Little information is available on the efficacy and safety of antiretroviral therapy (ART) of ritonavir-boosted darunavir (DRV/r) and fixed-dose abacavir/lamivudine (ABC/3TC) [1,2]. DRV/r is a protease inhibitor with proven efficacy and safety, and with high barrier to drug resistance [3,4]. ABC/3TC is an alternative choice of nucleoside reverse transcriptase inhibitors (NRTIs) in the American Department of Health and Human Services Guidelines . Here, we conducted a single-center, observational pilot study to compare the efficacy and safety of DRV/r and ABC/3TC versus tenofovir/emtricitabine (TDF/FTC) in patients with a baseline HIV-1 viral load of more than 100 000 copies/ml. Patients with such a viral load were chosen because ACTG 5202 demonstrated that the time to virologic failure was significantly shorter with ABC/3TC than with TDF/FTC in patients with a viral load of more than 100 000 copies/ml on efavirenz or ritonavir-boosted atazanavir . All patients were treatment-naïve who commenced once-daily DRV/r and either fixed-dose ABC/3TC or TDF/FTC from November 2009 to August 2011 at the AIDS Clinical Center, Tokyo. Baseline data (basic demographics, CD4 count, and viral load) were collected. Viral load was measured by Cobas TaqMan HIV-1 real-time PCR version 1.0 assay (Roche Diagnostics, NJ) to the end of November 2011, and later by Cobas TaqMan version 2.0 assay. It was the decision of the attending physician to start ART with either TDF/FTC or ABC/3TC, because the Japanese guidelines consider both TDF/FTC and ABC/3TC as the preferred NRTIs .
The efficacy outcomes were the time from commencing ART to virologic failure (defined as a viral load > 1000 copies/ml at or after 16 weeks and before 24 weeks, or >200 copies/ml at or after 24 weeks) , and the proportion of patients with a viral load < 50 copies/ml at 48 weeks regardless of previous virologic failure. The tolerability outcome was the time to any regimen modification. Intent-to-treat (ITT) population, comprising all patients, was used for all efficacy and tolerability analyses, whereas per protocol population was used in the efficacy analysis of the suppressed viral load. Censored cases represented those who dropped out, referred to other facilities, or reached 48 weeks. Time-to-event distributions were estimated using the Kaplan–Meier method. Univariate and multivariate Cox hazards models estimated the impact of ABC/3TC use over TDF/FTC on the incidence of virologic failure.
The study included 80 patients [ABC/3TC: 21, TDF/FTC: 59, median age: 37.9 years, men: 74 (92.5%), East Asian origin: 72 (90%)], of whom 66 (82.5%) were infected with HIV-1 through homosexual contact. Patients on ABC/3TC had a lower baseline CD4 count (46/μl versus 100, P = 0.031), higher viral load (5.75 log10 copies/ml versus 5.58, P = 0.044), and were more likely to have a history of AIDS (71.4% versus 37.3, P = 0.010), than patients with TDF/FTC. All subjects were HLA-B*5701-negative, and all underwent HIV-1 drug-resistance tests before commencement of ART and none had resistant mutations.
The time to virologic failure with ABC/3TC [3 patients (14.3%)] was not significantly different from that with TDF/FTC [4 (6.8%)] by 48 weeks (Fig. 1a), by univariate and multivariate analyses adjusted by CD4 count and viral load (HR, 2.651; 95% CI, 0.592–11.88; P = 0.203, adjusted HR, 1.589; 95% CI, 0.341–7.401; P = 0.555). At week 48, ITT analysis showed more patients with TDF/FTC had a viral load of less than 50 copies/ml (ABC/3TC: 38.1%, TDF/FTC: 64.4%, P = 0.043) (Fig. 1c), whereas with per protocol analysis, no difference was noted (ABC/3TC: 57.1%, TDF/FTC: 73.1%, P = 0.328) (Fig. 1d).
Among the seven patients with virologic failure, three (ABC/3TC: 1, TDF/FTC: 2) achieved sustained viral load suppression after week 60 of the initial regimen. The other four underwent drug-resistance tests. One on ABC/3TC was switched to TDF/FTC at week 41; however, viral suppression was not achieved until raltegravir was added at week 74. The other with ABC/3TC was switched to TDF/FTC at week 49 and achieved viral suppression despite the emergence of protease mutation M46I. Another patient on TDF/FTC had persistent viremia (100–200 copies/ml) without mutation. Another patient on TDF/FTC showed the emergence of reverse transcriptase mutation V75L and viremia persisted with 200–500 copies/ml. Reverse transcriptase mutation M184I/T/V did not emerge in any patients.
More patients on ABC/3TC changed or discontinued the initial regimen during the research period [ABC/3TC: 8 (38.1%), TDF/FTC: 4 (6.8%), P = 0.001] (Fig. 1b). Six [ABC/3TC: 4 (19%), TDF/FTC: 2 (3.4%)] changed ART due to adverse events or virologic failure [ABC/3TC: virologic failure (n = 1), limb paresthesia (n = 1), and nausea (n = 2); TDF/FTC: tenofovir nephrotoxicity (n = 2)]. None developed ABC-associated hypersensitivity.
This is the first comparison report of the efficacy and safety of ABC/3TC against TDF/FTC with DRV/r in treatment-naïve patients with a viral load of more than 100 000 copies/ml. The time to virologic failure by 48 weeks was not different between the two groups. Although a higher percentage of patients on TDF/FTC showed viral suppression than those on ABC/3TC at week 48 with ITT population, the difference was not significant with per protocol population. TDF/FTC showed better tolerability, as more patients on ABC/3TC changed regimen than those on TDF/FTC.
These results need to be interpreted with caution, because the baseline characteristics of patients of the two groups were not well matched due to the nature of the observational study, and this study did not have sufficient power due to the small number of enrolled patients. Because our patients had small stature with median body weight of 58.1 kg, a risk factor for TDF nephrotoxicity, it is sometimes our practice to avoid TDF in patients with multiple risks, such as advanced HIV-1 infection, to prevent possible acute kidney injury [8–10]. This is presumably the reason for prescribing ABC/3TC to patients with worse disease condition in this study. This allocation bias might have worked as a disadvantage for the efficacy and tolerability results of ABC/3TC.
The usefulness of ABC/3TC has recently received higher recognition than it did in the past; the FDA meta-analysis did not confirm the association between ABC use and myocardial infarction , and it became clear that TDF use is associated with decreased bone mineral density and renal dysfunction, both of which might develop into serious complications with long-term TDF use [12–17]. Thus, once-daily DRV/r, a protease inhibitor with high barrier to drug resistance, and ABC/3TC could be good alternative, especially in patients, who cannot tolerate TDF. A randomized trial to elucidate the efficacy and safety of ABC/3TC and TDF/FTC with once-daily DRV/r is warranted.
The authors thank the patients and all the clinical staff at the AIDS Clinical Center.
All authors contributed to the concept and design of the study and/or the analyses and interpretation of the data. The article was drafted by T.N., H.K., H.G., and S.O. and critically reviewed and subsequently approved by all authors.
Conflicts of interest
S.O. received research grants from MSD K.K., Abbott Japan, Co., Janssen Pharmaceutical K.K., Pfizer, Co., and Roche Diagnostics K.K. The other authors declare that they have no conflicts of interest.
This work was supported by Grants-in Aid for AIDS research from the Japanese Ministry of Health, Labour, and Welfare (H23-AIDS-001), and the Global Center of Excellence Program (Global Education and Research Center Aiming at the Control of AIDS) from the Japanese Ministry of Education, Science, Sports and Culture.
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