Reappearance of minority K103N HIV-1 variants after interruption of ART initiated during primary HIV-1 infection

Abstract

Background: In the Zurich Primary HIV infection study (ZPHI), minority drug-resistant HIV-1 variants were detected in some acutely HIV-1-infected patients prior to initiation of early antiretroviral therapy (ART). Here, we investigated the reappearance of minority K103N and M184V HIV-1 variants in these patients who interrupted efficient early ART after 8-27 months according to the study protocol. These mutations are key mutations conferring drug resistance to reverse transcriptase inhibitors and they belong to the most commonly transmitted drug resistance mutations.

Methodology/principal findings: Early ART was offered to acutely HIV-1-infected patients enrolled in the longitudinal prospective ZPHI study. Six patients harboring and eleven patients not harboring drug-resistant viruses at low frequencies prior to ART were included in this substudy. Minority K103N and M184V HIV-1 variants were quantified in longitudinal plasma samples after treatment interruption by allele-specific real-time PCR. All 17 patients were infected with HIV-1 subtype B between 04/2003 and 09/2005 and received LPV/r+AZT+3TC during primary HIV-1 infection (PHI). Minority K103N HIV-1 variants reappeared after cessation of ART in two of four patients harboring this variant during PHI and even persisted in one of those patients at frequencies similar to the frequency observed prior to ART (<1%). The K103N mutation did not appear during treatment interruption in any other patient. Minority M184V HIV-1 variants were detected in two patients after ART interruption, one harboring and one not harboring these variants prior to ART.

Conclusion: Minority K103N HIV-1 variants, present in acutely HIV-1 infected patients prior to early ART, can reappear and persist after interruption of suppressive ART containing two nucleoside/nucleotide analogue reverse transcriptase inhibitors and a ritonavir-boosted protease inhibitor.

Trial registration: Clinicaltrials.gov NCT00537966.

Conflict of interest statement

Competing Interests: K.J.M. has received travel grants and honoraria from Gilead, Roche Diagnostics, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, and Abbott, and has received a research grant from Gilead. R.W. has received travel grants or speakers honoraria from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dome, Pfizer, LaRoche, TRB Chemedica, and Tibotec. H.F.G. has been an adviser and/or consultant for the following companies: GlaxoSmithKline, Abbott, Gilead, Novartis, Boehringer Ingelheim, Roche, Tibotec, Pfizer, ViiV Healthcare, and Bristol-Myers Squibb, and has received unrestricted research and educational grants from Roche, Abbott, Bristol-Myers Squibb, Gilead, Astra-Zeneca, GlaxoSmithKline, and Merck Sharp & Dohme. All other authors declare no conflict of interest.

Figures

Figure 1. Kinetics of minority K103N and M184V HIV-1 variants in patients receiving early ART and undergoing intended treatment interruption.

Plasma viral load was measured using the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test (black and green circles, the latter represent the time points that were used for the quantification of minority drug-resistant HIV-1 variants). The limit of 40 HIV-1 RNA copies/ml plasma is shown in dashed lines. Periods of ART are depicted in grey shaded areas; the durations of specific drugs in the early ART regimens are indicated by differently coloured lines. In addition, the initial ART regimen after reintroduction of ART is depicted. Minority K103N (blue triangles) and M184V (red diamonds) HIV-1 variants were quantified by AS-PCR; percentages are given and were used to calculate the absolute amounts of these variants based on the viral load. Percent values below the assays discriminatory abilities (0.2% for M184V and 0.01% for K103N) or the individually calculated detection limits based on the viral load are shown by less-than signs. ART, antiretroviral therapy; AZT, zidovudine; 3TC, lamivudine; LPV, lopinavir; /r, ritonavir-boosted; EFV, efavirenz; TDF, tenofovir; ddI, didanosine; ATV, atazanavir; FTC, emtricitabine.