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Pretreatment Coreceptor Preference Affects Virologic Response in Naive
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Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
Which HIV coreceptor on CD4 cells the virus prefers using before antiretroviral therapy begins independently affected 24- and 48-week virologic response in previously untreated people starting either atazanavir/ritonavir or nevirapine plus tenofovir/emtricitabine [1]. In contrast, pretreatment coreceptor preference (tropism) had no discernible impact on CD4-cell response in these ARTEN trial participants.
This analysis involved ARTEN enrollees with pretreatment plasma samples and 48-week data. The investigators excluded people who stopped treatment before week 48 because of side effects or loss to follow-up, but they included those who stopped treatment because of virologic failure. They determined tropism by analyzing the HIV V3 gene sequence with the geno2pheno tool. The investigators defined virologic response at attaining a viral load below 50 copies and immunologic response as the extent of CD4-cell recovery.
Eduardo Seclen (Carlos III Hospital, Madrid) and colleagues focused on 428 of 569 ARTEN participants, 146 randomized to atazanavir/ritonavir and 282 randomized to nevirapine. Most analyzed study participants (86%) were men, 22% were infected with non-B subtypes, and 10.5% had HCV infection, with no significant differences between the atazanavir and nevirapine arms. Pretreatment viral load (median 5.18 log) and CD4 count (median 183) were also statistically similar between treatment arms.
The investigators successfully amplified the V3 region in 391 study participants and classified pretreatment virus as R5-using in 336 people (86%) and as X4-using in 55 (14%). Median pretreatment viral load was significantly lower in the R5 group (median 5.16 versus 5.38 log, P = 0.044), and pretreatment CD4 count was significantly higher (188 versus 145, P < 0.001).
CD4 gains at 24 and 48 weeks did not differ significantly in people with R5 or X4 virus, but virologic response did. After 24 weeks of treatment, 83% with R5 virus versus 61% with X4 virus had a viral load below 50 copies (P = 0.001). After 48 weeks, proportions with a sub-50 load were 92% in the R5 group and 77% in the X4 group (P = 0.009). Virologic response did not differ significantly by treatment arm at week 24 or 48.
To identify response predictors, Seclen built a multivariate model that considered gender, age, viral tropism, treatment arm, pretreatment viral load and CD4 count, HCV coinfection, and HIV-1 subtype. Each 10-fold higher viral load before treatment independently lowered chances of response at weeks 24 and 48. At week 48 each 10-fold higher pretreatment viral load lowered virologic response chances almost 60% (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20 to 0.84, P = 0.014). Each 100-cell higher pretreatment CD4 count improved chances of 48-week virologic response 68% (OR 1.68, 95% CI 1.04 to 2.72, P = 0.035).
Having R5 virus before treatment more than doubled chances of virologic response at week 24 (OR 2.62, 95% CI 1.24 to 5.52, P = 0.012). At week 48, pretreatment R5 virus also more than doubled chances of virologic response, though the association fell short of statistical significance (OR 2.43, 95% CI 0.96 to 6.16, P = 0.061). When the investigators considered only people with subtype B virus, R5 tropism before treatment more than tripled chances of virologic response at week 24 (OR 3.50, 95% CI 1.61 to 7.64, P = 0.002) and quadruped chances of virologic response at week 48 (OR 4.02, 95% CI 1.48 to 10.96, P = 0.007). Pretreatment tropism did not affect CD4 response in ARTEN participants.
Infection with a non-B subtype tended to lower virologic response chances at 48 weeks (OR 0.43, 95% CI 0.18 to 1.01, P = 0.054). Seclen and colleagues suggested that "lower accuracy of genotypic tools to assess viral tropism in non-B subtypes might have precluded a proper evaluation of the impact of viral tropism in this population."
Because of the correlation between pretreatment tropism and virologic response, the investigators proposed that "baseline assessment of HIV tropism might be considered before beginning any first-line antiretroviral therapy." At this meeting a 60-member European panel of tropism and antiretroviral experts recommended geno2pheno or ESTA tropism testing for antiretroviral-naive people "in whom toxicity or limited therapeutic options are foreseen" [2].
References
1. Secklen Gonzalez M, Martin-Carbonero L, et al. Impact of baseline HIV-1 tropism on viral response and CD4 gains in antiretroviral-naive patients. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract O124.
2. LPR, Wensing AMJ, Kaiser R, et al. Consensus statement of the European guidelines on clinical management of HIV-1 tropism testing. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract O121.
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