with unrecognised acute HIV infection at the time of randomisation. Two of these patients were in the treatment arm. Both developed resistance to FTC.

There were 131 post-randomisation seroconversions, 48 of which involved patients taking FTC/tenofovir.

None of the patients infected post randomisation had FTC- or tenofovir-selected resistance mutations or reduced phenotypic susceptibility to these drugs.

Two patients showed minor variant FTC-associated resistance, but in both cases this was at a very low level (<1.0%).

“Minor variant DR mutations were rare, and when detected, were measured at very low frequencies,” emphasise the authors.

Could poor adherence explain the rarity of drug resistance and minor variant drug resistance in the treated patients who seroconverted? To test this hypothesis, the investigators examined plasma and PBMC (peripheral blood mononuclear cells) levels of FTC/tenofovir in all patients with an incident infection who had at least one measurement that was detectable within 90 days of their seroconversion.

Only one patient with low-level minor variant drug resistance had low but detectable PBMC concentrations of FTC/tenofovir prior to seroconversion.

“Periods of low drug exposure were not sufficient for selection of drug resistance,” write the authors.

They conclude, “clinically significant DR selected by PrEP was limited to those who initiated drug after established infection, and was associated with FTC exposure.” Resistance was absent in people who seroconverted after randomisation. The authors believe this was due to insufficient drug levels and the short duration of therapy.  “Continued surveillance of PrEP exposure and DR in seroconverters from ongoing PrEP demonstration projects will extend these findings from randomized controlled trials.”


Liegler T et al. HIV-1 drug resistance in the iPrEx pre-exposure prophylaxis trial. J Infect Dis, online edition, 2014.

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