Library Volume 1, Issue 1: Resistance Reporter© from CROI 2007



14TH CROI (Conference on Retroviruses and Opportunistic Infections): Feb. 25-28, 2007, Los Angeles, CA: CROI 2007

While at CROI 2007, our expert staff along with Resistance Reporter©'s highly respected editorial board sorted through the many presentations related to HIV resistance and selected 6 scientifically-important presentations to cover here in our premier 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 presentations related to epidemiology of transmitted HIV drug resistance and effects of specific baseline resistance
  • Section 2: Select presentations related to new ART


    • Section 1 (Section 2 Also Available)

    Select presentations related to epidemiology of transmitted HIV drug resistance and effects of specific baseline resistance


    Antiretroviral Drug-resistance Mutations and Subtypes in Drug-naive Persons Newly Diagnosed with HIV-1 Infection, US, March 2003 to October 2006

    Poster# 648, Wheeler W (CDC)

    Data from the Variant, Atypical and Resistant HIV Surveillance systems were used to estimate the prevalence of antiretroviral drug resistance mutations and to determine HIV-1 subtypes in this CDC study. Using specimens drawn from March 2003 to October 2006 from 409 sites in 11 states, RT and PR sequence data were identified from newly diagnosed, confidentially tested, and drug-naive persons. Major ARV drug resistance mutations were defined according to the International AIDS Society - USA guidelines, and HIV subtypes were derived using the Stanford online HIV Drug Resistance Database. Antiretroviral drug resistance mutations were observed in 10.4% of 3130 specimens, ranging from 6.3% to 13.0%. Drug resistance to nucleoside analog reverse transcriptase inhibitors (NRTIs) was found in 3.6%, to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 6.9%, and to protease inhibitors (PIs) in 2.4%. Multi-drug resistance mutations were noted in 1.9% of persons. Samples were overwhelmingly subtype B (94.9%). Most common other subtypes were C and CRF02_AG. The presence of resistance mutations in the non-B subtypes was not significantly different from the subtype B samples. See Oral Presentation 59, Schapiro, J, Impact of Subtype on HIV Drug Resistance for a discussion of the implications of non-B subtypes on HIV drug resistance.


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    Transmission of HIV Drug Resistance and Treatment Response

    Oral Presentation# 60, Little S

    Transmitted Drug Resistance (TDR) in newly infected patients was in the range of 11-15%, above the threshold of 4-5% at which primary resistance testing is cost-effective. Genotypic testing is suggested for this population due to faster turnaround time. Little reported that resistant virus persisted about 2 years before there was any evidence of the emergence of wild type virus. Transmission of drug resistant virus was not associated with decreased replication capacity. Overall, patients with drug resistant virus at baseline (viral load at time of ART initiation) did not have viral loads significantly different from patients with wild type virus. However, there were significant differences depending on the drug class. Patients with NNRTI - resistant virus had significantly higher viral loads at initial evaluation , whereas those with NRTI -resistant virus had lower viral loads; those with PI - resistant virus had marginally lower viral loads. These effects persisted even after three years of follow up, except that VL differences among patients with PI-resistant virus disappeared over time . The study has been going on for just over 10 years (n=793). Little showed data from two subgroups: The first group contained those who initiated ART from 1995 to mid 2000 period; the second, those who initiated later. The earlier time period predated the recommendations for prospective drug resistance testing for patients with primary infection. Patients who were identified during this time period received on average a smaller number of active antiretroviral agents in their initial regimen. During the latter time period prospective resistance testing became standard of care. Patients treated during this latter period on average received a significantly larger number of active drugs than did the earlier group . The data presented showed only a trend for patients with resistant virus to take longer to achieve complete suppression. However, it is difficult to assess these results for two reasons: the disparity between patient groups in regards to prospective resistance testing, and the fact that regardless of time period most patients in this study started treatment with more than three active agents. See also CROI 2007 abstracts 648 above and 665, below.


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    Baseline Resistance to NNRTI as a Predictor of Virologic Failure in Treatment-naïve Subjects Receiving Efavirenz-based Regimens in ACTG A5095

    Poster# 665, Kuritzkes D

    In ACTG5095, patients were randomized to receive either 2 or 3 NRTIs in addition to efavirenz (EFV). This sub-study analyzed those with treatment failure. They were compared to patients from the larger cohort, creating a case-cohort sample of 342 patients with analyzable data. The relative risk of virologic failure was compared in the presence or absence of baseline EFV resistance. In an analysis that adjusted for other risk factors including race/ethnicity and adherence, the presence of EFV resistance at baseline was associated with a 3.13 -fold increase in risk of virologic failure. All 13 subjects in the ZDV/3TC/EFV arm with EFV resistance at baseline experienced treatment failure. Interestingly, the only patients with EFV-resistant virus who did not experience virologic failure were patients who received EFV plus 3 NRTIs (n=3) . These findings support guidelines recommending resistance testing prior to initiating ART.


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    Section 2 (Section 1 Also Available)

    Select presentations related to new ART


    Defining the Upper and Lower Phenotypic Clinical Cut-offs for Darunavir/Ritonavir by the PhenoSense Assay

    Poster# 610, Coakley E

    The POWER 1, 2, and 3 trials demonstrated high efficacy of darunavir/ritonavir (DRV/r) in treatment-experienced patients. Four-week RNA outcomes were evaluated to define upper and lower efficacy cutoffs for DRV/r levels using the PhenoSense HIV test by Monogram Biosciences. Patients taking enfuvirtide (T-20, Fuzeon) were eliminated from the dataset. Eighty-seven patients had no active antiretroviral agents in their background therapy and so were on functional monotherapy with DRV/r. The lower clinical cut-off was defined as the fold change where the HIV RNA response was first observed to decline relative to the wild type reference population. The upper clinical cut-off was defined as the fold change above which the HIV RNA change from baseline was less than -0.3 log10 copies/mL. The week 4 HIV RNA reductions from baseline were analyzed to come up with the lower DRV phenotypic clinical cut-off of 10 fold. Additional analyses were performed using 2-week and 8-week data and generated consistent results. A gradual reduction in HIV RNA response was seen as the fold change increased above 10; the upper clinical cut-off for DRV was defined as a fold change of 90.


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    Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1

    Oral presentations# 104aLB, Nelson, M, and # 104bLB, Lalezari J

    24-Week Results of a Phase 2b/3 Study in (a) Europe, Australia, and USA and (b) in the US and Canada: 24-week results. These abstracts presented results of a planned 24-week interim analysis. Patients with triple-class ARV experience, only R5-tropic virus, and VL over 5000 were randomized to receive placebo or Maraviroc (MVC) 300 mg once or twice daily plus optimized background therapy (OBT) consisting t of 3 to 6 antiretroviral drugs with or without low -dose ritonavir. Dose adjustments were made when optimized background regimens (OBR) included a PI other than tipranavir and/or delavirdine. The primary endpoint was mean reduction in HIV-1 RNA from baseline to week 24. Motivate 1 in the US and Canada included 585 patients who received at least one dose of study drug. Motivate 2 in Europe, Australia, and the US included 464 patients who received at least one dose of study drug. Viral load and CD4 Results for patients taking MVC were significantly better than for those on placebo in both of these studies. The treatment difference compared to placebo exceeded 1 log of VL reduction, with slightly better results in the US and Canada. The % of patients achieving <50 VL exceeded 40% and the mean change in CD4 cells from baseline exceeded 100 across all of the MVC-containing arms. Maraviroc was generally well-tolerated, with no substantial difference in adverse events as compared to the placebo control arm.


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    Results of BENCHMRK-1 & 2, Phase III Studies Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus

    Oral presentations 105aLB Cooper D & 105bLB, Steigbigel R

    BENCHMRK 1 was conducted in Europe, Asia, the Pacific, and Peru. BENCHMRK-2 was conducted in North, Central and South America. These results are from a planned 16-week interim analysis of data from a 2:1 randomization of patients to MK-0518 400 mg bid vs placebo. This new compound, now called raltegravir, blocks the integration of the virus into host cell DNA. The Benchmrk 1 and 2 studies respectively enrolled 350 and 349 patients with triple-class drug failure defined as genotypic/phenotypic resistance to 1 or more drugs in each of the 3 classes and HIV RNA viral load of more than 1000 copies/mL. Background therapy was optimized. Combined interim analysis of the 2 studies found that 79% of patients receiving raltegravir plus optimized background therapy (OBT) suppressed the virus below 400 copies/mL at week 16 compared with 43% of those receiving placebo plus OBT. There was no significant difference in CD4+ cell increases between the placebo and treatment arms.


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