Initial viral decay to assess the relative antiretroviral potency of protease inhibitor-sparing, nonnucleoside reverse transcriptase inhibitor-sparing, and nucleoside reverse transcriptase inhibitor-sparing regimens for first-line therapy of HIV infection
Haubrich, Richard H.a; Riddler, Sharon A.b; Ribaudo, Heatherc; DiRenzo, Gregoryc,d; Klingman, Karin L.e; Garren, Kevin W.f; Butcher, David L.g; Rooney, James F.h; Havlir, Diane V.i; Mellors, John W.b; for the AIDS Clinical Trials Group (ACTG) A5160 and A5142 Study Teams
aAntiviral Research Center, University of California San Diego, San Diego, California
bUniversity of Pittsburgh, Pittsburgh, Pennsylvania
cStatistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts
dState University of New York at Albany, Albany, New York
eDivision of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland
fAbbott Laboratories, Abbott Park, Illinois
gVirology Medical Affairs, Bristol-Myers Squibb, Plainsboro, New Jersey
hGilead Sciences, Foster City
iUniversity of California San Francisco, San Francisco, California, USA.
Correspondence to Richard H. Haubrich, MD, Antiviral Research Center, University of California, San Diego, 200 West Arbor Drive, Mail Code 8208, San Diego, CA 92103, USA. Tel: +1 619 543 8080; fax: +1 619 543 5066; e-mail: email@example.com
Received 2 February, 2011
Revised 28 August, 2011
Accepted 2 September, 2011
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).
Objectives: To evaluate the effects of sex and initial antiretroviral regimen on decay of HIV-RNA and virologic outcome.
Methods: We conducted a viral dynamics substudy of A5142, a trial comparing lopinavir (LPV)/ritonavir with efavirenz (LPV/EFV) versus LPV and two nucleoside reverse transcriptase inhibitor (NRTI) (LPV) versus EFV and two NRTI (EFV) in antiretroviral (ARV)-naive individuals. HIV-RNA was measured at days 2, 10, and 14 in the substudy and at weeks 1, 4, and 8 in A5142 participants. Two-phase viral decay was estimated in the substudy with biexponential 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 or 200 copies/ml) at weeks 24–96 using logistic regression.
Results: Sixty-eight individuals were enrolled in the substudy (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) per day. 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 sex (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 at these time points or for any value at week 96.
Conclusion: Phase 1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV-RNA change predicted virologic outcome up 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 (EFV)-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 . EFV with nucleoside reverse transcriptase inhibitors (NRTIs) produced faster phase 1 decay than a triple nucleoside combination of zidovudine (ZDV), lamivudine (3TC), 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 EFV-containing regimens . Addition of enfuvirtide also increased viral decay when added to a four-drug regimen in treatment-naive individuals . 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) . 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 sex-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., tenofovir (TDF)/abacavir (ABC)/3TC] . Additionally, assessment of phase 1 decay requires multiple HIV-RNA levels, which is inconvenient and expensive. HIV-RNA changes over 1 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 .
The primary objectives of this study, therefore, were to compare phase 1 viral decay rate of three regimens for initial therapy: lopinavir (LPV)/ritonavir with EFV, LPV/ritonavir and two NRTI versus EFV with two NRTI; to evaluate sex 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.
Study design and population
ACTG A5142 was a phase 3, randomized, multicenter, open-label, 96-week trial that compared three class-sparing regimens for the initial treatment of HIV infection. HIV-infected, antiretroviral-naive male and nonpregnant female individuals of at least 13 years of age with plasma HIV-RNA levels of at least 2 000 copies/ml, acceptable laboratory values, and any CD4 cell count were enrolled into the main study. Eligible participants were randomized equally to three treatment regimens: LPV/ritonavir 533/133 mg twice daily with EFV 600 mg (LPV/EFV) or LPV/ritonavir 400/100 mg twice daily with two NRTI (LPV) or EFV 600 mg with two NRTI (EFV). LPV/ritonavir was given as the soft-gel capsule and NRTI included 3TC with investigator selection of ZDV 300 mg twice daily or stavudine extended release 100 mg once daily or TDF 300 mg once daily. Details of the A5142 study design have been published elsewhere [15,16]. A5160s, the viral dynamics substudy of A5142, aimed to accrue 66 individuals with equal numbers of men and women targeted for enrollment (11 of each for each group). HIV-RNA was measured on days 2, 10, and 14 in A5160s and on days 7, 28, and 56 in A5142.
The study protocol was approved by an institutional review board or ethics committee at each participating site. All individuals provided written informed consent.
Distributions of baseline characteristics were compared between the substudy and nonsubstudy participants and across sex using Kruskall–Wallis tests (continuous variables) and χ2-tests (categorical variables). Estimation of viral decay rates used a parametric biexponential nonlinear mixed-effects model . To ensure accurate estimation of viral decay rates, data points were excluded following treatment interruption or during documented periods of nonadherence (captured via individual diaries). Further, response profiles consistent with an undocumented treatment interruption (reflected by a nonmonotonic decline in viremia defined as an HIV-RNA increase of more than 0.35 log10 copies/ml from the previous value) were truncated at the point of rebound. HIV-RNA levels below the lower level of quantification of the assay (50 copies/ml) were imputed using a hybrid estimation–maximization multiple imputation . A grid-search was used to find the best initial values for the model-fitting. The ‘shoulder effect’ was handled using the simple method; model-fitting was repeated using the Wu–Ding method (using only on-treatment data from day 2 onwards) as a sensitivity analysis [19,20]. Wilcoxon rank-sum tests were used to compare the empirical Bayes estimates of first-phase and second-phase decay parameters by treatment group and sex.
The ability of change in log10 HIV-RNA from baseline to week 1 (week 1 change) to capture initial regimen potency (as estimated by phase 1 decay) was assessed using Spearman's rank correlation and re-evaluation of the treatment and sex group comparisons using Wilcoxon rank-sum tests. Week 1 change was estimated using HIV-RNA levels obtained between 5 and 8 days after starting treatment, and data were excluded for treatment interruption as described above for the substudy analyses.
In the A5142 population, associations between baseline and demographic variables and week 1 change were examined using Wilcoxon rank-sum tests and censored linear regression. Associations between week 1 change and longer term outcome (HIV-RNA >200 and >50 copies/ml at weeks 24, 48, and 96) used logistic regression models and Cox proportional hazards modeling; week 1 change was modeled as a continuous variable. These analyses included only treatment outcomes observed while on randomized treatment (as-treated); treatment outcomes for individuals discontinuing treatment prior to the time point of interest were imputed with the last on-treatment HIV-RNA (captured after day 21) and carried forward. All P values were two-sided and were not adjusted for multiple testing. Viral dynamic model fitting was implemented using statistical software Splus version 6 (MathSoft Inc., Cambridge, Massachusetts, USA) (function nonlinear mixed effects model); all other statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina, USA).
Accrual and individual characteristics of the substudy
Of the 757 individuals participating in A5142, 68 were enrolled into the A5160s substudy, including 34 men and 34 women (Fig. 1). Enrollment was completed by April 2004. Approximately equal numbers of individuals (21–25) were enrolled from each of the three randomized treatment groups. Overall, substudy individuals were predominantly black (47%) with a median age of 42 years and a median baseline HIV-RNA of 4.9 log10 copies/ml. The median baseline HIV-RNA in the substudy individuals was marginally different in the EFV group (4.8 log10 copies/ ml) compared with the LPV and LPV/EFV arms (5.0 and 4.9 log10 copies/ml respectively; P = 0.094). Substudy women tended to be older (median 44 versus 40 years for men; P = 0.05) and differed in their self-reported race/ethnicity (P = 0.02). Baseline HIV-RNA and CD4 cell counts were not significantly different between substudy men and women (P = 0.37 and 0.77, respectively). Substudy individuals were not different from the main 5142 study individuals with the exception of age (median 42 versus 38 years, respectively; P < 0.001) and NRTI use (a smaller proportion of substudy individuals chose to use TDF).
Phase 1 HIV-RNA decay in substudy participants
Phase 1 viral decay rate was significantly faster for the 25 individuals in the EFV group compared with the 22 individuals in the LPV group (P = 0.023); individuals in the former group had median [interquartile range (IQR)] decay rates of 0.63 (0.57–0.70) per day compared with 0.53 (0.38–0.66) per day in the latter group (Table 1 and Fig. 2a). The faster decay for EFV corresponded to a shorter virus half-life (1.09 days) compared with LPV (1.31 days). The rate of viral decay in the LPV/EFV group was 0.61 (0.52–0.68) per day and was not significantly different from the other two randomized regimens (P > 0.11). Sensitivity analyses using data collected after day 2 led to similar estimates of phase 1 parameters and similar findings for the between group comparisons (data not shown).
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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