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Initial Viral Decay (predicts viral suppression) to Assess the Relative Antiretroviral Potency of PI-, NNRTI- and NRTI-Sparing Regimens for First Line Therapy of HIV Infection
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AIDS: POST ACCEPTANCE, 21 September 2011

Haubrich, Richard H.; Riddler, Sharon A.; Ribaudo, Heather; DiRienzo, A. Gregory; Klingman, Karin L.; Garren, Kevin W.; Butcher, David L.; Rooney, James F.; Havlir, Diane V.; Mellors, John W.; for the AIDS Clinical Trials Group (ACTG) A5160 and A5142 Study Teams

"Importantly, we found that modeled phase-1 decay in the A5160 s sub-study population was strongly correlated week 1 HIV RNA reduction (Spearman correlation 0.78; P<0.001), indicating that HIV-1 RNA change after the first week of therapy can be used as a simpler

surrogate for the more complex sampling and modeling involved in estimating phase-1 decay."

"Taken together, these observations support the use of week 1 HIV-RNA change as an indicator of initial regimen activity and durability of suppression up to 48 weeks. The waning of the predictive effect of week 1 HIV RNA change over time is not surprising given the many other factors, such as adherence, side effects, and pill burden that influence longer-term virologic outcome."

"These findings add to the literature supporting the use of initial viral decay rate to assess new combinations of antiretrovirals for initial activity and durability of HIV suppression up to 48 weeks."


Objectives: To evaluate the effects of gender and initial antiretroviral regimen on decay of HIV RNA and virologic outcome.

Methods: We conducted a viral dynamics sub-study of A5142, a trial comparing lopinavir/ritonavir+efavirenz (LPV/EFV) versus LPV+2 NRTI (LPV) versus EFV+2 NRTI (EFV) in ARV-naive subjects. HIV RNA was measured at days 2,10, and 14 in the sub-study and at weeks 1,4, and 8 in A5142 participants. Two-phase viral decay was estimated in the sub-study with bi-exponential mixed-effects modeling and compared using Wilcoxon tests. Week 1 HIV RNA change was assessed as a predictor of virologic failure (HIV RNA above 50/ 200 copies/mL) at weeks 24-96 using logistic regression.

Results: 68 subjects were enrolled in the sub-study (median HIV RNA 4.9 log10 copies/mL). Median rates of phase-1 viral decay by treatment were 0.61(EFV/LPV), 0.53(LPV), and 0.63(EFV) day-1. Phase-1 decay was significantly faster for EFV than LPV (P = 0.023); other comparisons were not significant (P > 0.11). Viral decay did not differ by gender (P = 0.10). Week 1 HIV RNA change, calculated in 571 participants of A5142, was greater for the EFV (median -1.47 log10 copies/ml) than either the LPV/ EFV or LPV groups (-1.21 and -1.16 log10 copies/ml, respectively; P < 0.001). Week 1 HIV RNA change was associated with virologic failure above 50 copies/ mL at weeks 24 and 48 (P < 0.018), but not above 200 copies/mL or at week 96.

Conclusions: Phase-1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV RNA change predicted virologic outcome to week 48, but not at week 96.

Treatment with combination antiretroviral therapy (ART) results in rapid decay of plasma HIV RNA. Careful measurement of the initial viral decline (phase-1 decay half-life), using multiple HIV RNA measurements in the first 7-10 days of therapy, has been useful to compare regimen potency and may be a predictor of longer term virologic response [1-5]. Efavirenz- containing regimens have been shown to have faster phase-1 decay than nelfinavir-containing regimens and this greater decay rate was associated with better viral suppression at week 24 [1]. Efavirenz plus nucleoside reverse transcriptase inhibitors (NRTI) produced faster phase I decay than a triple nucleoside combination of zidovudine, lamivudine and abacavir in AIDS Clinical Trials Group (ACTG) study 5095; a result that was consistent with the primary virologic results that showed better virologic outcome in the efavirenz-containing regimens [6]. Addition of enfuvirtide also increased viral decay when added to a four drug regimen in treatment naïve subjects [7]. Phase-1 decay with raltegravir, given as monotherapy for 10 days yielded similar viral decay to some three drug combinations (half-life between 1.1 and 1.3 days) [8]. Although many factors ultimately determine the longer term success of a regimen, some studies have suggested that early virologic changes are associated with longer-term virologic outcomes, but other studies do not find associations [2,6,9-11]. Several cohort studies have described differences in HIV-1 RNA levels between men and women [12,13]. These differences have been most apparent in early disease and have not been associated with disease progression. Few studies have evaluated gender-based differences in the observed viral decay rate after initiation of therapy.

Not all antiretroviral combinations can be tested in large randomized studies designed to assess comparable efficacy; further, some combinations that intuitively seemed acceptable have resulted in early and substantial failure (i.e., TDF/ABC/3TC) [14]. Additionally, assessment of phase 1 decay requires multiple HIVRNA levels, is inconvenient and expensive. HIV RNA changes over one week of treatment have correlated with phase 1 decay and may represent an alternative method to assess regimen potency and predict longer term virologic responses [1].

The primary objectives of this study, therefore, were to compare phase-1 viral decay rate of three regimens for initial therapy: lopinavir/ritonavir . efavirenz, lopinavir/ritonavir plus 2 NRTI versus efavirenz plus 2 NRTI; to evaluate gender differences in viral decay rates; and to evaluate the change in HIV RNA from baseline to week 1 as a potential marker of phase 1 viral decay and as a predictor of longer term virologic outcome.

HIV RNA week 1 log10 Change from Baseline as a

Predictor of Longer Term Viral Suppression

The ability of week 1 change in HIV RNA to predict longer term virologic outcome was studied in multivariate logistic regression models adjusted for baseline HIV RNA with virologic failure defined by levels above 50 and 200 copies/mL at weeks 24, 48, and 96 (Table 2). Each additional log10 decrease in HIV RNA at week 1 was associated with a reduction in the odds of week 24 HIV RNA>50 copies/mL (odds ratio 0.22, 95% confidence interval 0.14, 0.35; P<0.001) but not significantly with virologic failure above 200 copies/mL (P=0.18). There was no evidence of an interaction between baseline HIV RNA and week 1 change (P=0.80) with respect to their association with week 24 outcomes. Similarly, after accounting for baseline HIV RNA, the week 1 change was associated with a lower odds of week 48 HIV RNA>50 copies/mL (0.61, 95% CI, 0.40, 0.91, P=0.018), but not with the virologic failure above 200 copies/mL (P=0.15). There were no significant associations between week 1 change and virologic failure at week 96 using either the 50 or 200 copies/mL failure thresholds.

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