Only very little information is available on the efficacy and safety of the combination antiretroviral therapy (ART) of ritonavir-boosted darunavir (DRV/r) and fixed-dose abacavir/lamivudine (ABC/3TC) . DRV/r is a protease inhibitor with proven efficacy and safety as well as with a high barrier to drug resistance [2,3]. ABC/3TC is an alternative choice of nucleoside reverse transcriptase inhibitor (NRTI) backbone in the American Department of Health and Human Services (DHHS) Guidelines and is the other preferred backbone regimen for treatment-naïve patients in other international guidelines [4,5]. In this pilot study, we evaluated the efficacy and safety of DRV/r and ABC/3TC for treatment-naïve patients in a single-center, observational cohort.
The participants of this retrospective study were all treatment-naïve patients with HIV infection who commenced once-daily DRV/r and fixed-dose ABC/3TC from November 2009 (when the first patient commenced such regimen at our clinic) to November 2010 at our clinic (AIDS Clinical Center, Tokyo, Japan). All patients were followed for at least 48 weeks after commencement of treatment at our facility. Baseline data, including age, sex, mode of infection, ethnicity, CD4 cell count, and HIV viral load, were collected from the medical charts. The Cobas TaqMan HIV-1 real-time PCR version 1.0 assay (Roche Diagnostics, NJ) was used to measure HIV-1 viral load throughout the research period. For those who discontinued either DRV/r or fixed-dose ABC/3TC before reaching 48 weeks, the reasons for discontinuation were collected. All patients provided written informed consent for the data to be published. Primary outcomes were the proportion of patients with viral load less than 50 copies/ml at 24 and 48 weeks. Safety parameters through 48 weeks were also collected.
The study included 22 patients [1 (4.6%) female] of East Asian origin, with a median age of 34.5 years [interquartile range (IQR) 27.5–43.8]. The route of transmission was homosexual intercourse 86.3%, heterosexual 9%, and unknown in one patient. HLA was examined in 20 patients and all were HLA-B*5701-negative. Twenty-one patients had HIV-1 drug-resistant testing before commencement of ART and none had resistant mutations related to NRTIs, protease inhibitors, or non-NRTIs. At baseline, the median CD4 cell count was 47/μl (IQR 27.5–187.8), whereas the HIV viral load was 5.61 log10 copies/ml (IQR 4.57–6.01 log10 copies/ml). In three patients, ART was either changed or discontinued during the study due to adverse events [skin rash (n = 1), vomiting (n = 1), and limb paresthesia (n = 1)] and one patient changed the regimen due to a concern with drug interactions with antipsychotics before 48 weeks. The skin rash was due to darunavir, because the rash disappeared after switching darunavir to raltegravir, while continuing ABC/3TC. This patient was HLA-B*5701-negative. None presented with ABC-associated hypersensitivity or with grade 3 or 4 liver enzyme elevation.
On-treatment analysis of the 18 patients (excluding the above four patients who discontinued the regimen) showed 72.2% had viral load less than 50 copies/ml at week 24 (88.9% viral load <200 copies/ml), and 66.7% had viral load less than 50 copies/ml at week 48 (88.9% viral load <200 copies/ml). Intention-to-treatment analysis showed 59.0% with viral load less than 50 copies/ml at week 24 (77.3% viral load <200 copies/ml), and 54.6% with viral load less than 50 copies/ml at week 48 (72.7% viral load <200 copies/ml) (Fig. 1). Four patients showed rebounds greater than 200 copies/ml (<1000 copies/ml) after 24 weeks; two of them were single rebounds and were considered blips. The other two patients showed two consecutive viral load greater than 200 copies/ml, fulfilling the criteria of virological failure (11.1% at 48 weeks). The latter two patients underwent a genotypic resistance test that detected, in one case, the reverse transcriptase mutation M184V and, in the other, the protease mutation M46I.
In the 12 patients with baseline viral load above 100 000 copies/ml, on-treatment analysis showed viral load of less than 200 copies/ml at 24 weeks in 10 (83.3%) patients, and less than 50 copies/ml at both 24 and 48 weeks in seven (58.3%). In comparison, all six patients with baseline viral load below 100 000 copies/ml showed suppression of the load to below 50 copies/ml at both 24 and 48 weeks. The median increment in CD4 cell count at 48 weeks was 187/μl (IQR 82.5–264.5/μl).
To our knowledge, this is the first published study on the efficacy and safety of the combination of once-daily DRV/r and fixed-dose ABC/3TC in treatment-naïve patients. This combination ART resulted in viral suppression, although the baseline viral load was above 100 000 copies/ml in 66.6% of the patients. Only 13.6% discontinued this regimen due to adverse events before 48 weeks and none of the adverse events was serious. Considering that most patients in this cohort were at an advanced stage of HIV infection with a low median baseline CD4 cell count of 47/μl, we conclude that DRV/r and ABC/3TC is a well tolerated and efficacious combination ART.
The DHHS guidelines for the treatment of HIV infection in the USA list ABC/3TC as alternative NRTIs since abacavir can potentially cause serious hypersensitivity reaction in 5–8% of the patients and its viral efficacy in patients with baseline viral load of above 100 000 copies/ml is inferior to fixed-dose tenofovir/emtricitabine (TDF/FTC) when used with efavirenz or ritonavir-boosted atazanavir as a key drug [4,6]. However, the incidence of ABC-related hypersensitivity is low among the HLA-B*5701-negative population, such as the Japanese [7,8]. Moreover, the HEAT study demonstrated that the viral efficacy of ABC/3TC was not inferior to that of TDF/FTC when used with lopinavir/ritonavir for treatment-naive patients . Taking this background into account, once-daily DRV/r and ABC/3TC could be a good alternative, especially in patients with a low prevalence of HLA-B*5701 who cannot tolerate tenofovir due to its nephrotoxicity .
In conclusion, this single-center pilot study demonstrated the viral efficacy and safety of once-daily DRV/r and ABC/3TC in treatment-naïve patients with HIV-1 infection. This regimen could be a suitable alternative to DRV/r and tenofovir/emtricitabine or other first-line regimens. Nevertheless, the number of patients in this cohort is too small to allow firm conclusions and further studies of larger samples (ideally a clinical trial that compares the viral efficacy of TDF/FTC to ABC/3TC with once-daily DRV/r) are needed to elucidate this issue.
The authors thank all the clinical staff at the AIDS Clinical Center.
Author contributions: All of the authors contributed to the conception and design of the study and/or the analyses and interpretation of the data. The manuscript was drafted by T.N., H.G. and S.O. and was critically reviewed and subsequently approved by all authors.
Conflicts of interest
There are no conflicts of interest.
No financial support was received for this research.
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