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Limited evolution of inferred HIV-1 tropism while viremia is undetectable during standard HAART therapy.

Lee GQ, Dong W, Mo T, Knapp DJ, Brumme CJ, Woods CK, Kanters S, Yip B, Harrigan PR - PLoS ONE (2014)

Bottom Line: We compared pre-therapy and post-suppression viral genotypic tropism in patients who initiated on PI/NNRTI-based antiretroviral regimens between 1996-1999 (n = 462).Viral tropism was inferred by V3-loop-population-sequencing and geno2pheno[coreceptor] with cutoff at 5.75% false positive rate (FPR).Our study supports the use of pre-suppression tropism results if maraviroc is being considered during virologic suppression in this subgroup of patients.

View Article: PubMed Central - PubMed

Affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.

ABSTRACT

Background: HIV 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.

Methods: We 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).

Results: When 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).

Conclusion: R5-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.

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454 “deep” sequencing results of pre-therapy “R5” samples by population sequencing.In patients with pre-therapy baseline R5-viruses (n = 156), “deep” sequencing reveals that the prevalence of non-R5 viruses before starting HAART was a significant predictor of R5-to-non-R5 change (p<0.0001, Mann-Whitney test). Median non-R5 prevalence by “deep” sequencing among subjects who were tested as having R5 virus that remained R5 by population sequencing was 0.2% in comparison to 3.2% among those who had switched from R5 to non-R5. Horizontal bars indicate median values. For graphing and visualization purposes, values less than or equal to 1 were given randomized numbers between 0.01 and 0.8 such that samples with <1% non-R5 prevalence would randomly disperse across the plot from −2 to −0.1 log copies/mL. The dotted line at 2% non-R5 represents our group's optimized cutoff value (>2% non-R5 sequences) used for dichotomizing samples into non-R5 or R5. The dashed line at 20% represents the approximate sensitivity limit of population sequencing; five samples in this figure had %non-R5 above this sensitivity limit indicating 454 and population sequencing discordance. Detailed examination of these five samples suggested the high %non-R5 observed was a summation effect from multiple less prevalent non-R5 sequences in four, and was due to random sampling bias in one sample (Table S1).
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pone-0099000-g002: 454 “deep” sequencing results of pre-therapy “R5” samples by population sequencing.In patients with pre-therapy baseline R5-viruses (n = 156), “deep” sequencing reveals that the prevalence of non-R5 viruses before starting HAART was a significant predictor of R5-to-non-R5 change (p<0.0001, Mann-Whitney test). Median non-R5 prevalence by “deep” sequencing among subjects who were tested as having R5 virus that remained R5 by population sequencing was 0.2% in comparison to 3.2% among those who had switched from R5 to non-R5. Horizontal bars indicate median values. For graphing and visualization purposes, values less than or equal to 1 were given randomized numbers between 0.01 and 0.8 such that samples with <1% non-R5 prevalence would randomly disperse across the plot from −2 to −0.1 log copies/mL. The dotted line at 2% non-R5 represents our group's optimized cutoff value (>2% non-R5 sequences) used for dichotomizing samples into non-R5 or R5. The dashed line at 20% represents the approximate sensitivity limit of population sequencing; five samples in this figure had %non-R5 above this sensitivity limit indicating 454 and population sequencing discordance. Detailed examination of these five samples suggested the high %non-R5 observed was a summation effect from multiple less prevalent non-R5 sequences in four, and was due to random sampling bias in one sample (Table S1).

Mentions: Pre-therapy baseline “deep” sequencing results were available for a subset of patients (n = 156) with baseline R5 virus by population sequencing (Figure 1). In these patients a median of 0.2% (IQR 0.1–0.7%) of detected sequences were inferred to be non-R5. Using this method, 11/18 (61%) of individuals who switched tropism from R5 at baseline to non-R5 after viral rebound by population sequencing were called “non-R5” at baseline by “deep” sequencing (≥2% “non-R5” sequences), compared to 12/138 (9%) of individuals who did not switch tropism (p<0.0001, Chi-square test). Also, an increased prevalence of non-R5 viruses in pre-therapy samples was significantly associated with R5-to-non-R5 tropism switches (p<0.0001, Mann-Whitney test, Figure 2). This suggests that dichotomized results from the “deep” sequencing tropism prediction assay of pre-therapy samples also predicted tropism switches after viral rebound.


Limited evolution of inferred HIV-1 tropism while viremia is undetectable during standard HAART therapy.

Lee GQ, Dong W, Mo T, Knapp DJ, Brumme CJ, Woods CK, Kanters S, Yip B, Harrigan PR - PLoS ONE (2014)

454 “deep” sequencing results of pre-therapy “R5” samples by population sequencing.In patients with pre-therapy baseline R5-viruses (n = 156), “deep” sequencing reveals that the prevalence of non-R5 viruses before starting HAART was a significant predictor of R5-to-non-R5 change (p<0.0001, Mann-Whitney test). Median non-R5 prevalence by “deep” sequencing among subjects who were tested as having R5 virus that remained R5 by population sequencing was 0.2% in comparison to 3.2% among those who had switched from R5 to non-R5. Horizontal bars indicate median values. For graphing and visualization purposes, values less than or equal to 1 were given randomized numbers between 0.01 and 0.8 such that samples with <1% non-R5 prevalence would randomly disperse across the plot from −2 to −0.1 log copies/mL. The dotted line at 2% non-R5 represents our group's optimized cutoff value (>2% non-R5 sequences) used for dichotomizing samples into non-R5 or R5. The dashed line at 20% represents the approximate sensitivity limit of population sequencing; five samples in this figure had %non-R5 above this sensitivity limit indicating 454 and population sequencing discordance. Detailed examination of these five samples suggested the high %non-R5 observed was a summation effect from multiple less prevalent non-R5 sequences in four, and was due to random sampling bias in one sample (Table S1).
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getmorefigures.php?uid=PMC4048224&req=5

pone-0099000-g002: 454 “deep” sequencing results of pre-therapy “R5” samples by population sequencing.In patients with pre-therapy baseline R5-viruses (n = 156), “deep” sequencing reveals that the prevalence of non-R5 viruses before starting HAART was a significant predictor of R5-to-non-R5 change (p<0.0001, Mann-Whitney test). Median non-R5 prevalence by “deep” sequencing among subjects who were tested as having R5 virus that remained R5 by population sequencing was 0.2% in comparison to 3.2% among those who had switched from R5 to non-R5. Horizontal bars indicate median values. For graphing and visualization purposes, values less than or equal to 1 were given randomized numbers between 0.01 and 0.8 such that samples with <1% non-R5 prevalence would randomly disperse across the plot from −2 to −0.1 log copies/mL. The dotted line at 2% non-R5 represents our group's optimized cutoff value (>2% non-R5 sequences) used for dichotomizing samples into non-R5 or R5. The dashed line at 20% represents the approximate sensitivity limit of population sequencing; five samples in this figure had %non-R5 above this sensitivity limit indicating 454 and population sequencing discordance. Detailed examination of these five samples suggested the high %non-R5 observed was a summation effect from multiple less prevalent non-R5 sequences in four, and was due to random sampling bias in one sample (Table S1).
Mentions: Pre-therapy baseline “deep” sequencing results were available for a subset of patients (n = 156) with baseline R5 virus by population sequencing (Figure 1). In these patients a median of 0.2% (IQR 0.1–0.7%) of detected sequences were inferred to be non-R5. Using this method, 11/18 (61%) of individuals who switched tropism from R5 at baseline to non-R5 after viral rebound by population sequencing were called “non-R5” at baseline by “deep” sequencing (≥2% “non-R5” sequences), compared to 12/138 (9%) of individuals who did not switch tropism (p<0.0001, Chi-square test). Also, an increased prevalence of non-R5 viruses in pre-therapy samples was significantly associated with R5-to-non-R5 tropism switches (p<0.0001, Mann-Whitney test, Figure 2). This suggests that dichotomized results from the “deep” sequencing tropism prediction assay of pre-therapy samples also predicted tropism switches after viral rebound.

Bottom Line: We compared pre-therapy and post-suppression viral genotypic tropism in patients who initiated on PI/NNRTI-based antiretroviral regimens between 1996-1999 (n = 462).Viral tropism was inferred by V3-loop-population-sequencing and geno2pheno[coreceptor] with cutoff at 5.75% false positive rate (FPR).Our study supports the use of pre-suppression tropism results if maraviroc is being considered during virologic suppression in this subgroup of patients.

View Article: PubMed Central - PubMed

Affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.

ABSTRACT

Background: HIV 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.

Methods: We 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).

Results: When 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).

Conclusion: R5-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.

Show MeSH
Related in: MedlinePlus