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Library Volume 1, Issue 4: Resistance Reporter^© from IAS 2007

4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 22-25, 2007
This important International AIDS Society conference features reports on the latest developments in the areas of basic, clinical and prevention science. The members of Resistance Reporter©'s highly respected editorial board were there; we selected the 6 scientifically-important presentations that would best support your clinical practice. These selections have been grouped into two sections that provide clinically-relevant information related to a specific 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 clinical and epidemiological factors associated with genotypic resistance
Section 2: Select presentations related to new agents

Section 1 (Section 2 Also Available)

Clinical and epidemiological factors associated with genotypic resistance

Analysis of Multi-class Drug Resistance in a NYC Clinic

Abstract #CDB021, Sandkovsky U

To determine the risk factors and clinical outcomes associated with extensive multi-class drug resistance, Sandkovsky and colleagues conducted a retrospective review of 505 HIV-infected individuals who underwent genotype testing at a New York City HIV clinic between January 2002 and December 2004 and then tracked the outcomes of these patients up to 48 months later. Although 22% of patients (n=110) showed resistance to 2 drug classes and 10% (n=52) demonstrated resistance to at least 1 drug in all 3 classes, only 6% of individuals (n=30) exhibited severe multi-class resistance, defined as resistance to at least 6 nucleoside reverse transcriptase inhibitors (NRTIs), at least 2 nonnucleoside reverse transcriptase inhibitors (NNRTIs), and at least 5 protease inhibitors (PIs). A comparison of characteristics between the 30 patients with severe multi-class resistance and the group of 80 patients with 2- or 3-class resistance revealed a significantly higher proportion of men who have sex with men in the former versus latter group (47% vs. 31%; P=.04). Other significant differences between the patient groups with severe multi-class resistance versus 2- or 3-class resistance included the median CD4+ cell count prior to genotyping (155 vs. 203 cells/mm ³; P=.024), the most recent median CD4+ cell count (101 vs. 285 cells/mm ³; P=.0029), and the mortality rate during follow-up (30% vs 6.25%; odds ratio [OR]: 6.42; 95% confidence interval [CI]: 1.94-21.2; P=.003). In addition, only 13% of patients with severe multi-class resistance achieved virologic suppression below 400 copies/mL at any point during follow-up compared with 45% of patients with 2- or 3-class resistance (OR: 5.31; 95% CI: 1.7-16.6; P=.004).

Baseline Antiretroviral Resistance Profile and Correlation with Clinical Events in the OPTIMA Trial

Abstract #TUPEB044, Holodniy M

The OPTIMA trial is an ongoing study with a 2 x 2 factorial design in which 368 patients have been randomized to (a) a 3-month drug-free period versus no drug-free period and (b) mega-HAART (> 4 drugs) versus standard HAART ( < 4 drugs). All patients had documented 3-class drug-resistant virus at baseline or had failed at least 2 different multi-drug regimens that contained drugs in all 3 classes. Holodniy and colleagues employed logistic regression analysis to determine which baseline characteristics correlate with clinical outcomes in these individuals. After a mean follow-up period of 1.5 years, 55.2% of patients achieved a successful viral load response (HIV-1 RNA decline > 1 log10 copies/mL at 24 weeks), and 32% of individuals died or experienced a new or recurrent AIDS event. Baseline CD4+ cell count was the only strong predictor of both virologic response (OR: 1.004; 95% CI: 1.001-1.007; P=.0145) and clinical events (OR: 0.992; 95% CI: 0.988-0.996; P<.0001) according to multivariate analysis. The PI mutation score predicted for virologic response according to multivariate analysis (OR: 0.850; 95% CI: 0.733-0.985; P=.0309). No specific antiretroviral resistance markers (e.g., phenotypic susceptibility score; number of thymidine analog mutations; presence of M184V; NRTI, NNRTI, or PI mutation score) predicted future clinical events or death according to multivariate analysis. Interestingly, individuals who were naïve to tenofovir had a higher likelihood of experiencing a clinical event (OR: 3.257; 95% CI: 1.603-6.618; P=.0011).

RELATED ARTICLES:

Jaén A, Buira E, Giménez A, et al. Clinical and epidemiological factors associated with genotypic resistance among HIV+ patients exposed to antiretrovirals with treatment failure. Program and abstracts of the 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 22-25, 2007; Sydney, Australia. Abstract CDB118.
Tozzi V, Zaccarelli M, Bonfigli S, et al. Drug-class-wide resistance to antiretrovirals in HIV-infected patients failing therapy: prevalence, risk factors and virological outcome. Antivir Ther. 2006;11:553-560.
Ross L, Lim ML, Liao Q, et al. Prevalence of antiretroviral drug resistance and resistance-associated mutations in antiretroviral therapy-naive HIV-infected individuals from 40 United States cities. HIV Clin Trials. 2007;8:1-8.
Richard N, Juntilla M, Abraha A, et al. High prevalence of antiretroviral resistance in treated Ugandans infected with non-subtype B human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 2004;20:355-364.

Section 2 (Section 1 Also Available)

Select presentations related to new agents

Relationship Between HIV Co-receptor Tropism and Disease Progression in Persons with Untreated Chronic HIV Infection

Abstract #TUPEB092, Goetz M

A prospective epidemiologic study conducted by Goetz and colleagues confirmed that individuals with dual/mixed-tropic HIV experience faster disease progression in the absence of treatment compared with individuals with CCR5-tropic HIV. A total of 294 treatment-naive individuals with a CD4+ cell count above 450 cells/mm ³and a viral load greater than 1000 copies/mL underwent viral tropism testing and were then prospectively followed. The majority of patients had R5-tropic HIV (89%), whereas only 32 patients had dual/mixed-tropic HIV. Patients with dual/mixed-tropic virus versus R5-tropic virus were more likely to be Latino (25% vs. 8%) and to have a lower CD4+ cell count at baseline (571 vs. 624 cells/mm ³). No other baseline characteristics differed between the tropism groups. During the study, patients with dual/mixed-tropic HIV demonstrated faster disease progression to the composite endpoint of a CD4+ cell count below 350 cells/mm ³, the need to initiate treatment, or death compared with individuals with R5-tropic HIV (P=.004 for the composite endpoint). The presence of dual/mixed-tropic virus was also significantly associated with a CD4+ cell count below 350 cells/mm ³and the need to initiate treatment in separate regression analyses. After adjusting for potential confounding factors, the presence of dual/mixed-tropic HIV was associated with a 2.11-fold increased risk of disease progression compared with the presence of R5-tropic virus (P=.004). This finding was similar to the increased risk of disease progression associated with each 1-log ₁₀ increase in viral load (relative risk: 1.91; P<.001).

Efficacy of Maraviroc in Combination with at Least One Other Potent New Antiretroviral Drug: 24-Week Combined Analysis of the MOTIVATE 1 and 2 Studies

Abstract #WEPEB115LB, van der Ryst E

A pooled analysis of the ongoing, randomized, double-blind, placebo-controlled, phase III MOTIVATE trials showed that maraviroc produces better virologic efficacy in treatment-experienced individuals when combined with at least 1 active agent in the optimized background regimen (OBR). The 1076 individuals enrolled in these studies were all resistant to at least 1 agent from the 3 standard antiretroviral classes or they were resistant to at least 2 PIs. According to virologic data collected at 24 weeks, higher proportions of individuals who received either once-daily or twice-daily maraviroc achieved undetectable viral loads if they also received enfuvirtide, lopinavir, tipranavir, (fos)amprenavir, or atazanavir for the first time. (Approximately 87% of individuals receiving these agents also received low-dose ritonavir.) For example, 53%-64% of maraviroc-treated patients achieved a viral load below 50 copies/mL if they also received enfuvirtide for the first time, compared with 31%-34% of maraviroc-treated patients who received enfuvirtide but who were experienced (i.e., had a history of enfuvirtide use) or resistant to the agent. In comparison, 36% and 6% of placebo-treated patients who received enfuvirtide and who were enfuvirtide naive or experienced, respectively, achieved a viral load below 50 copies/mL. In accord with these findings, the virologic response rate increased with an increasing genotypic susceptibility score (GSS) (i.e., the number of agents in the OBR to which a patient's virus was susceptible). The proportion of maraviroc-treated patients versus placebo-treated patients who attained a viral load below 50 copies/mL at 24 weeks was 28%-33% versus 2% for individuals with a GSS of 0, 47% (for both arms) versus 11% for individuals with a GSS of 1, 54%-56% versus 37% for individuals with a GSS of 2, and 59%-62% versus 51% for individuals with a GSS of 3 or more.

DUET-2: 24-Week Results of a Phase III Randomised Double-blind Trial to Evaluate the Efficacy and Safety of TMC125 Versus Placebo in 591 Treatment-experienced HIV-1 Infected Patients

Abstract #WESS204-2, Katlama C

Similar to the above study, a pooled interim analysis of the ongoing DUET trials showed that use of etravirine in combination with an OBR of darunavir/ritonavir and optimized NRTIs, with or without enfuvirtide, produced better virologic response rates compared with placebo plus the OBR after 24 weeks of therapy in 1203 treatment-experienced individuals. Most patients - about 95% received darunavir/ritonavir for the first time, meaning that most individuals received at least 1 active agent regardless of their assigned treatment arm. In both DUET studies, more individuals who received etravirine plus an OBR (essentially 2 active agents) versus placebo and an OBR (essentially 1 active agent) achieved a viral load below 50 copies/mL (DUET-1: 56% vs. 39%, P=.005; DUET-2: 62% vs.44%; P=.0003). Also similar to the MOTIVATE findings, the virologic response rate increased with an increasing number of active agents in the OBR. The proportion of etravirine-treated patients versus placebo-treated patients who attained a viral load below 50 copies/mL at 24 weeks was 44%-47% versus 7%-9% for individuals with no active agents in the OBR, 59%-62% versus 24%-35% for individuals with 1 active agent, 68%-82% versus 61%-70% for individuals with 2 active agents, and 66%-80% versus 65%-73% for individuals with 3 or more active agents. Thirteen mutations associated with a diminished response to etravirine were identified (V90I, L100I, V106I, Y181C/I/V, A98G, K101E/P, V179D/F, G190A/S), but at least 3 of these mutations had to be present in combination before the response to etravirine was diminished to levels on par with that of placebo.

A Multicenter, Randomized, Double-blind, Comparative Trial of a Novel CCR5 Antagonist, Maraviroc Versus Efavirenz, Both in Combination with Combivir (Zidovudine [ZDV]/Lamivudine [3TC]), for the Treatment of Antiretroviral Naive Subjects Infected with R5 HIV-1: Week 48 Results of the MERIT Study

Abstract #WESS104, Saag M

Although maraviroc has demonstrated potent activity in treatment-experienced patients, its efficacy in treatment-naïve patients, who are more likely to have R5-tropic HIV, is not yet well defined. This phase III trial compared maraviroc 300 mg twice daily with efavirenz 600 mg once daily, both in combination with zidovudine/lamivudine, in 740 treatment-naïve patients with R5-tropic HIV and detectable viral loads. The primary endpoint was non-inferiority at < 400 c/mL; if the study met non inferiority at that endpoint the pre-planned primary analysis was then to test the < 50 c/mL endpoint for non-inferiority. Maraviroc treatment met the noninferiority criteria in comparison with efavirenz (difference in the lower bounds of the 97.5% CIs for each arm < -10%) with regard to the proportion of patients with a viral load below 400 copies/mL at 48 weeks (70.6% vs. 73.1%; difference in lower bound of 97.5% CI: -9.5%), but not for a viral load below 50 copies/mL at 48 weeks (65.3% vs. 69.3%; difference in lower bound of 97.5% CI: -10.9%). Maraviroc produced a greater increase in CD4+ cell count at 48 weeks than efavirenz (+170 vs. +144 cells/mm ³). Although there were more discontinuations due to adverse events in the efavirenz arm (13.6% for EFV vs 4.2% for MVC) there were more discontinuations due to lack of efficacy in the maraviroc arm (4.2% for EFV vs 11.9% for MVC).