Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.     

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment‐naïve patients with hepatitis C virus genotype 1 infection

Grazoprevir (GZR) is a second‐generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12‐week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response‐guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow‐up week 12 (HCV RNA <25 IU/mL) in the per‐protocol (PP) population (excluding patients with important protocol deviations). Twenty‐six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24‐week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24‐week arm who relapsed after follow‐up week 12. All three breakthrough patients had wild‐type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir‐based regimens (NCT01716156; protocol P039).     

Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment‐naïve,noncirrhotic HCV genotype 3‐infected patients

Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed‐dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3‐infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment‐naïve, noncirrhotic HCV GT3‐infected patients. Randomized patients received open‐label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On‐treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance‐associated substitutions (RASs) with a >five‐fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3‐infected patients due to a high rate of on‐treatment virologic failure and treatment‐emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3‐infected patients.clinicaltrials.gov: NCT01717326.     

Long‐term follow‐up of 11 protease inhibitor (PI)‐naïve and PI‐treated HIV‐infected patients harbouring virus with insertions in the HIV‐1 protease gene

Objectives

Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long‐term viro‐immunological follow‐up of HIV‐infected patients harbouring virus with protease insertions.

Methods

Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected.

Results

Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI‐naïve patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI‐naïve patients were infected with an HIV‐1 non‐B subtype. Follow‐up of these PI‐naïve patients showed that the insert‐containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI‐experienced patients, 63% were infected with HIV‐1 subtype B; one had been antiretroviral‐free for 5 years and seven were heavily PI‐experienced (median duration of follow‐up 24 months; range 10–62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI‐resistance mutations, and following long‐term exposure to PIs. The insert‐containing virus persisted for a median of 32 months (range 12–62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity.

Conclusion

Our data, obtained during long‐term follow‐up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI‐based regimens, although further work is required to confirm it.     

Long‐term (96‐week) follow‐up of antiretroviral‐naïve HIV‐infected patients treated with first‐line lopinavir/ritonavir monotherapy in the MONARK trial*

Background

The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral‐naïve patients.

Methods

A total of 136 antiretroviral‐naïve patients, with a CD4 cell count above 100 cells/μL and a plasma HIV RNA below 100 000 HIV‐1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n=83) or lopinavir/ritonavir+zidovudine/lamivudine (n=53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent‐to‐treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n=83), and then focused on patients who had an HIV RNA <50 copies/mL at week 48 (n=56).

Results

At week 96, 39 of 83 patients (47%) had HIV RNA <50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA >400 copies/mL. Focusing on the 56 patients with an HIV RNA <50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA <50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI‐associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96.

Conclusion

By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA <50 copies/mL at week 96. The occurrence in some patients of low‐level viraemia (50–500 copies/mL) may increase the risk of drug resistance. First‐line lopinavir/ritonavir monotherapy cannot be systematically recommended.