Antiviral Therapy

Burger, David; Oosterhof, Piter

doi: 10.3851/imp3321pmid: 31172976

Vannappagari, Vani; Ragone, Leigh; Henegar, Cassidy; van Wyk, Jean; Brown, Dannae; Demarest, James; Quercia, Romina; Clair, Marty St.; Underwood, Mark; Gatell, Jose M; de Ruiter, Annemiek; Aboud, Michael

doi: 10.3851/imp3331pmid: 31503008

BackgroundPretreatment and acquired drug resistance mutations (DRMs) can limit antiretroviral therapy effectiveness.MethodsWe review prevalence of DRMs with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), focusing on lamivudine and rilpivirine, from 127 articles with >100,000 individuals with HIV-1 infection.ResultsEstimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Most prevalent DRMs resistant to lamivudine or rilpivirine were at positions E138 (4%), V179 (1%) and M184 (1%). Estimated acquired DRM prevalence was 58% for any NRTIs and 67% for any NNRTIs, most frequently at positions M184 (58%) and Y181 (21%).ConclusionsThis review suggests low risk of lamivudine-or rilpivirine-resistant mutations in treatment-naive, HIV-1-infected individuals.

Zhou, Feng; Jia, Weidong; Yang, Shuo; Chen, Ge; Li, Guanhai; Li, Yueping; Liang, Yingfang; Yang, Yi; Gao, Yanhui; Chen, Yue

doi: 10.3851/imp3326pmid: 31348006

BackgroundThe aims of this study were to describe antiviral drug (AD) utilization and costs in patients with chronic HBV infection.MethodsWe conducted a retrospective study of patients in the hospital and calculated annual proportions of AD utilization and costs among patients. A two-part model was used to estimate adjusted odds ratio (OR) for antiviral therapy and cost ratios for antiviral costs associated with demographics.ResultsOf a total of 14,920 records, 143,658 records were involved in the analysis. The annual proportions of AD utilization were 56.99% (45.65%) for inpatients (outpatients) during 2008–2015 and increased annually. Entecavir (ETV), in particular, increased from 11.08% to 70.26% (11.05% to 49.35%) for inpatients (outpatients). The patients with medical insurance were more likely to use AD than patients without insurance, and the adjusted OR was 1.11 (95% CI: 1.03, 1.19) for inpatients and 1.66 (1.59, 1.73) for outpatients. With the disease progressing, the proportion of antiviral costs in total direct medical costs decreased from 13.91% to 4.07% (71.29% to 49.29%) for inpatients (outpatients).ConclusionsThe use of AD for chronic HBV infection was less than expected based on established guidelines, and only half of patients received antiviral treatment. However, the AD utilization, especially ETV, increased annually. Reimbursement policy was the most important factor affecting antiviral treatment. Antiviral therapy was an important part of the direct medical costs, especially in the early stage of disease.

Rodriguez, Christophe; Mercier-Darty, Mélanie; Soulier, Alexandre; Poiteau, Lila; Wlassow, Mélanie; Fourati, Slim; Hézode, Christophe; Pawlotsky, Jean-Michel; Chevaliez, Stéphane

doi: 10.3851/imp3318pmid: 31112134

BackgroundInternational liver society guidelines recommended to perform HCV resistance testing at baseline of first-line therapy with certain combination regimens or prior to retreatment in patients previously exposed to a direct-acting antiviral (DAA) containing regimen. Currently, no standardized assays have been developed as purchasable kits for HCV resistance testing. The aim of this study was to evaluate the performance of the Sentosa SQ HCV Genotyping Assay, a novel deep sequencing-based assay, to identify resistance-associated substitutions (RASs) in the NS3 protease, NS5A protein domain I and NS5B polymerase regions for patients infected with HCV genotypes-1a and 1b.MethodsSerum samples collected from patients with chronic hepatitis C infection who failed to achieve a sustained virological response after receiving a DAA-containing treatment regimen were extracted and sequenced by two methods including population sequencing of the NS3, NS5A and NS5B coding region reference method and the deep sequencing-based Sentosa SQ HCV Genotyping Assay.ResultsA high concordance rate with Sanger sequencing, the reference method, was found for the NS3, NS5A and NS5 coding regions, regardless of the genotype-1 subtypes. The deep sequencing-based assay was more sensitive than population sequencing to detect minority variants, representing less than 10% of the viral populations, but also some variants representing up to 30% of the viral quasispecies, as expected.ConclusionsThe Sentosa SQ HCV Genotyping Assay can be confidently used in clinical practice in the indications of HCV resistance testing for these subtypes. Technical improvements are now required to allow for pangenotypic coverage.

Gatell, Jose M; Morales-Ramirez, Javier O; Hagins, Debbie P; Thompson, Melanie; Arastéh, Keikawus; Hoffmann, Christian; Raffi, François; Osiyemi, Olayemi; Dretler, Robin; Harvey, Charlotte; Xu, Xia; Plettenberg, Andreas; Smith, Don E; Portilla, Joaquín; Rugina, Sorin; Kumar, Sushma; Frobose, Colleen; Wan, Hong; Rodgers, Anthony;

Peveling-Oberhag, Jan; Bankov, Katrin; Dultz, Georg; Ballo, Olivier; Lohmeyer, Julian; Brunnberg, Uta; Marcu, Vasile; Walter, Dirk; Zeuzem, Stefan; Hansmann, Martin-Leo; Welzel, Tania M; Vermehren, Johannes

doi: 10.3851/imp3322pmid: 31180334

BackgroundPatients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interferon (IFN). However, only about two-thirds of patients with sustained virological response (SVR) also had a consecutive lymphoma response. miRNA-26b is associated with HCV-NHL response to antiviral therapy. Recent data suggest that IFN-free direct-acting antiviral (DAA) regimens also have anti-lymphoma activity in this patient population.MethodsWe report four patients with HCV-NHL who were treated with different IFN-free DAA regimens as oncological monotherapy in our centre between 2015 and 2016. We analysed the virological and lymphoproliferative disease response. Moreover, we analysed miRNA-26b expression in peripheral blood mononuclear cells at different time points during antiviral therapy for all included patients as well as for a total of 10 controls with (n=5) and without (n=5) chronic HCV infection.ResultsAll patients had marginal zone lymphoma subtype and received different DAA regimens for 12–24 weeks. All four patients achieved SVR, but only three patients also had lymphoma response (one complete response, two partial responses). One patient showed progression to a high-grade lymphoma subtype after SVR. miRNA-26b expression was generally decreased in patients with HCV-NHL. Moreover, miRNA-26b expression was restored in those HCV-NHL patients with lymphoma response after 6 months (P=0.009).ConclusionsWe have demonstrated that IFN-free DAA treatment of HCV can improve or even cure NHL. miRNA-26b-levels could be a potentially useful biomarker to predict lymphoma response in HCV-NHL patients.

Anderson, Matt S; Gilmartin, Jocelyn; Fan, Li; Yee, Ka Lai; Kraft, Walter K; Triantafyllou, Ilias; Reitmann, Christina; Guo, Ying; Liu, Rachael; Iwamoto, Marian

doi: 10.3851/imp3324pmid: 31433304

BackgroundDoravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with coadministration.MethodsTwo trials were conducted. Study 1: two-period, fixed-sequence; eight healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, coadministration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC 300 mg + TDF 300 mg; ≥7-day washout between periods.ResultsStudy 1: geometric mean ratios (GMRs; 90% confidence interval [CI]) of DOR area under the concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and observed plasma concentrations at 24 h post-dose (C24 h; DOR+TDF/DOR) were 0.95 (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. Study 2: GMRs (90% CI) of DOR AUC0–∞ and C24 h (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and tenofovir AUC0–∞ (DOR+3TC+TDF/3TC+TDF) were 0.94 (0.88, 1.00) and 1.11 (0.97, 1.28), respectively. Study drugs were generally well tolerated.ConclusionsMultiple doses of TDF did not have a clinically meaningful effect on DOR PK. The PK of DOR were similar when administered alone or in combination with 3TC and TDF. DOR had no meaningful effect on the PK of 3TC and tenofovir.

Balmaceda, Julia B; Aepfelbacher, Julia; Belliveau, Olivia; Chaudhury, Chloe S; Chairez, Cheryl; McLaughlin, Mary; Silk, Rachel; Gross, Chloe; Kattakuzhy, Sarah; Rosenthal, Elana; Kottilil, Shyam; Kleiner, David E; Hadigan, Colleen

doi: 10.3851/imp3327pmid: 31359874

BackgroundWhile acute changes in hepatic fibrosis are recognized shortly after achieving sustained virological response (SVR) using direct-acting antiviral therapies, long-term outcomes for the growing population of successfully treated patients with HCV remain uncertain. The aim of this study is to characterize long-term changes in fibrosis following SVR in patients with and without HIV and to identify potential factors associated with progression or regression of fibrosis.MethodsWe completed a prospective longitudinal study of 162 subjects with HCV (34% HIV-coinfected) with pre-treatment fibrosis stage determined by liver biopsy and post-SVR transient elastography. Progression of fibrosis was defined as a two-stage or greater increase in fibrosis, while regression was defined as a two-stage or greater decrease at last follow-up. The median duration of follow-up was 4.1 years.ResultsFibrosis progression occurred in 4% of subjects while regression occurred in 7% and 89% were stable and did not differ by HIV coinfection. Fibrosis progression was associated with increased body mass index (BMI), hepatic steatosis and smoking pack-years. In a multivariable logistic regression, HIV coinfection (P=0.009), lower steatosis score (P<0.05) and lower smoking pack-years (P=0.0007) were associated with a lower fibrosis score at last follow-up.ConclusionsWe identify potentially important relationships between BMI, hepatic steatosis and smoking, and changes in hepatic fibrosis post-SVR in patients with and without HIV coinfection. Attention to modifiable risk factors such as body weight and smoking may reduce the risk of liver disease progression in the growing population of successfully treated chronic HCV patients.

Chastain, Daniel B; Veve, Michael P; Wagner, Jamie L

doi: 10.3851/imp3335pmid: 31570667

BackgroundThe purpose of this review is to critically analyse data regarding the prevalence and risk factors for developing a prolonged QTc interval and subsequent sudden cardiac death (SCD) in persons living with HIV (PLWH).MethodsA systematic literature search using PubMed and Google Scholar databases was performed using the following search terms: ‘HIV and prolonged QTc’ and ‘managing HIV-patients with prolonged QTc’. References within articles of interest were also evaluated.Results/DiscussionPLWH are at an increased risk of having a prolonged QTc interval. Some risk factors for this include the virus itself, concomitant medications, comorbid conditions, addictions and electrolyte disturbances. PLWH who have an increased HIV RNA viral load or decreased CD4+ T-cell count are at further risk for progressing to sudden cardiac death (SCD). Many medications commonly prescribed in the PLWH population, such as antiretrovirals and antimicrobials used in opportunistic infection prophylaxis, have also been shown to promote QTc prolongation through inhibition of human ether-a-go-go potassium channels or through drug metabolism inhibition of other QTc prolonging drugs.ConclusionsDue to the high number of risk factors associated with QTc prolongation, clinicians should incorporate baseline and routine ECG monitoring for PLWH to potentially lower the increased risk of SCD in PLWH.

Vizcarra, Pilar; Fontecha, María; Monsalvo, Marta; Vivancos, María J; Rojo, Aurora; Casado, Jose L

doi: 10.3851/imp3319pmid: 31172977

BackgroundDual therapies decrease toxicity, pill-burden and treatment-associated cost. The combination of high genetic barrier drugs such as dolutegravir plus boosted-darunavir may be suitable as simplification regimen for patients harbouring multidrug-resistant virus.MethodsPatients switched to a once-daily regimen consisting of dolutegravir plus darunavir, boosted with cobicistat or ritonavir, were included in this cohort study. The primary end point was the proportion of patients with HIV RNA viral load <37 copies/ml at week 48 (NCT02491242).ResultsOverall, 51 patients were enrolled. At baseline, all patients had failed to ≥2 antiretroviral classes. Genotypic resistance profiles showed a mean of primary mutations of 1.2 for non-nucleoside reverse transcriptase inhibitors, 2.4 for nucleoside/nucleotide reverse transcriptase inhibitors and 3.5 for protease inhibitors (PIs), but they were virologically suppressed for a median of 33 months (IQR 12–60). Only five patients had reduced sensitivity to darunavir and mean genotypic susceptibility score of dual therapy was 1.95 over 2. At week 48, there were no virological failures, three patients discontinued the regimen due to neuropsychiatric adverse events, two were lost to follow-up, and therefore the efficacy was 90% (95% CI, 82, 99%, intention-to-treat analysis). Mean estimated glomerular filtration rate decreased by 8.8 ml/min/1.73 m2, though kidney tubular parameters, high density lipoprotein-cholesterol and triglycerides levels improved after switching to dual therapy.ConclusionsIn highly treatment-experienced patients who were virologically suppressed, switching to the combination of dolutegravir plus boosted-darunavir dual therapy was effective and well tolerated, improving lipid and renal parameters.