Limited Evolution of Inferred HIV-1 Tropism while Viremia Is Undetectable during Standard HAART Therapy

Abstract

BackgroundHIV patients on suppressive antiretroviral therapy have undetectable viremia making it impossible to screen plasma HIV tropism if regimen change is required during suppression. We investigated the prevalence and predictors of tropism switch from CCR5-using (“R5”) to non-CCR5-using (“non-R5”) before and after viral suppression in the initially therapy-naïve HOMER cohort from British Columbia, Canada.MethodsWe compared pre-therapy and post-suppression viral genotypic tropism in patients who initiated on PI/NNRTI-based antiretroviral regimens between 1996-1999 (n = 462). Virologic suppression was defined as having two consecutive viral loads of <500 copies/mL, which was the sensitivity limit of most viral load assays at the time. Viral tropism was inferred by V3-loop-population-sequencing and geno2pheno[coreceptor] with cutoff at 5.75% false positive rate (FPR).ResultsWhen virologic suppression was defined as two-consecutive viral loads <500 copies/mL, 34 (9%) of the 397 patients with pre-therapy R5-virus switched to non-R5 at viral load rebound after a median of 19 months (IQR 8–41 months) of undetectable viremia. Duration of viral load suppression was not a predictor of switch, but lower CD4 count during suppression (median 400 versus 250 cells/mL) and an increased prevalence of pre-therapy non-R5 HIV by “deep” sequencing (median 0.2% versus 3.2%) were independently associated with switch (p = 0.03 and p<0.0001, respectively).ConclusionR5-to-non-R5 tropism switches in plasma virus after undetectable viremia were relatively rare events especially among patients with higher CD4 counts during virologic suppression. Our study supports the use of pre-suppression tropism results if maraviroc is being considered during virologic suppression in this subgroup of patients.

Non-R5-tropic HIV-1 in subtype A1 and D infections were associated with lower pretherapy CD4+ cell count but not with PI/(N)NRTI therapy outcomes in Mbarara, Uganda

“…Reverse transcription and cDNA synthesis was performed for HIV-1 env V3 loop, protease/reverse transcriptase and gp41 independently with SuperScript® III One-Step RT-PCR System (Invitrogen) followed by “nested” second-round PCR (Supplementary Tables 1 and 3) [modified based on 20,21]. Bulk sequencing was performed on ABI 3730 DNA Sequencer using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems) (Supplementary Table 2).…”

Tropism Switching Is Rare in Aviremic HIV-Infected Patients Virologically Suppressed With Non–Entry-Inhibiting Antiretroviral Regimens

“…1 However, there are limited data suggesting that plasma HIV-1 RNA can predict tropism switching in fully suppressed patients. 2,3 In view of this, we conducted a prospective, single-arm, open-label study using Trofile-DNA to assess tropism changes over 96 weeks in patients treated with non-entry inhibitors who have achieved total virological suppression (HIV-1 RNA < 50 copies/mL).…”

Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients

“…Therefore several commercial laboratories have developed proviral DNA tropism assays. The “ Appendix ” summarizes the rationale for proviral drug resistance and tropism assays in virologically suppressed patients [ 50 , 51 , 135 – 140 ].…”

“…Most studies suggest that little HIV-1 evolution occurs during ART-mediated virological suppression—particularly with most current regimens [ 15 ]. Therefore, if co-receptor tropism was determined shortly before virological suppression, it is unlikely to have changed during therapy [ 140 ]. However, if tropism was not determined previously and if a switch to maraviroc is being considered, genotypic or phenotypic PBMC tropism tests are considered reasonable but have not been validated for predicting maraviroc activity [ 1 ].…”