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Simplified treatment regimens for HIV management may increase adherence. In this open-label, randomized, controlled trial, longer-acting (monthly) injectable cabotegravir plus rilpivirine was compared with standard oral treatment. At 48 weeks, similar viral suppression was seen with the two regimens.

Simplified treatment regimens for HIV-1 may have advantages. In this open-label, randomized, controlled trial, patients with HIV-1 infection who had not previously received antiretroviral therapy were given oral induction therapy, then treated with either monthly injections of long-acting cabotegravir and rilpivirine or standard treatment. At 48 weeks, similar viral suppression was observed with the two regimens.

Background. Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation. Methods. Serum HCV RNA from patients who experienced viral breakthrough, partial response, or nonresponse in 2 clinical trials in which patients received mericitabine plus peginterferon alfa-2a (40KD)/ribavirin were analyzed by population and donai sequence analysis as well as phenotypic assay for assessment of in vivo mericitabine resistance. Results. Among 405 patients treated with mericitabine plus peginterferon alfa-2a/ribavirin in PROPEL and JUMP-C, virologie breakthrough or nonresponse were not observed; 12 patients experienced a partial response. The NS5B S282T resistance mutation was not observed in any patient. A number of treatment-associated NS5B changes were observed and characterized. A novel double mutant (L159F/L320F) with impaired replication capacity was detected in one HCV genotype 1b-infected patient. Introduction of double mutant L159F/L320F into genotype la (H77) and 1b (Con-1) replicons, respectively, increased the EC₅₀ for mericitabine by 3.1- and 5.5-fold and the EC₉₀ by 3.1-and 8.9-fold. The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and GS-938 but not setrobuvir, relative to wild-type. Conclusions. A novel and replication-deficient double mutation (L159F/L320F) confers low-level resistance to mericitabine and cross-resistance to both sofosbuvir and GS-938.

Abstract Background Letermovir (LET), a cytomegalovirus (CMV) deoxyribonucleic acid (DNA) terminase inhibitor, was recently approved for prophylaxis of CMV infection in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation. Cytomegalovirus genotyping was performed to identify LET-resistance-associated variants (RAVs) among subjects in a Phase 3 trial. Methods The CMV UL56 and UL89 genes, encoding subunits of CMV DNA terminase, were sequenced from plasma collected from subjects with clinically significant CMV infection (CS-CMVi). Novel variants were evaluated by recombinant phenotyping to assess their potential to confer resistance to LET. Results Genotyping was successful for 50 of 79 LET subjects with CS-CMVi. Resistance-associated variants (encoding pUL56 V236M and C325W) were detected independently in subjects 1 and 3 who experienced CS-CMVi while receiving LET prophylaxis, and 2 other variants (encoding pUL56 E237G and R369T) were detected >3 weeks after subjects 2 and 3, respectively, had discontinued LET prophylaxis and received preemptive therapy with ganciclovir. Conclusions The detected incidence of CMV resistance among subjects who received LET as prophylaxis in this Phase 3 trial was low. The LET RAVs that were detected mapped to the CMV UL56 gene at positions associated with reduced susceptibility to LET based on resistance selections in cell culture. In a Phase 3 trial of letermovir for cytomegalovirus (CMV) prophylaxis in hematopoietic stem cell transplant recipients, UL56 gene mutations conferring letermovir resistance were identified in 3 subjects among 50 who developed clinically significant CMV infection and had genotyping results.

In patients with HCV genotypes 2 and 3, sofosbuvir plus ribavirin was administered for 12 weeks in patients with genotype 2 and for 24 weeks in those with genotype 3. Rates of sustained virologic response were 93% in patients with genotype 2 and 85% in those with genotype 3. Of the six main genotypes of the hepatitis C virus (HCV), genotypes 2 and 3 account for approximately 30% of chronic infections worldwide. 1 Although these two genotypes have historically been grouped together in treatment guidelines and clinical trials, 2 , 3 accumulating evidence suggests that there are important clinical differences between them. 1 , 4 , 5 HCV genotype 3 infection is associated with a higher incidence of hepatic steatosis, more rapid progression of fibrosis, and possibly a greater risk of hepatocellular carcinoma than is HCV genotype 2 infection. 6 Moreover, patients with HCV genotype 3 infection are less responsive to peginterferon-based treatment than are patients . . .

In subgroups of two phase 3 studies, patients with high-risk features for failure of antiretroviral therapy, such as a low CD4 count, high base-line level of human immunodeficiency virus (HIV) type 1 RNA, or unfavorable genotypic or phenotypic sensitivity score, raltegravir was superior to placebo in terms of a virologic response at 48 weeks. However, among these patients, in whom antiretroviral therapy had been used previously, 23% of raltegravir recipients had virologic failure by 48 weeks. In patients with high-risk features for failure of antiretroviral therapy, raltegravir was superior to placebo in terms of a virologic response at 48 weeks. However, among these patients, in whom antiretroviral therapy had been used previously, 23% of raltegravir recipients had virologic failure by 48 weeks. Despite the substantial decrease in mortality and morbidity rates associated with highly active antiretroviral therapy over the past decade, there is still a substantial need for effective antiretroviral drugs for patients infected with resistant human immunodeficiency virus type 1 (HIV-1). 1 , 2 The majority of licensed antiretroviral drugs belong to three classes targeting either the HIV-1 protease or reverse transcriptase, and considerable cross-resistance exists among drugs within each class. 3 , 4 In patients with resistant virus, use of antiretroviral agents from new classes offers considerable potential benefit because of the absence of cross-resistance. 5 – 7 HIV-1 integrase represents a new therapeutic target. 8 , . . .

Appropriate second-line antiretroviral therapy for HIV infection is needed in resource-limited settings. In a comparison of three protease-inhibitor–based regimens in sub-Saharan Africa, the one that included nucleoside reverse-transcriptase inhibitors performed favorably. The public health approach of the World Health Organization (WHO), 1 together with large-scale donor funding, has enabled millions of adults and children in sub-Saharan Africa who are infected with the human immunodeficiency virus (HIV) to have access to lifesaving antiretroviral therapy. 2 The key principle is the use of simplified, standardized approaches that are feasible on a large scale in resource-limited settings, 1 , 3 including a first-line regimen of two nucleoside reverse-transcriptase inhibitors (NRTIs) plus one non-NRTI (NNRTI). In most settings, treatment is monitored clinically and with the use of CD4+ counts, with typically late detection of treatment failure, accompanied by substantial . . .

Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. NCT02342249, 2014-004068-39, and CR107745.

The selection of viral strains with resistance-associated substitutions at hepatitis C virus (HCV) NS5A and NS5B genes is considered one of the limiting factors for achieving sustained virologic response (SVR) to combination of direct-acting antivirals daclatasvir (DCV) and sofosbuvir (SOF). Since 2015, this interferon-free regimen has been available in Brazilian clinical routine for treating mono- and HCV/HIV-coinfected patients chronically infected with genotypes 1 and 3. Our aim was to assess SVR rate for Brazilian patients chronically infected with genotypes 1 and 3 after DCV/SOF therapy and the frequency of baseline RASs in HCV NS5A and NS5B genes. Serum samples were collected from 107 monoinfected patients and 25 HCV/HIV co-infected patients before antiviral therapy with DCV/SOF. Genetic diversity of NS5A and NS5B genes was assessed by direct nucleotide sequencing. Overall, SVR rate was 95.4% (126/132), and treatment failure occurred in five monoinfected and one HCV/HIV co-infected patient. NS5A RASs frequency was higher for HCV/HIV patients (28%) than monoinfected patients (16.8%). No difference was evidenced between mono- and HCV/HIV-coinfected groups (15% vs. 16%) regarding NS5B gene. Genotype (GT) 1b strains had significantly more baseline substitutions in NS5A (31.6%) than GT 1a and 3a. At least one primary NS5A RAS described in literature at loci 28, 30, 31 or 93 was identified in HCV GTs 1 strains for both groups. As for NS5B, RASs at positions 159 and 316 was observed only in GT 1b strains. This study highlighted that SVR rate in clinical routine in Brazil was similar to randomized clinical trials (89-98%). Our research provided genetic data about the circulation of resistant variants in Brazil. Despite its presence, most of identified baseline mutations did not negatively impact treatment outcome. Genetic diversity of circulating strains suggested that most of the Brazilian HCV chronic carriers are susceptible to new therapeutic regimens including recently approved DAAs.

HIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15-24 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15-24 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control. A cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure (VL ≥1,000 copies/mL) underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes. A total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine. There is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing.