Library Volume 1, Issue 6: Resistance Reporter© Targeting HIV Entry from 3rd International Workshop




Selection from the Targeting HIV Entry: 3rd International Workshop, December 7-8, 2007, Washington, DC

Our expert staff, along with Resistance Reporter©'s highly-respected editorial board, sorted through numerous recent journals for articles related to HIV resistance and hand-picked 4 scientifically-important presentations plus one presentation from Targeting HIV Entry: 3rd International Workshop to cover in this issue. These selections have been grouped into two sections that provide clinically-relevant information related to a certain topic. The selections and summaries we have provided are of truly noteworthy research; hot links to the abstracts and suggestions for related reading makes broadening your existing knowledge on a complex topic logical and easy.

  • Section 1: Select articles related to the prevalence and persistence of HIV drug resistance and its correlation with virological failure
  • Section 2: Select presentations and articles related to new agents and the diagnostic utility of tropism testing in the strategic sequencing of CCR5 inhibitor use in HIV treatment

Section 1 (Section 2 Also Available)

Select articles related to the prevalence and persistence of HIV drug resistance and its correlation with virological failure


Long-Term Persistence of Transmitted HIV Drug Resistance in Male Genital Tract Secretions: Implications for Secondary Transmission

J Infect Dis. 2007;196(3):356-360, Smith D et al.

Transmitted drug-resistant virus may persist longer in the unique environment of the male genital tract than it does in blood plasma. The current study included 5 individuals who were newly infected with HIV carrying resistance mutations to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and assessed the decay of HIV resistance in blood versus semen over time using population-based pol sequencing. At enrollment, the individuals had an average age of 37 years (range: 22-59 years). Three of the five individuals had detectable NNRTI-resistant HIV present in both blood and semen throughout the mean follow-up of 296 days (approximately 0.8 years) after the estimated date of infection. These individuals have been monitored for the shortest amount of time. The other two individuals had persistent NNRTI-resistance that was detectable in both blood and semen through 871 (2.4 years) and 1179 days (3.2 years) after the estimated date of infection. In these latter two individuals, resistant virus was still detectable in seminal fluid well after 3 years (at 1193 days and beyond 1179 days of follow-up, respectively), even though it had reverted  back to wild type in blood plasma. Transmission linkage analysis determined that one individual had acquired NNRTI-resistant HIV from a source partner who developed drug resistance following antiretroviral treatment. Analysis of another individual with primary NNRTI-resistant HIV who remained antiretroviral naive showed that this individual serially transmitted the drug-resistant virus to two sexual partners. The investigators speculate that the male genital tract may serve as a sanctuary site, thereby allowing prolonged persistence of drug-resistant virus up to years after initial infection in select individuals, which may allow for further transmission of drug resistance.


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Prevalence of Darunavir Resistance-Associated Mutations: Patterns of Occurrence and Association with Past Treatment

J Infect Dis. 2007;196(8):1177-1179, Mitsuya Y et al.

This study retrospectively analyzed two mutually exclusive cohorts of HIV-infected patients to identify the prevalence and covariates of darunavir resistance-associated mutations (DRV-RAMs). The clinic population included 1847 patients receiving treatment under a managed-care program in Northern California, of whom 1175 had received 1 or more PIs. The database population included 11,697 patients in the Stanford HIV Drug Resistance Database, of whom 2744 had received 1 or more PIs. The DRV-RAMs assessed included V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V, which were previously defined in other analyses. The prevalence of each DRV-RAM in PI treatment-naïve patients was very rare, typically occurring in less than 0.5% of patients in any of the 8 most common HIV subtypes. In contrast to their almost complete absence in isolates from PI-naive persons, the 11 DRV-RAMs did occur in PI-treated persons:, 29.8% of the 1175 PI-treated patients in the clinical cohort while 23.7% of the 2744 PI-treated patients in the Stanford database had 1 or more DRV-RAM . Despite the prevalence of these mutations, 96% of PI-treated patients in the clinical cohort and 99% of PI-treated patients in the database cohort had fewer than 3 DRV-RAMs, which portends a favorable response to darunavir (DRV). In accord with prior reports, the number of DRV-RAMs was significantly and independently predicted by the number of PIs previously received (P<10-16) and with prior receipt of amprenavir or fosamprenavir (P<10-16), which are structurally very similar to DRV. The investigators also identified 17 additional mutations that correlated with the presence of DRV-RAMs (L10I/F, G16A, Q18H, K43T, M46I, F53L, K55R, I62V, L63P, C67F, A71V, I72L, G73C/T, I85V, L90M). The authors noted that common mutations such as M46I and L90M, which they found to be highly correlated with the number of DRV-RAMs, may have an effect on virologic outcome despite not having had a significant effect when added to a model that already contained 11 mutations with which they were highly correlated.


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Risk of Extensive Virological Failure to the Three Original ART Drug Classes Over Long-term Follow-up From the Start of Therapy in Patients With HIV Infection: an Observational Cohort Study.

Lancet. 2007;370(9603):1923-1928, Phillips A et al.

This study assessed the longitudinal risk of developing extensive virologic failure to the three original antiretroviral classes among a prospective cohort of 7916 patients being followed in the UK Collaborative HIV Cohort Study. Virologic failure was defined as HIV RNA > 400 copies/mL despite > 4 months of continuous use of a specific drug. Extensive virologic failure to the PI class was defined as virologic failure of at least one ritonavir-boosted PI, and extensive failure of the NNRTI class was defined as virologic failure of either nevirapine or efavirenz. Extensive failure of the nucleoside reverse transcriptase inhibitor (NRTI) class was defined as virologic failure of one drug within three subclasses: zidovudine or stavudine; lamivudine or emtricitabine; and didanosine, tenofovir, or abacavir. All patients initiated treatment with three or more antiretrovirals. At baseline, patients had a median age of 36 years (range: 31-42), 25% were female, 61% initiated treatment with an NNRTI-based regimen, the median CD4+ cell count was 187 cells/mm3 (range: 90-282), and the median viral load was 5.0 log10 copies/mL (range: 4.4-5.5). Extensive virologic failure to all three classes developed in 167 patients (2.1%) during 27,441 patient-years of follow-up. The majority of patients (77%) who developed extensive triple-class failure had previously had a viral load below 50 copies/mL. The estimated risk of extensive triple-class failure was 3.5% (95% confidence interval [CI]: 2.9%-4.1%) by 5 years and 9.2% (95% CI: 5.0%-13.4%) by 10 years, and these rates appear to have decreased over time (adjusted hazard ratio: 0.86 per each successive year; P = .006). The risk of extensive triple-class failure at 10 years was markedly lower in patients who initiated treatment with a CD4+ cell count of 200 cells/mm3 or more (5.5%; 95% CI: 3.5%-7.5%) compared with those who initiated treatment with a CD4+ cell count below 200 cells/mm3 (12.1%; 95% CI: 5.1%-19.1%). In a multivariate analysis, independent predictors of an increased risk of extensive triple-class failure included a low CD4+ cell count at the start of therapy (P < .0001), younger age (P = .001), heterosexual risk of contracting HIV (P < .0001), and initiation of treatment long ago (p=.006). Strikingly, 60% and 44% of patients had one or two consecutive viral load measurements, respectively, below 50 copies/mL after being diagnosed with extensive triple-class failure. The risk of death from extensive triple-class failure by 5 years was 10.6% (95% CI: 2.4%-18.8%; included 9 deaths). The authors concluded that these findings illustrate that the development of extensive virologic failure to the three main classes of antiretrovirals occurs slowly and is associated with a relatively low risk of death in routine clinical practice.


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Section 2 (Section 1 Also Available)

Select presentations and articles related to new agents and the diagnostic utility of tropism testing in the strategic sequencing of CCR5 inhibitor use in HIV treatment


Enhancements to the Trofile™ HIV Co-receptor Tropism Assay Enable Improved Detection of CXCR4-using Subpopulations and Earlier Detection of CXCR4-using Viruses in Sequential Patient Samples.

Targeting HIV Entry: 3rd International Workshop Abstract #11, Reeves J

The phenotypic TrofileTM assay is typically used to screen patients prior to the administration of CCR5 inhibitors. The CCR5 inhibitor, maraviroc, was FDA approved in 2007, and it is known that patients with dual/mixed- or CXCR4 (X4)-tropic virus are unlikely to benefit from this agent or others in the CCR5 inhibitor class. The standard TrofileTM assay is only 85% sensitive at detecting minor X4-using variants present at 5% in a mixed-virus population, and minor variants present at less that 5% can be missed entirely, which may contribute to rapid selection of X4-using variants if CCR5 inhibitors are administered. Several modifications were made to the TrofileTM assay to enhance its sensitivity, including varying virus input, varying coreceptor expression levels, and optimizing transfection and infection conditions in the event that this will further optimize selection of patients who may benefit from therapy with entry inhibitors targeting CCR5. Compared with the standard TrofileTM assay, these enhancements improved the detection of minor X4-using variants in a mixed viral population 10-fold, enabled detection of X4-using variants present at only 0.1% of a total mixed viral population, and allowed for earlier detection of the emergence of X4-using variants in longitudinal samples collected from treatment-experienced individuals at various comparative time points. Applying the enhanced assay to 258 sequential samples taken from a cohort of 77 treatment-experienced individuals with incomplete virologic suppression on therapy that had already been classified using the standard TrofileTM assay resulted in reclassification of 20 of the samples (8%). Nineteen samples originally classified as CCR5 (R5)-tropic by the standard TrofileTM assay were determined to be dual/mixed by the enhanced assay, as was one sample originally classified as X4 tropic. This resulted in reclassification of HIV coreceptor use for 14 of the 77 patients. Additional testing of the enhanced TrofileTM assay in CCR5 inhibitor clinical trial samples is planned to determine the clinical utility of this assay.


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Current V3 Genotyping Algorithms Are Inadequate for Predicting X4 Co-receptor Usage in Clinical Isolates.

AIDS. 2007;21(14):F17-F24, Low A et al.

There is a desire to identify faster and less costly methods to determine HIV coreceptor tropism to better integrate CCR5 antagonists into clinical practice and exclude individuals with X4-using HIV from receiving ineffective treatment. This study compared the accuracy of six different V3 genotyping algorithms for predicting HIV coreceptor usage with that of actual phenotypic results. Genotypic information was obtained by bulk sequencing, whereas phenotypic information was obtained using the Trofile™ assay. Matched genotype and phenotype data were available for 920 clinical samples collected from treatment-naïve individuals. Although specificity of the genotypic algorithms was high, sensitivities were quite low for all six algorithms: the 11/25 rule (93% specificity/31% sensitivity), a neural network (88%/44%), a subtype-b position-specific scoring matrix (PSSM) of syncytium-inducing to nonsyncytium-inducing virus (96%/34%), PSSM of X4 to R5 virus (97%/24%), support vector machine (SVM) genomiac (90%/22%), and SVM geno2pheno (89%/50%). The poor sensitivity of these methods was attributed to the inability of bulk sequencing to reliably detect minority X4-using virus present below 22% of the total population. The investigators argued that the sensitivity of select genotypic algorithms could be enhanced by optimizing cut-off methods, by using a more sensitive sequencing technique, and/or by including clinical data on CD4+ cell count. These findings indicate that current coreceptor prediction algorithms that rely on genotype are inadequate for accurately identifying X4-using HIV.


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