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Library Volume 2, Issue 3: Resistance Reporter © XVII International HIV Drug Resistance Workshop and Journal Review


Selections from the XVII International HIV Drug Resistance Workshop (IHDRW); 10-14 June, 2008; Sitges, Spain and a recent journal article.

  • Section 1: Select presentations concerning integrase inhibitors and discussion of possible clinical implications

  • Section 2: Select presentations concerning nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance

  • Section 3: Select presentations concerning the new, enhanced tropism assay

Section 1 (Section 2 and Section 3 Also Available)

Select presentations concerning integrase inhibitors and discussion of possible clinical implications


Longitudinal analysis of resistance to the HIV-1 integrase inhibitor raltegravir: Results from P005 a Phase II study in treatment-experienced patients
IHDRW Abstract 6, Miller MD, et al.

Initial analysis from the Phase II trials of raltegravir (RAL) and the mechanistically related integrase inhibitor elvitegravir suggest the potential for several resistance pathways, each involving multiple mutations with different effect on resistance and viral replication capacity. Understanding resistance and cross-resistance to these agents will become important in clinical practice but is still limited. For RAL, two pathways characterized by signature mutations at either N155(H) or Q148(R/H/K) have been observed. In this presentation, Merck investigators presented the longitudinal analysis of the results of Phase II protocol PN005 (treatment-experienced), which included genotypic and phenotypic analysis and documented evolution of viral populations from N155H to Q148H. From their analysis of the 005 studies the authors noted the definition of four distinct evolutionary patterns for ongoing selective pressure and clear preference to evolve pathways associated with higher level resistance. They concluded that integrase genotype can evolve over time, noting evidence of selective pressure on viruses with 1 mutation and that single mutations do not persist; signature mutations reduce viral replication, and secondary mutations variably affect viral replication when added to signature mutations. "Stable" isolates have ≥2 mutations, generally with Q148R/H/K as the primary, and viruses with Q148 (± secondary mutations) are fitter and have greater RAL resistance than those with N155H. In 7 patients, virus evolved from N155N/H + Q148Q/X mix to pure Q148 pathway. The time to loss of virologic response was longer for patients whose viruses evolved N155H but not Q148 mutations. In people who had two or three genotypes after RAL failure, N155H populations faded and Q148 mutations rose to dominance, while additional mutations accumulated. To further answer and validate questions that have meaning for clinicians (1-Do viruses with mutations at codon Q148 have greater replicative capacity than those with N155H? 2-What is the significance of time to virologic loss?) confirmation from larger datasets (e.g., PN018/019) will be needed. (For further information, click this summary's title to see Tables and Figures, click here to view the IHDRW 2008 program guide)


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Loss of raltegravir susceptibility in treated patients is conferred by multiple non-overlapping genetic pathways
IHDRW Abstract 7, Fransen S, et al.

In this study, investigators from Merck and Monogram Biosciences scrutinized the genetic linkage of N155H and Q148R(H/K) and the effect of these mutations alone and in combination with other resistance-associated mutations on raltegravir (RAL) susceptibility and IN replication capacity (IN RC) in a subset of subjects failing RAL (n=11). Clones were obtained and an analysis performed which demonstrated that (1) the N155H mutation and mutations at integrase position Q148 do not appear in the same viral variant, (2) distinct secondary mutations appear with these primary mutations, and (3) viral replication capacity varies depending on which primary and secondary mutations emerge. The investigators also created site-directed mutants to analyze the impact of N155H, Q148R/H/K, E92Q, and G140S/A alone and in combination. Although 9 of 11 patients in this subset had viral populations including mutations at N155 and Q148, clonal analysis showed that no viral population harbored single viral variants with mutations at both positions. As the summary above (Miller M, IHDRW Abstract 6) validates, resistance pathways stemming from these primary mutations do not appear to overlap. These primary mutations alone and, occasionally, solitary secondary mutations that were sometimes preferential as to which primary they appeared with, reduced susceptibility to RAL as measured by the PhenoSense assay. Replication capacity was reduced in viruses from RAL treatment failures in the majority of samples tested (p<0.0001, paired t test; p<0.0001, single value t test). Although N155H and Q148R/H/K proved the dominant initial pathways to failure, a small number of failure samples featured the Y143C/R mutation, either alone or with N155H or N155H plus Q148R/H/K. Analysis of site-directed mutants showed that E92Q plus N155H lowered susceptibility to RAL and decreased replication capacity much more than N155H alone. E92Q alone could also confer reduced susceptibility to RAL, and susceptibility was further reduced in G140S+Q148R or H double mutants, relative to the single mutant. G140A and G140S usually increased resistance when combined with G148 mutations. The exception to this rule was G140S plus G148K: G140S suppressed resistance conferred by Q148K alone. G140S plus Q148H or Q148K had lower replication capacity than Q148H or Q148K alone. But G140S plus Q148R did not have lower replication capacity than Q148R alone. Combinations of resistance mutations can have differential effects on RAL susceptibility and IN RC depending upon which amino acid is selected at a particular position. Together these findings disclose subtle variation in measures of resistance and replication capacity with separate mutation sets. But this study could not address whether these differences have any clinical relevance. (For further information, click this summary's title to see Tables and Figures, click here to view the IHDRW 2008 program guide)


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Section 2 (Section 3 and Section 1 Also Available)

Select presentations concerning nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance and the danger of leaving patients on failing NRTI regimens


Detection of Nonnucleoside Reverse-Transcriptase Inhibitor-Resistant HIV-1after Discontinuation of Virologically Suppressive Antiretroviral Therapy
Clin Infect Dis 2008;47. Hare CB, Mellors J, et al.

In this study, the investigators used standard and ultrasensitive techniques to detected nonnucleoside reverse-transcriptase inhibitor (NNRTI)-associated resistance mutations in 11 (20%) of 54 subjects who discontinued virologically suppressive NNRTI-containing antiretroviral therapy that included either efavirenz (EFV) or nevirapine (NVP). High-performance liquid chromatography was used to quantify EFV and NVP concentrations in plasma at the time of continuation of NNRTI therapy and every 4 weeks thereafter until levels were below the limits of detection (50 ng/mL for EFV and 200 ng/mL for NVP). The investigators considered therapeutic concentrations of EFV and NVP to be 1-4 mg/mL and 3-12 mg/mL, respectively. Resistance was detected in 45% and 14% of subjects with a baseline human immunodeficiency virus type 1 RNA level of 51-400 copies/mL and <50 copies/mL, respectively.Mutations remained detectable for at least 48 weeks in some subjects. It was observed that individuals who discontinue NNRTI-containing antiretroviral therapy when their plasma HIV-1 RNA level is <400 copies/mL are at substantial risk (20%) of virologic rebound with a NNRTI-resistant virus. Allele-specific PCR detected more resistance mutations in these subjects. This assay has also been shown to detect more transmitted HIV-1 drug resistance, which was associated with higher rates of virologic failure (VL). The risk of resistance was greater for those who discontinued therapy when HIV-1 RNA level was 51-400 copies/mL than when it was <50 copies/mL. This viral load may represent either intermittent or sustained low-level replication. And in contrast to earlier studies, discontinuation of NNRTIs 2 days before the other components of the antiretroviral regimen did not completely protect against resistance. In this multivariable analyses, both an HIV-1 RNA level of 51-400 copies/mL (OR, 4.9; 95% CI, 1.0-25.4;P=0.05) and subtherapeutic NNRTI concentrations (OR, 6.0; 95% CI, 1.2-32.4; P=.0.03) were predictive of resistance by either assay at the time of virologic rebound. Some study limitations were disclosed, but in aggregate, these observations suggest that prolonged interruption or discontinuation of NNRTI regimens during periods of low-level viral load should be avoided and underscore the importance of developing strategies that minimize resistance during planned interruptions of NNRTI-containing antiretroviral therapy. (For further information, click this summary's title to see abstract)


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Failing therapy with efavirenz results in significantly fewer mutations limiting to etravirine than failing therapy with nevirapine: on-treatment analyses from the CPCRA FIRST study

IHDRW Abstract 129, MacArthur R, Huppler Hullsiek K, et al.

The recently-approved nonnucleoside inhibitor (NNRTI) etravirine (ETV) has demonstrated virologic and clinical efficacy in the presence of previously-selected NNRTI mutations. In particular, the K103N mutation, which was the most frequently selected NNRTI mutation at baseline in DUET-1 and 2 clinical trials of ETV, appears to have no limiting effect on the activity of ETV. Conversely, 13 mutations in the reverse transcriptase (V90, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S)have been identified as limiting the activity of ETV. FIRST investigators sought to compare the risk of virological failure (VF) in 915 persons who started therapy on either EFV or NFV. Genotypic resistance testing was done at initial VF, defined as HIV RNA > 1,000 copies/ml at or after 4 months. The risk of VF was summarized with hazard ratios (HR) from COX proportional hazards models with time-updated indicators for NNRTI use and adjusted for baseline covariates. In this analysis, the use of EFV resulted in less NNRTI, NRTI or any class resistance than the use of NVP. Of note, the risk of VF and VF with any NNRTI, or any class resistance was significantly less for those taking EFV compared with NVP (HR=0.71, 0.53, 0.37, 0.55, respectively; all P-value < 0.001). Of those who experienced VF, 149 were on EFV at VF and 145 were on NVP. On those failing on EFV and NVP, respectively, specific NNRTI mutations were detected included 103N (47% vs. 28%), 106A/M (2% vs. 9%), 181C/I (2% vs. 53%) and 190A/S (5% vs. 14%); all P-value < 0.01. The authors noted that the mutation patterns suggest that subsequent suppression of HIV RNA with ETV-containing regimens may be more successful if initial therapy with EFV is used rather than NVP, although immunologic and clinical outcomes were similar for both groups; at least one of the mutations related to ETV (90I, 98G, 100I, 101E/P, 106I, 179D/F, 181C/I/V and 190 A/S) occurred less frequently in persons failing on EFV than on NVP (58% vs. 71%; P=0.02). (For further information, click this summary's title to view the poster)


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Increased phenotypic susceptibility to etravirine in HIV-1 with nucleoside reverse transcriptase inhibitor resistance

IHDRW Abstract 22. Benhamida J, Coakley E, Parkin NT, Chappey

Increased susceptibility, also known as hypersusceptability (HS), to the non-nucleoside RT inhibitors (NNRTIs) efavirenz (EFV), nevirapine (NVP) and delavirdine (DLV), associated with mutations selected by nucleoside RT inhibitors (NRTIs), has been previously reported and has been shown to have clinical benefit in some cases. However, HS has not been explored with the newest NNRTI etravirine (ETV). In this study, the median fold change (MFC) in ETV IC50 of groups of viruses containing various NRTI resistance-associated mutations (NAMs) was determined using data derived from 2,056 subtype B samples submitted for routine resistance testing. NAMs were defined as M41L, K65R, D67N, T69X, K70E/R, L74I/V, V75A/M/S/T, Y115F, Q151M, M184I/V, L210W, T215F/Y, and K219X (X =any non-WT amino acid). In addition, V118I and H208Y were considered based on previous associations with NNRTI HS. NNRTI mutations were defined as A98G, L100I, K101E/P, K103N/S, V106A/M, Y181X, Y188X, G190X, P225H, F227L, M230L, and P236L. In this study, HS was defined as fold change (FC) <0.4, and FC distributions between groups were compared). When present as the only NAM, V118I, M184V, and T215Y were significantly associated with reduced ETR MFC (P= < 0.05 vs. no NAMS control). Groups of viruses lacking NNRTI mutations containing various NAMs (often in combination with others) demonstrated varying degrees of increased ETV susceptibility. Statistically significant associations were observed for M41L, D67N, T69D/N, K70R L74I/V V118I M184V H208Y L210W, T215F/Y, and K219N/Q/R (P= < 0.05 vs. no NAMS control). In combination with 0 or 1 NNRTI mutations, ETR FC decreased with increasing number of NAMs. ETR FC was also reduced when one or multiple NAMs were present in combination with 2 or more NNRTI mutations. Resistance to NRTIs is associated with increased ETV susceptibility, causing HS when NNRTI resistance mutations are absent or few and reducing the level of resistance in combination with multiple NNRTI mutations. The authors noted that the clinical relevance of this phenomenon is unknown but deserves further study and may affect the derivation of genotype algorithms for prediction of reduced ETV susceptibility. Further validation of this data can be found in another presentation (i.e., Abstract 23 Picchio G, et al). Click this summary's title to see Tables and Figures, click here to view the entire IHDRW 2008 program guide)

 

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Section 3 (Section 2 and Section 1 Also Available)

Select presentation concerning an enhanced tropism assay.


 

Response to vicriviroc in HIV-Infected treatment-experienced subjects using an enhanced version of the Trofile HIV Co-receptor tropism assay [Trofile (ES)]: reanalysis of ACTG5211 results
IHDRW Abstract 88 Su Z, Reeves JD, et al.

A new, enhanced version of the Trofile HIV co-receptor tropism assay (Monogram Biosciences), Trofile (ES), is more useful for the selection of patients for CCR5 antagonist therapy and better determines if a patient's viral population is CCR5- (R5), CXCR4- (X4) or dual/mixed- (D/M) using. CCR5 antagonists have shown efficacy in suppressing R5 but not X4 or D/M HIV, according to a reanalysis of ACTG5211, a placebo controlled, dose ranging (5, 10, 15 mg), Phase 2b study of vicriviroc (VCV), a CCR5 antagonist in development, 118 treatment-experienced subjects with R5 virus were originally screened by the original, standard Trofile assay, VCV demonstrated potent virologic suppression in subjects with R5 virus at study screen and entry (1.83 log reduction at week 24, n=71). A reduced virologic response (P=0.007) was observed among 10 VCV recipients with R5 virus at study screen but D/M at entry (0.77 log reduction at week 24) by standard Trofile. The ACTG 5211 investigators hypothesized that enhanced Trofile (ES) might better identify low level CXCR4-using virus in the screening samples from subjects enrolled into this study and further optimize selection of patients who may benefit from CCR5 antagonists. Consequently, they used the enhanced Trofile (ES) to recheck stored viral samples from the highly experienced study participants randomized to 5, 10, or 15 mg of VCV or placebo plus an optimized background regimen (OBT). The investigators found that the enhanced Trofile (ES) assay allows improved detection of minor CXCR4-using variants in env clone mixtures (100% sensitivity at detecting X4 envs as low as 0.3%) and earlier detection of minor CXCR4-using subpopulations in longitudinal samples from multi-treatment experienced patients. The enhanced assay determined that 89 people had virus that used only the CCR5 (R5) coreceptor at screening for the trial. Re-checking these samples also found that 25 people had virus that could use either coreceptor (dual/mixed or DM virus) before they started VCV. Fifteen of those people--all with HIV classified as R5 virus-using by the standard assay--took VCV during the trial. Amongst all the VCV recipients and according to classification by Trofile (ES), subjects with R5 virus at study screen and entry by enhanced Trofile (ES) had greater reductions (p≤0.0001) in viral load at day 14 (-1.15 log) compared to subjects with D/M virus at screen (-0.09 log) and also greater reductions (p=0.0003) in viral load at week 24 (-1.95 log) compared to subjects with D/M virus at screen (-0.57 log). The authors also noted that reclassification of R5 virus as DM did not affect virologic response rates among people randomized to take placebo plus OBT and concluded that reanalysis of key study endpoints based on Trofile (ES) demonstrates improved antiretroviral activity of VCV and indicates that the recently approved Trofile (ES) is an improved .screening tool for determining patient eligibility for CCR5 antagonist therapy. (For further information, click here to view the IHDRW 2008 program guide)


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