Overall, individuals with higher baseline HIV-RNA levels tended to have larger phase 1 viral decay rates, but this difference was not statistically significant (P = 0.26; Fig. 2b), and caution is needed in interpretation because of the small number of participants in the high HIV-RNA stratum. The difference in phase 1 viral decay rate between the EFV and LPV groups was observed in the stratum with lower screening HIV-RNA (<100 000 copies/ml). In this stratum, the median viral decay rate was 0.64 (IQR 0.56–0.72, n = 20) per day for the EFV group compared with 0.50 (IQR 0.32–0.60, n = 16) per day for LPV group (P = 0.01). In contrast, there was no significant difference between the viral decay rates in the EFV versus LPV groups with higher screening HIV-RNA [EFV (n = 5) median 0.62 versus LPV (n = 6) 0.66; P = 1.0).
There was no significant difference between men and women in the phase 1 viral decay rates (Fig. 2c). The median (IQR) decay rate for women was 0.57 (038–0.67) per day and for men was 0.63 (0.55– 0.67) per day (P = 0.10). The treatment group differences in phase 1 decay were observed across the subgroups of men and women.
Phase 2 HIV-RNA decay in substudy participants
Phase 2 HIV-RNA decay rates by treatment group (Table 1) showed an opposite pattern compared with the phase 1 decay of the LPV and LPV/EFV groups having similar decay rates, and the EFV group having a slower decay rate (0.046, 0.045 and 0.036 per day, respectively; LPV versus EFV, P = 0.003; others P > 0.2). Phase 2 viral decay rates were higher across treatment groups in individuals with HIV-RNA of at least 100 000 copies/ml versus less than 100 000 copies/ml (median 0.048 per day compared with 0.038 per day; P < 0.001), but because of small numbers of individuals in the high HIV-RNA stratum, most of the difference in phase 2 decay between LPV and EFV groups was in the stratum with screening HIV-RNA less than 100 000 copies/ml. Phase 2 values in this stratum were 0.043 and 0.034 per day, respectively (P < 0.001). No difference in phase 2 decay rates were detected between men and women (P = 0.54).
Transition from first-phase to second-phase decay
To explore further the treatment group differences in the phase 1 and phase 2 decay, the transition between phases was evaluated by identifying the HIV-RNA level and the day when the rate of change of the phase 2 decay processes became greater than the rate of change of the phase 1 decay process. Individuals in the EFV group transitioned from phase 1 to phase 2 at a lower HIV-RNA value than the LPV group (median 398 versus 1100 copies/ml) and at an earlier time point (median 12 versus 14 days; Fig. 3). Although censoring of HIV-RNA values in the EFV group could partially explain the observations (there were five individuals in the EFV group versus one in the LPV group that were censored before day 56), the biexponential model includes multiple imputation methods to partially account for the greater censoring in the EFV group. Phase 1 and phase 2 transition at a lower HIV-RNA in the EFV group may represent greater reduction in short-lived virus-producing cells in the EFV versus LPV group and relative enrichment for longer living cells manifest as slower phase 2 decay in the EFV. However, given the lower baseline HIV-RNA in the EFV group and the variation in the estimated decay parameters, these data should be interpreted with caution and considered to be hypothesis generating.
Correlation between phase 1 decay and week 1 change in substudy participants
To evaluate the utility of using the single HIV-RNA measurement at week 1 of therapy as a potential surrogate for the more detailed phase 1 decay modeling, the correlation between the phase 1 decay rate and week 1 change in HIV-RNA was evaluated in the substudy. A high degree of correlation was observed between the two measures (Spearman's correlation −0.78; P < 0.001, Supplemental Figure 1, http://links.lww.com/QAD/A184) and were consistent across all treatment group and sex comparisons (Fig. 2). Consequently, further analyses of potential parameters influencing initial HIV decline including treatment group, sex, race/ethnicity, and choice of NRTI were performed using the larger A5142 population to improve statistical power.
Week 1 HIV-RNA change in A5142 individuals
A total of 573 individuals were evaluable for the week 1 log10 change in HIV-RNA analysis (Fig. 4). Individuals randomized to the EFV group had a significantly greater median week 1 log10 change in HIV-RNA (−1.47, IQR −1.83 to −1.15) than those in either the LPV/EFV (−1.21, −1.58 to −0.90) or the LPV group (−1.16, −1.52 to −0.87; P < 0.001 for each pairwise comparison with EFV; Fig. 4). Across all treatment groups combined, individuals with baseline HIV-RNA of at least 100 000 copies/ml had larger week 1 change compared with those with lower baseline HIV-RNA (P < 0.001); the median change was −1.62 copies/ml (IQR −1.92 to −1.29) compared with −1.15 copies/ml (IQR −1.48 to −0.85; P < 0.001). After adjusting for initial HIV-RNA level, the week 1 change associated with the EFV group remained greater than both the LPV and LPV/EFV groups (P < 0.001). There was no interaction between treatment and initial HIV-RNA (P = 0.11 overall, pairwise interaction terms >0.26). No differences in week 1 change were detected between men and women (P = 0.51), by self-reported race/ethnicity (P = 0.60), or by choice of NRTI (P = 0.82).
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 of more than 50 copies/ml [odds ratio 0.22, 95% confidence interval (CI) 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 of more than 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.
Initial viral clearance, as evaluated by phase 1 HIV-RNA decay, was significantly greater for individuals treated with EFV with two NRTI than LPV with two NRTI. The NRTI-sparing regimen of LPV–EFV had initial viral clearance similar to that for EFV with two NRTI. These results are concordant with the overall results of A5142, which found that individuals randomized to the EFV group reached HIV-RNA of less than 50 copies/ml faster (78% for the EFV and 62% for the LPV groups at week 24) and had significantly longer time to virologic failure than those in the LPV group . The viral decay rate for the LPV/EFV arm was also consistent with the overall results of A5142, suggesting that phase 1 decay on this regimen is driven by EFV. As with other reports, phase 1 decay was not significantly different for individuals by sex and race/ethnicity [1,6,11].
Importantly, we found that modeled phase 1 decay in the A5160s substudy population strongly correlated with week 1 HIV-RNA reduction (Spearman's 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. Furthermore, week 1 HIV-RNA decline was greatest in the EFV with two NRTI arm of A5142 and that greater week 1 HIV-RNA reductions were predictive of lower odds of virologic failure at weeks 24 and 48 (but not 96), as defined by HIV-RNA values above 50 copies/ml. 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. Furthermore, week 1 HIV-RNA change was not predictive of virologic failure at more than 200 copies/ml, suggesting that other factors are involved in the extent of virologic failure, including emergence of HIV drug resistance.
Some limitations of this study should be noted, particularly for the substudy. Censoring of HIV-RNA values below 50 copies/ ml could affect estimates of phase 2 decay in the substudy, although we used multiple imputation methods to partially address this issue. Differences, although minor, in pretherapy HIV-RNA levels between substudy treatment groups could have impacted decay estimates, and the relatively small number of substudy individuals in the high HIV-RNA stratum complicates interpretation, as we have cautioned. In addition, the relationship between week 1 HIV-RNA changes and week 24–96 HIV-RNA suppression in A5142 could be confounded by factors such as drop out and differential regimen adherence. This is, in fact, suggested by stronger correlations with week 24 than week 96 results. Despite these limitations, this study provides important new insight into the relations between phase 1 decay, week 1 HIV-RNA change, and longer term virologic outcome.
These findings add to the body of evidence that early viral decay after initiation of combination ART can be useful to evaluate the likelihood of longer term viral suppression. Potentially, novel combinations of two or more antiretroviral agents could be assessed in short-term studies of 7–14 days; and, if adequate phase 1 decay or week 1 HIV-RNA reductions are achieved, then further testing of the combinations could be pursued and combinations that have inadequate potency could be avoided. However, these findings do not guarantee a link between early viral decay and longer term suppression for combinations other than the ones evaluated here such as those that contain raltegravir. Early response to new drug combinations having different mechanisms of action may be less predictive.
Phase 2, and to a lesser extent phase 1, HIV-RNA decay correlated directly with pretherapy HIV-RNA. Specifically, phase 2 decay was greater in individuals with pretherapy HIV-RNA of at least 100 000 copies/ml than those with less than 100 000 copies/ml. The reason for greater phase 2 decay with higher pretherapy viremia is unknown, but may be the consequence of a larger, pretherapy-infected cell population such that more cells with relatively short half-lives contribute to decay after the modeled transition between phase 1 and phase 2. The transition between phase 1 and phase 2 is postulated to be the time when the slope of decay becomes dominated by long-lived productively infected cells as opposed to short-lived cells [21–23]. Phase 2 decay was significantly slower in the EFV group, which had the highest phase 1 decay rate, compared with the LPV-containing treatment groups. This inverse relationship was observed in individuals with HIV-RNA below 100 000 copies/ml. There are several potential explanations for this observation including greater censoring at the 50 copies/ml detection limit in the EFV group with greater reliance on imputation for modeling of phase 2 decay or intrinsic differences in the mechanism of action of the ARV studied (protease inhibitors act later in the virus life cycle and potentially could have activity against the chronically infected cell populations that may contribute to phase 2 viral decay) [24,25]. Alternatively, greater inhibition of productive infection of short-lived cells by EFV, which acts before HIV integration, could enrich for infected cells with longer half-lives, which would lower the apparent rate of phase 2 decay rate.
In summary, we have shown that faster phase 1 viral decay rate, as assessed either by modeled dynamics in A5160s or by week 1 change in HIV-RNA in A5142, was greater in individuals who received two NRTI with EFV compared with LPV, and that greater initial HIV-RNA decline was predictive of longer term virologic outcome up to week 48, but not at week 96. Regimen potency, as assessed by these measures, was not influenced by demographic factors. 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.
All authors read and contributed to the manuscript. The initial concept for the study was conceived by S.A.R., R.H.H., H.R., A.G.R., D.V.H., and J.W.M. The final clinical trial protocol was developed by the study team, including all authors. All data were collected at the study sites of the AIDS Clinical Trials Group and analyzed by H.R. and A.G.R. at the Statistical and Data Management Center for the ACTG. R.H.H., H.R., J.W.M., D.V.H., and S.A.R. wrote the first draft of the article with critical review by all authors. K.L.K., D.L.B., K.W.G., and J.F.R. participated in the development of the study protocol and analysis plan, reviewed the study data reports, and approved the final manuscript.
ClinicalTrials.gov identifier: NCT00050895.
This work was supported by grants AI 068636 (AIDS Clinical Trials Group Central Grant), AI 068634, AI 069471, AI 27661, AI 069439, AI 25859, AI 069477, AI 06951, AI 069452, AI 27673, AI 069470, AI 069474, AI 069411, AI 069423, AI 069494, AI 069484, AI 069472, AI 38858, AI 069501, AI 32783, AI 069450, AI 32782, AI 069465, AI 069424, AI 38858, AI 069447, AI 069495, AI 069502, AI 069556, AI 069432, AI 46370, AI 069532, AI 46381, AI 46376, AI 34853, AI 069434, AI 060354, AI 064086, AI 36214, AI 069419, AI 069418, AI 50410, AI 45008, RR 00075, RR 00032, RR 00044, RR 00046, RR 02635, RR 00051, RR 00052, RR 00096, RR 00047, RR 00039, and DA 12121 from the National Institute of Allergy and Infectious Disease, National Institutes of Health. The collaborating pharmaceutical companies provided lopinavir–ritonavir (Abbott), efavirenz and stavudine XR (Bristol-Myers Squibb), and tenofovir DF (Gilead).
Conflicts of interest
R.H.H. reports having received honoraria or consultant fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, GSK, Merck, Monogram, Pfizer, Roche, Tibotec, and ViiV, and research support (to UCSD) from Abbott, GlaxoSmithKline, Merck, Pfizer, and ViiV.
J.W.M. reports being a consultant for Merck, Gilead Sciences, and RFS Pharma, and owning share options in RFS Pharma.
D.V.H. is the principal investigator of a NIH-sponsored study in which Abbott pharmaceuticals provides study drug.
K.W.G. is an employee of Abbott Laboratories.
D.L.B. is an employee of Bristol-Myers Squibb.
J.F.R. is an employee of Gilead Sciences.
S.A.R., H.R., K.L.K. and G.D. report no conflicts.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; nonnucleoside reverse transcriptase inhibitor; protease inhibitor; treatment outcome; viral dynamics