Lathouwers E, Wong EY, Luo D, Seyedkazemi S, De Meyer S, Brown K. HIV-1 resistance rarely observed in patients using darunavir once-daily regimens across clinical studies. HIV Clin Trials. 2017;18(5-6):196-204. doi: 10.1080/15284336.2017.1387690.
Successful highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection is contingent on limiting or avoiding the development of resistance-associated mutations (RAMs). Ideally, agents used in a HAART regimen should have a robust genetic barrier to resistance. The propensity of protease inhibitors to possess such barriers to resistance makes them highly desirable components of HAART.1 The US Department of Health and Human Services (HHS) and the European AIDS Clinical Society recommend initial treatment of HIV-1 infection with once-daily boosted darunavir 800 mg (with ritonavir or cobicistat as additional boosters) combined with 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs). Once-daily darunavir dosing is indicated for the treatment of HIV-1 infection in treatment-naïve or treatment-experienced patients, provided they do not have any darunavir RAMs.1
Previous study findings have demonstrated that darunavir has a high genetic barrier to the development of resistance, with virologic efficacy shown to be compromised only when 3 or more darunavir RAMs are present in the background of approximately 14 to 15 International Antiviral Society—USA protease inhibitor RAMs.1 Lathouwers and colleagues sought to analyze the outcomes from 7 phase 2 and phase 3 clinical trials that investigated darunavir 800-mg once-daily—containing HAART regimens to determine the observed rates of post-baseline resistance in patients with HIV-1.1
Seven phase 2 and phase 3 trials with available genotypic and phenotypic data were investigated in this analysis (see Table1): ARTEMIS (ClinicalTrials.gov identifier: NCT00258557), GS-US-299-0102 (NCT01565850), GS-US-216-0130 (NCT01440569), ODIN (NCT00524368), INROADS (NCT01199939), MONET (NCT00458302), and PROTEA (NCT01448707). Outcomes from these studies included in the analysis by Lathouwers et al refer only to the once-daily 800-mg dose in keeping with the recommended dosing for darunavir.1 The adult populations in these 7 studies comprise both treatment-naïve and treatment-experienced patients. Among the latter group, participants reported diverse histories of antiretroviral use, whereas their viral suppression status at screening varied considerably, including patients with <50 copies/mL and those with ≥50 copies/mL. Variation was also observed between study populations as to which boosting agent, ritonavir or cobicistat, was used with darunavir, as well as which agents were components of the treatment regimen.1 Three of the studies—ARTEMIS, GS-US-216-0130, and ODIN—were pivotal phase 3 trials conducted in treatment-naïve patients (ARTEMIS), treatment-experienced patients (ODIN), or both treatment-naïve and treatment-experienced patients (GS-US-216-0130) and ranged from 48 weeks to 192 weeks in duration. PROTEA and MONET were both phase 3 switching studies conducted in virologically suppressed patients and were 96 weeks and 144 weeks in duration, respectively. The other 2 studies—GS-US-299-0102 and INROADS—were both phase 2 trials, each 48 weeks in duration.1
Overall, 5 of the 7 studies were conducted in patients with virologic failure, with the viral load entry criteria for these ranging from >500 copies/mL (INROADS) to ≥1000 copies/mL (ODIN and GS-US-216-0130) to ≥5000 copies/mL (ARTEMIS and GS-US-299-0102).1 There were also differences between the studies as to which RAMs were permitted, what requirements of genotypic or phenotypic antiretroviral susceptibility applied, and which histories of prior virologic failure were allowed.1 Protocol-defined virologic failure (PDVF) was defined somewhat differently among the studies.
For ARTEMIS, ODIN, and INROADS, virologic failure was defined primarily as 2 consecutive viral loads <50 copies/mL, followed by 2 consecutive viral loads ≥50 copies/mL. For GS-US-299-0102 and GS-US-216-0130, the criteria included a viral load <50 copies/mL, followed by 2 consecutive viral loads ≥400 copies/mL. For the MONET study, PDVF was defined as 2 consecutive viral loads ≥50 copies/mL, whereas for the PROTEA study, PDVF was defined as 2 consecutive viral loads ≥400 copies/mL. Patients who were designated as experiencing PDVF underwent resistance testing, apart from those in MONET and PROTEA, in whom any sample that exceeded the viral load threshold was tested for resistance.1
A total of 2328 patients were enrolled in the 7 studies; 1686 received once-daily darunavir 800 mg. The large majority of nonvirologically suppressed patients harbored HIV-1 subtype B. Having RAMs at baseline was more common among treatment-experienced patients, and although all 7 studies excluded patients with darunavir RAMs, 3 darunavir-treated participants in the ODIN study experienced ≥1 darunavir RAM at baseline.1 Of the 1686 patients in the 7 studies, 184 experienced PDVF, of whom 182 underwent postbaseline genotypic analysis. Four participants (0.2% of 1686; 2.2% of 184) were reported to have developed primary protease inhibitor and/or darunavir RAMs post-baseline.1
Of the 4 participants, 1 (enrolled in the ARTEMIS study) developed V11I—a darunavir RAM (also a secondary protease inhibitor RAM)—after discontinuing treatment because of nonadherence. This patient experienced no loss of phenotypic susceptibility to darunavir or to any protease inhibitor.11 A second patient, who was treatment experienced and participating in GS-US-216-0130, developed I84I/V—a primary protease inhibitor and darunavir RAM—but did not lose phenotypic susceptibility to darunavir or to any protease inhibitor.1 A third patient, who was participating in the ODIN study, developed 3 primary protease inhibitor and darunavir RAMs (V32I, L76V, and I84V) and 1 primary protease inhibitor RAM (M46I) at week 48. This patient achieved a viral load <50 copies/mL but never achieved 2 consecutive viral loads; the patient also lost phenotypic susceptibility to darunavir, amprenavir, atazanavir, indinavir, and nelfinavir. The patient’s resistance profile suggested that this resistance was possibly linked to a prior ritonavir-boosted lopinavir regimen, as all observed primary and secondary RAMS are also associated with lopinavir resistance.1 The fourth patient, who was a participant in the MONET study, developed L33F, a primary protease inhibitor and darunavir RAM. This mutation was detected at week 12 of the study, when the patient had a viral load of 63 copies/mL. The patient was subsequently found to be resuppressed at the next visit and remained so through week 144. Phenotypic resistance to darunavir did not occur, and it is possible that the mutation was present at baseline but was not detected, as sequencing was not conducted because the patient had been suppressed at baseline.1
Taken together, these results indicate that 1 patient of 1686 (<0.1%) treated with a regimen that included once-daily darunavir 800 mg experienced a loss of phenotypic susceptibility to darunavir. Of additional interest is the fact that 264 of the 1686 participants were treated with ritonavir-boosted darunavir monotherapy, generating a rate of 0.4% (1 in 264) postbaseline darunavir RAMs in those receiving a ritonavir-darunavir—only regimen.1 Also noteworthy is the observation that of 1103 nonvirologically suppressed patients who used an N(t)RTI backbone, 10 (0.9%) developed N(t)RTI RAMs, 9 of whom lost phenotypic susceptibility to ≥1 of the N(t)RTIs in their treatment regimen.1
The results of this analysis of 7 phase 2 and phase 3 trials of darunavir-based regimens for the treatment of patients with HIV-1 infection are consistent with the high genetic barrier to resistance previously observed with darunavir. This analysis adds value to our understanding of the low susceptibility of darunavir to developing resistance, having been conducted in a diverse patient population, under variable study conditions, and with diverse criteria for study inclusion and resistance testing.1 The high barrier to resistance exhibited by darunavir is underscored by the fact that among patients in all 7 studies, no treatment-naïve patients developed a primary protease inhibitor RAM or lost phenotypic susceptibility to darunavir, and none of those who were treatment-experienced but protease inhibitor—naïve developed phenotypic resistance to darunavir.1 The single patient among the 1686 participants who developed phenotypic resistance to darunavir had previously experienced virologic failure with a ritonavir-boosted lopinavir regimen, which may have increased that patient’s risk for developing a cross-resistant protease inhibitor RAM.1
1. Lathouwers E, Wong EY, Luo D, Seyedkazemi S, De Meyer S, Brown K. HIV-1 resistance rarely observed in patients using darunavir once-daily regimens across clinical studies. HIV Clin Trials. 2017;18(5-6):196-204. doi: 10.1080/15284336.2017.1387690.