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.
Highlights
HIV requires host cell coreceptors such as CCR5 and/or CXCR4 in addition to CD4 for cell-entry [1]
Viruses that use CCR5-molecules for cellular entry are referred to as ‘‘R5.’’ Viruses that use receptors other than CCR5, including the CXCR4-using ‘‘X4’’ viruses and the ‘‘dual/mixed-tropic’’ populations can collectively be termed ‘‘non-R5.’’ As CCR5-antagonists are only effective against R5 virus, viral tropism must be determined before prescribing this drug class
Genotypic methods are based on the amplification and population-sequencing of the V3-loop from patient viruses; ‘‘deep’’ sequencing technologies such as 454 (Roche) offers sensitivity comparable to phenotypic assays and outperforms populationsequencing in the detection of viral quasispecies for HIV tropism prediction and have recently gained popularity [6]
Summary
HIV requires host cell coreceptors such as CCR5 and/or CXCR4 in addition to CD4 for cell-entry [1]. Genotypic methods are based on the amplification and population-sequencing of the V3-loop from patient viruses; ‘‘deep’’ sequencing technologies such as 454 (Roche) offers sensitivity comparable to phenotypic assays and outperforms populationsequencing in the detection of viral quasispecies for HIV tropism prediction and have recently gained popularity [6]. The V3-loop sequences are interpreted using prediction algorithms such as geno2pheno[coreceptor] (g2p) [7]. Both phenotypic and genotypic tropism prediction methods are limited to testing samples with sufficient plasma viral load typically above 250 HIV RNA copies/mL. 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-naıve HOMER cohort from British Columbia, Canada
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