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The MOTIVATE-1 and 2 studies compared maraviroc (MVC) along with optimized background therapy (OBT) vs. placebo along with OBT in treatment-experienced patients screened as having R5-HIV (original Monogram Trofile). A subset screened with non-R5 HIV were treated with MVC or placebo along with OBT in a sister safety trial, A4001029. This analysis retrospectively examined the performance of population-based sequence analysis of HIV-1 env V3-loop to predict coreceptor tropism.Triplicate V3-loop sequences were generated using stored screening plasma samples and data was processed using custom software ('ReCall'), blinded to clinical response. Tropism was inferred using geno2pheno ('g2p'; 5% false positive rate). Primary outcomes were viral load changes after starting maraviroc; and concordance with prior screening Trofile results.Genotype and Trofile results were available for 1164 individuals with virological outcome data (N = 169 non-R5 by Trofile). Compared with Trofile, V3 genotyping had a specificity of 92.6% and a sensitivity of 67.4% for detecting non-R5 virus. However, when compared with clinical outcome, virological responses were consistently similar between Trofile and V3 genotype at weeks 8 and 24 following the initiation of therapy for patients categorized as R5.Despite differences in sensitivity for predicting non-R5 HIV, week 8 and 24 week virological responses were similar in this treatment-experienced population. These findings suggest the potential utility of V3 genotyping as an accessible assay to select patients who may benefit from maraviroc treatment. Optimization of the predictive tropism algorithm may lead to further improvement in the clinical utility of HIV genotypic tropism assays.

OBJECTIVE Integrating CCR5 antagonists into clinical practice would benefit from accurate assays of co-receptor usage (CCR5 versus CXCR4) with fast turnaround and low cost. DESIGN Published HIV V3-loop based predictors of co-receptor usage were compared with actual phenotypic tropism results in a large cohort of antiretroviral naive individuals to determine accuracy on clinical samples and identify areas for improvement. METHODS Aligned HIV envelope V3 loop sequences (n = 977), derived by bulk sequencing were analyzed by six methods: the 11/25 rule; a neural network (NN), two support vector machines, and two subtype-B position specific scoring matrices (PSSM). Co-receptor phenotype results (Trofile Co-receptor Phenotype Assay; Monogram Biosciences) were stratified by CXCR4 relative light unit (RLU) readout and CD4 cell count. RESULTS Co-receptor phenotype was available for 920 clinical samples with V3 genotypes having fewer than seven amino acid mixtures (n = 769 R5; n = 151 X4-capable). Sensitivity and specificity for predicting X4 capacity were evaluated for the 11/25 rule (30% sensitivity/93% specificity), NN (44%/88%), PSSM(sinsi) (34%/96%), PSSM(x4r5) (24%/97%), SVMgenomiac (22%/90%) and SVMgeno2pheno (50%/89%). Quantitative increases in sensitivity could be obtained by optimizing the cut-off for methods with continuous output (PSSM methods), and/or integrating clinical data (CD4%). Sensitivity was directly proportional to strength of X4 signal in the phenotype assay (P < 0.05). CONCLUSIONS Current default implementations of co-receptor prediction algorithms are inadequate for predicting HIV X4 co-receptor usage in clinical samples, particularly those X4 phenotypes with low CXCR4 RLU signals. Significant improvements can be made to genotypic predictors, including training on clinical samples, using additional data to improve predictions and optimizing cutoffs and increasing genotype sensitivity.

Background: There exist concerns regarding the potential for elevated rates of anti-retroviral resistance among HIV-infected injection drug users (IDUs) prescribed highly active antiretroviral therapy (HAART), however, no population-based study has examined if IDUs have elevated rates of antiretroviral resistance in comparison to non-IDUs. Objective: To evaluate the time to the development of antiretroviral resistance among antiretroviral-naive patients with and without a history of injection drug use. Methods: In British Columbia there is a province-wide HIV/AIDS treatment program that provides antiretrovirals free of charge. We examined all antiretroviral-naive patients initiating HAART between 1 August 1996 and 30 September 2000 and who were followed to 31 March 2002. The main outcome measure was the time to class-specific antiretroviral resistance. Cumulative antiretroviral resistance rates among IDUs and non-IDUs were evaluated using Kaplan-Meier methods and relative hazards were estimated using Cox regression. Results: Overall, 1191 antiretroviral-naive patients initiated HAART during the study period. Resistance mutations were observed in 298 (25%) subjects during the first 30 months of HAART. In comparison with non-IDUs, the risk of protease inhibitor resistance [relative hazard (RH), 0.9; 95% confidence interval (Cl), 0.5-1.6] and non-nucleoside reverse transcriptase inhibitor resistance (RH, 1.5; 95% Cl, 1.0-2.2) were similar among IDUs, and there were no differences in the rates of resistance to the sub-classes of nucleoside reverse transcriptase inhibitors. Conclusions: Resistance to all major classes of antiretrovirals were similar among IDUs and non-IDUs after 30 months of follow-up. These findings should help to allay fears that prescribing HAART to IDUs may result in elevated rates of resistance.

Objective: Single nucleotide polymorphisms (SNP) in the genes encoding the human CX 3 CR1 chemokine receptor and the P-glycoprotein multidrug transporter have been associated with accelerated disease progression in untreated individuals and implicated in therapeutic response, respectively. This retrospective study assessed the influence of SNP in the CX 3 CR1 and MDR-1 genes on initial virological and immunological response in 461 HIV-infected, antiretroviral-naive individuals initiating antiretroviral therapy in British Columbia, Canada. Methods: CX 3 CR1 and MDR-1 SNP were determined by PCR amplification of human DNA from plasma, followed by DNA sequencing. Time to virological success [time to HIV plasma viral load (pVL) ≤ 500 copies/ml], virological failure (subsequent time to the second of two consecutive pVL ≥ 500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan-Meier methods. Results: Frequencies of CX 3 CR1 amino acid haplotypes were 249V 280T (0.75), 2491 280M (0.15), and 2491 280T (0.1). Frequencies of MDR-1 nucleotide polymorphisms were 3435C (0.47) and 3435T (0.53). There was no effect detected for SNP in CX 3 CR1 or MDR-1 on time to virological success, nor of CX 3 CR1 and MDR-1 SNP on time to virological and immunological failure, respectively (P>0.1). There was a trend to earlier virological failure in the MDR-1 3435C/C genotype group (P = 0.07), and a statistically significant trend to earlier immunological failure in individuals with the CX 3 CR1 2491 polymorphism (P= 0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence (P ≤ 0.05). Conclusion: Polymorphisms in MDR-1 and CX 3 CR1 may be associated with accelerated virological and immunological therapy failure, respectively.

OBJECTIVE Natural genetic polymorphisms within the CCR5 gene and promoter have been linked to patterns of HIV-1 clinical disease progression in untreated individuals. The objective of this retrospective study was to assess the influence of the CCR5Delta32 mutation and promoter polymorphisms on virological and immunological treatment outcome in 436 antiretroviral-naive individuals initiating their first therapy, over a mean follow-up time of 22 months. METHODS Genotypes for the CCR5Delta32 and promoter were determined by polymerase chain reaction amplification of human DNA from plasma, followed by gel electrophoresis for CCR5Delta32 or DNA sequencing for the promoter polymorphisms. Time to virological failure [defined as the second plasma viral load > or = 400 copies HIV-1 RNA/ml) and immunological failure (defined as time to achieve two successive CD4 cell counts below baseline) were analyzed by Kaplan-Meier methods. RESULTS The five most common CCR5 promoter polymorphisms were observed at positions 208(G/T), 303(A/G), 627(C/T), 676(A/G), and 927(C/T). Allele frequencies were 0.24(208T), 0.38(303G), 0.44(627T), 0.35(676G) and 0.18(927T). The CCR5Delta32 allele frequency was 0.08. The promoter polymorphisms existed in strong linkage disequilibrium with each other and the Delta32. No significant effect of the individual CCR5Delta32 or promoter polymorphisms could be demonstrated with respect to time to treatment failure as defined by virological or immunological parameters (P > or = 0.07). Similarly, when combined CCR5Delta32 and promoter genotypes were analyzed in order to account for linkage disequilibrium, no significant effect was observed on time to virological or immunological failure (P > 0.6). CONCLUSION CCR5Delta32 and promoter genotypes may not be of clinical relevance in predicting initial virological or immunological response to antiretroviral therapy.