Impact of low-level-viremia on HIV-1 drug-resistance evolution among antiretroviral treated-patients

Abstract

Background: Drug-resistance mutations (DRAM) are frequently selected in patients with virological failure defined as viral load (pVL) above 500 copies/ml (c/mL), but few resistance data are available at low-level viremia (LLV). Our objective was to determine the emergence and evolution of DRAM during LLV in HIV-1-infected patients while receiving antiretroviral therapy (ART).

Methods: Retrospective analysis of patients presenting a LLV episode defined as pVL between 40 and 500 c/mL on at least 3 occasions during a 6-month period or longer while on the same ART. Resistance genotypic testing was performed at the onset and at the end of LLV period. Emerging DRAM was defined during LLV if never detected on baseline genotype or before.

Results: 48 patients including 4 naive and 44 pretreated (median 9 years) presented a LLV episode with a median duration of 11 months. Current ART included 2NRTI (94%), ritonavir-boosted PI (94%), NNRTI (23%), and/or raltegravir (19%). Median pVL during LLV was 134 c/mL. Successful resistance testing at both onset and end of the LLV episode were obtained for 37 patients (77%), among who 11 (30%) acquired at least 1 DRAM during the LLV period: for NRTI in 6, for NNRTI in 1, for PI in 4, and for raltegravir in 2. During the LLV period, number of drugs with genotypic resistance increased from a median of 4.5 to 6 drugs. Duration and pVL level of LLV episode, duration of previous ART, current and nadir CD4 count, number of baseline DRAM and GSS were not identified as predictive factors of resistance acquisition during LLV, probably due to limited number of patients.

Conclusion: Persistent LLV episodes below 500 c/ml while receiving ART is associated with emerging DRAM for all drug classes and a decreasing in further therapeutic options, suggesting to earlier consider resistance monitoring and ART optimization in this setting.

Figure 1. Resistance-associated mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and integrase inhibitors (INI) before and after the low-level viremia (LLV) period, according to the 2009 International AIDS Society-USA list.

Figure 2. Resistance to antiretroviral drugs at the onset and the end of the low-level viremia period, assessed using the 2009 ANRS HIV-1 drug-resistance algorithm v18.

LLV: low level viremia, 3TC/FTC: lamivudine/emtricitabine, ZDV: zidovudine, d4T: stavudine, ABC: abacavir, ddI: didanosine, TDF: tenofovir, EFV: efavirenz, NVP: nevirapine, ETV: etravirine, IDV: indinavir, NFV: nelfinavir, TPV: tipranavir, SQV: saquinavir, LPV: lopinavir, ATV: atazanavir, FPV: fosamprenavir, DRV: darunavir, RAL: raltegravir.