Single-tablet Regimen Research Articles

SVR12 rates higher than 99% after sofosbuvir/velpatasvir combination in HCV infected patients with F0-F1 fibrosis stage: A real world experience.

Background and objectivesThe pangenotypic single tablet regimen of NS5B inhibitor sofobuvir (SOF) and NS5A inhibitor velpatasvir (VEL) is advised for 12 weeks in HCV-infected patients including those with compensated cirrhosis. Addition of ribavirin (RBV) may be considered in genotype 3 (GT3) with compensated and is recommended in decompensated cirrhosis. Real-life results with SOF/VEL are limited. To evaluate efficacy and safety in a large real-world-cohort including patients with different GTs and various fibrosis stages.DesignIn total, 1429 patients were treated with SOF/VEL 400/100 mg for 12 weeks in the Puglia registry between June 2017 and May 2018. 1319 (92.3%) reached week 12 post-treatment (SVR12) at the moment. Only 41 received RBV. Diagnosis of cirrhosis was based on transient elastography and/or APRI or FIB-4 scores. Sensitivity analysis in the population including all patients except non virological failure was conducted. Primary efficacy endpoint was the percentage of patients with SVR12.ResultsPatients’ mean age was 63.8 years, 42.3% had GT1. The majority were naïve and 735 (55.5%) F0/F2. Of the remaining 587, 282 had cirrhosis. SVR12 was 98.5%, 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4. Overall, SVR12 by sensitivity analysis was 99.4%; 99.7% among F0-F1. Among 218 PWID, SVR12 was 94.5%. Discontinuation rates were 3.7% among PWID and 0.7% among non-PWID (p = 0.004).ConclusionsSOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID.

Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial

Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated dolutegravir, abacavir, and lamivudine at week 96. This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607930. Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the dolutegravir group. These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance. Gilead Sciences, Inc.

Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial

The single-tablet regimen consisting of bictegravir, emtricitabine, and tenofovir alafenamide is recommended for treatment of HIV-1 infection on the basis of data from 48 weeks of treatment. Here, we examine the longer-term efficacy, safety, and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with dolutegravir plus co-formulated emtricitabine and tenofovir alafenamide at week 96. This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 126 outpatient centres in ten countries. We enrolled treatment-naive adults (aged ≥18 years) with HIV-1 infection who had an estimated glomerular filtration rate of at least 30 mL/min and sensitivity to emtricitabine and tenofovir. People with chronic hepatitis B or C infection, or both, and those who had used antivirals previously for prophylaxis were allowed. We randomly assigned participants (1:1) to receive treatment with either co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or dolutegravir 50 mg with co-formulated emtricitabine 200 mg and tenofovir alafenamide 25 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607956. Between Nov 13, 2015, and July 14, 2016, we screened 742 individuals, of whom 657 were enrolled. 327 participants were assigned to the bictegravir group and 330 to the dolutegravir group. Of these, 320 in the bictegravir group and 325 in the dolutegravir group received at least one dose of study drug. At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen. Both treatments continued to be well tolerated through 96 weeks; 283 (88%) of 320 participants in the bictegravir group and 288 (89%) of 325 in the dolutegravir group had any adverse event and 55 (17%), and 33 (10%) had any serious adverse event. The most common adverse events were diarrhoea (57 [18%] of 320 in the bictegravir group vs 51 [16%] of 325 in the dolutegravir group) and headache (51 [16%] of 320 vs 48 [15%] of 325). Deaths were reported for three (1%) individuals in each group (one cardiac arrest, one gastric adenocarcinoma, and one hypertensive heart disease and congestive cardiac failure in the bictegravir group and one unknown causes, one pulmonary embolism, and one lymphoma in the dolutegravir group); none were considered to be treatment related. Adverse events led to discontinuation in six (2%) participants in the bictegravir group and five (2%) in the dolutegravir group; one of these events in the bictegravir group versus four in the dolutegravir group occurred between weeks 48 and 96. Study drug-related adverse events were reported for 64 (20%) participants in the bictegravir group and 92 (28%) in the dolutegravir group. These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV. Gilead Sciences, Inc.

Discovery of velpatasvir (GS-5816): A potent pan-genotypic HCV NS5A inhibitor in the single-tablet regimens Vosevi® and Epclusa®.

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.

Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in Asian participants with human immunodeficiency virus 1 infection: A sub-analysis of phase 3 clinical trials

Background: The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naive and ART-experienced Asian participants infected with human immunodeficiency virus (HIV)-1 through 96 or 144 weeks.Objective: In Asian population requiring treatment, it is imperative to have data specific to this group, particularly as there is a general concern that Asians with lower body weight have increased risk of tenofovir disoproxil fumarate (TDF)-related renal dysfunction.Methods: Studies -104 and 111 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naive participants, comparing E/C/F/TAF versus E/C/F/TDF. Study 109 was a randomized, open-label, 96-week study conducted in virologically suppressed, ART-experienced participants, who switched to E/C/F/TAF from ritonavir/cobicistat-boosted atazanavir ATV+(RTV or COBI) + F/TDF regimens, from non-nucleoside reverse transcriptase inhibitors (NNRTI) + F/TDF regimens, or from E/C/F/TDF. Study 112 was a single arm, open-label, 144-week study conducted in HIV suppressed, ART-experienced participants with mild-moderate renal impairment, who switched to E/C/F/TAF.Results: Asian participants in these studies had sustained efficacy safety and tolerability. In Study 104/111, Asian participants achieved 93% virologic suppression on TAF vs 88% on TDF at week 144. At baseline, there were numerically more Asians with median CD4 counts < 200 cells/uL and VL > 100,000 c/mL. In Study 109, 95% of Asians on TAF vs 86% on TDF maintained virologic suppression at week 96. Lastly, in Study 112, 91% maintained virologic suppression at week 144. There were no discontinuations due to renal AE, no cases of PRT or Fanconi syndrome in any of the studies.

PIN17 RAPID INITIATION OF ANTIRETROVIRAL TREATMENT (ART) FOLLOWING DIAGNOSIS OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) AMONG MEDICAID BENEFICIARIES: A REAL-WORLD EVALUATION

This study aims to assess real-world time to ART initiation and describe outcomes in Medicaid patients based on timeliness of ART initiation. A retrospective longitudinal analysis was conducted using multi-state Medicaid data (01/1997-03/2017). Adults with HIV-1 and ≥6 months of continuous eligibility pre-HIV-1 diagnosis, no ART pre-HIV-1 diagnosis, no HIV-2 diagnosis at any time, and initiating an ART (including one protease inhibitor [PI], or one integrase strand transfer inhibitor [INSTI], or one non-nucleoside reverse transcriptase inhibitor [NNRTI], with ≥2 nucleoside reverse transcriptase inhibitors) in 2012 or later were included. Patients initiating ART >360 days post-HIV-1 diagnosis were excluded. Patients were classified into mutually exclusive groups based on timeliness of receipt of ART post-HIV-1 diagnosis. Healthcare costs were evaluated over the first 36 months post-HIV-1 diagnosis. Among 974 patients, 347 (35.6%) were excluded (initiated ART >360 days post-diagnosis) and 627 eligible patients were analyzed; mean age was 40.1 years (SD=12.3), 42.7% were females, and 53.9% were black. ART was initiated within 14 days of diagnosis in 20.4% of patients, between 15-60 days in 36.4%, between 61-180 days in 26.0%, and between 181-360 days in 17.2%. In total, 24.1%, 34.1%, and 41.8% patients initiated a PI-, INSTI-, or NNRTI-based regimen, respectively. Darunavir (9.6%), elvitegravir (16.9%), and efavirenz (26.5%) were the most commonly used ART across classes, and most patients (58.5%) initiated a single-tablet regimen. Over 36 months following HIV-1 diagnosis, total healthcare costs (i.e., sum of medical and pharmacy costs) increased with delayed ART initiation from $74,092 for patients treated within 14 days to $83,157 for patients treated between 181-360 days post-diagnosis. This study revealed that only 20% of Medicaid patients initiated ART within 14 days post-diagnosis and that patients with delayed initiation accumulated more healthcare costs than those with rapid initiation, highlighting the long-term benefits of rapid ART initiation.

A potential long-acting bictegravir loaded nano-drug delivery system for HIV-1 infection: A proof-of-concept study

Bictegravir (BIC), a newly FDA-approved integrase strand transfer inhibitor (INSTI), as a single tablet regimen has proven efficacious in treating HIV-1 and SIV viruses, with reduced resistance. BIC clinical trials have not investigated its prophylaxis potency. This study investigates the HIV prevention potency of a novel long-acting BIC nano-formulation aimed to improve adherence. Poly (lactic-co-glycolic acid) loaded BIC nanoparticles (BIC NPs) were formulated using an oil-in-water emulsion methodology. BIC NPs were <200 nm in size, with 47.9 ± 6.9% encapsulation efficiency. A novel, sensitive and high throughput LC-MS/MS method was used to estimate intracellular pharmacokinetics (PK) of BIC NPs and compared to BIC solution demonstrated prolonged intracellular BIC retention. BIC NPs safety was assessed based on cytotoxicity. Further, in-vitro prevention study of BIC NPs vs BIC solution was assessed against HIV-1NLX and HIV-1ADA on TZM-bl cell line and PBMCs, respectively. BIC nanoencapsulation demonstrated elevated cellular cytotoxicity concentration (CC50: 2.25 μM (BIC solution) to 820.4 μM (BIC NPs)] and lowers HIV-1 inhibitory concentration [EC50: 0.604 μM (BIC solution) to 0.0038 μM (BIC NPs)) thereby improving selectivity index (SI) from 3.7 (BIC solution) to 215,789 (BIC NP) for TZM-bl cells. Comparable results in PBMCs were obtained where BIC NPs improved SI from 0.29 (BIC solution) to 523.33 (BIC NPs). This demonstrates long-acting BIC nano-formulation with sustained drug-release potency, improved BIC cytotoxicity and enhanced HIV-1 protection compared to BIC in solution.

Adherence to HIV treatment regimens: systematic literature review and meta-analysis.

BackgroundAntiretroviral therapy (ART), when taken consistently, reduces morbidity and mortality associated with human immunodeficiency virus and viral transmission. Suboptimal treatment adherence is associated with regimen complexity and high tablet burden. Single-tablet regimens (STRs) provide a complete treatment regimen in a single tablet. This study examined the relationship between STRs (vs multiple-tablet regimens [MTRs]), treatment adherence, and viral suppression.MethodsA systematic review was conducted to identify studies investigating at least one of the following: (1) STR/MTR use and adherence; (2) levels of adherence and viral suppression; and (3) STR/MTR use and viral suppression. Meta-analysis was performed to assess the relationship between STR vs MTR use and adherence in observational settings at ≥95% and ≥90% adherence thresholds.ResultsIn total, 29 studies were identified across the three objectives; two studies were relevant for all objectives. STRs were associated with higher treatment adherence than MTRs in 10/11 observational studies: a 63% greater likelihood of achieving ≥95% adherence (95% CI=1.52–1.74; P<0.001) and a 43% increase in the likelihood of achieving ≥90% adherence (95% CI=1.21–1.69; P<0.001). Higher adherence rates were associated with higher levels of viral suppression in 13/18 studies. Results were mixed in five studies investigating the association between STR or MTR use and viral suppression.ConclusionAlthough the direct effect of STRs vs MTRs on viral suppression remains unclear, this study provided a quantitative estimate of the relationship between STRs and ART adherence, demonstrating that STRs are associated with significantly higher ART adherence levels at 95% and 90% thresholds. Findings from the systematic review showed that improved adherence results in an increased likelihood of achieving viral suppression in observational settings. Future research should utilize similar measures for adherence and evaluate viral suppression to improve assessment of the relationship between pill burden, adherence, and viral suppression.

Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV.

Remarkable progress has been achieved in the identification of HIV infection in pregnant women and in the prevention of vertical HIV transmission through maternal antiretroviral treatment (ART) and neonatal antiretroviral drug (ARV) prophylaxis in the last two decades. Millions of women globally are receiving combination ART throughout pregnancy and breastfeeding, periods associated with significant biological and physiological changes affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of ARVs. The objective of this review was to summarize currently available knowledge on the PK of ARVs during pregnancy and transport of maternal ARVs through the placenta and into the breast milk. We also summarized main safety considerations for in utero and breast milk ARVs exposures in infants. We conducted a review of the pharmacological profiles of ARVs in pregnancy and during breastfeeding obtained from published clinical studies. Selected maternal PK studies used a relatively rich sampling approach at each ante- and postnatal sampling time point. For placental and breast milk transport of ARVs, we selected the studies that provided ratios of maternal to the cord (M:C) plasma and breast milk to maternal plasma (M:P) concentrations, respectively. We provide an overview of the physiological changes during pregnancy and their effect on the PK parameters of ARVs by drug class in pregnancy, which were gathered from 45 published studies. The PK changes during pregnancy affect the dosing of several protease inhibitors during pregnancy and limit the use of several ARVs, including three single tablet regimens with integrase inhibitors or protease inhibitors co-formulated with cobicistat due to suboptimal exposures. We further analysed the currently available data on the mechanism of the transport of ARVs from maternal plasma across the placenta and into the breast milk and summarized the effect of pregnancy on placental and of breastfeeding on mammal gland drug transporters, as well as physicochemical properties, C:M and M:P ratios of individual ARVs by drug class. Finally, we discussed the major safety issues of fetal and infant exposure to maternal ARVs. Available pharmacological data provide evidence that physiological changes during pregnancy affect maternal, and consequently, fetal ARV exposure. Limited available data suggest that the expression of drug transporters may vary throughout pregnancy and breastfeeding thereby possibly impacting the amount of ARV crossing the placenta and secreted into the breast milk. The drug transporter's role in the fetal/child exposure to maternal ARVs needs to be better understood. Our analysis underscores the need for more pharmacological studies with innovative study design, sparse PK sampling, improved study data reporting and PK modelling in pregnant and breastfeeding women living with HIV to optimize their treatment choices and maternal and child health outcomes.

New strategy for determination of anti-viral drugs based on highly conductive layered composite of MnO2/graphene/ionic liquid crystal/carbon nanotubes

In the last decade, the biomedical field has benefited from the progressive development of antiviral drugs. Antiviral drugs Sofosbuvir (SOF), ledipasvir (LED) and acyclovir (ACY) are a class of medications used specifically for treating viral infections as hepatitis C (HCV) and B (HBV) viruses. Sofosbuvir (SOF) and ledipasvir (LED) in a single-tablet regimen represent a revolution in the treatment of chronic hepatitis C which inhibits viral production of HCV. The major problem with simultaneous determination of SOF, LED and ACY by electrochemical methods is the closeness of their oxidation potentials resulting in overlapped voltammetry responses. In such frame an innovative strategy is introduced, based on a novel GC/CNT/ILC/RGO/MnO2 layered electrode, obtained by modifying a glassy carbon surface with layers of multi-walled carbon nanotubes (CNT), an ionic liquid crystal (ILC), graphene (RGO) and MnO2. The layered sensor showed excellent current responses for the simultaneous electrochemical analysis of SOF, LED and ACY in human serum in the concentration ranges 0.20–150μmoldm−3, 0.0070–15μmoldm−3 and 0.010–30μmoldm−3 with low detection limit values of 9.8nmoldm−3, 0.11nmoldm−3 and 0.84nmoldm−3 respectively. Moreover, on the new layered electrode the electro-oxidation of a quinary mixture of ascorbic acid (AA), dopamine (DA), paracetamol (APAP), SOF and LED yielded five well-separated peaks. This electrochemical method is advantageous over other methods mentioned in the literature in terms of cost, time effectiveness, sensitivity, selectivity and lower detection limit. Analysis of ACY and a combination from LED and SOF in their pharmaceutical formulations were achieved with good recovery results.

Antiretroviral adherence and virologic suppression in partnered and unpartnered HIV-positive individuals in southern Brazil.

BackgroundAn undetectable serum HIV-1 load is key to effectiveness of antiretroviral (ARV) therapy, which depends on adherence to treatment. We evaluated factors possibly associated with ARV adherence and virologic response in HIV-infected heterosexual individuals.MethodsA cross-sectional study was conducted in 200 HIV-1 serodiscordant couples and 100 unpartnered individuals receiving ARV treatment at a tertiary hospital in southern Brazil. All subjects provided written informed consent, answered demographic/behavioral questionnaires through audio computer-assisted self-interviews (ACASI), and collected blood and vaginal samples for biological markers and assessment of sexually transmitted infections (STIs). HIV-negative partners were counseled and tested for HIV-1.ResultsThe study population mean age was 39.9 years, 53.6% were female, 62.5% were Caucasian, 52.6% had incomplete or complete elementary education, 63.1% resided in Porto Alegre. Demographic, behavioral and biological marker characteristics were similar between couples and single individuals. There was an association between adherence reported on ACASI and an undetectable serum viral load (P<0.0001). Logistic regression analysis demonstrated that single-tablet ARV-regimens were independently associated with adherence (OR = 2.3; 95CI%: 1.2–4.4; P = 0.011) after controlling for age, gender, education, marital status, personal income, ARV regimen, and median time of ARV use. A positive correlation between genital secretion PCR results and serum viral load was significant in the presence of STIs (r = 0.359; P = 0.017). Although HIV PCR detection in vaginal secretions was more frequent in women with detectable viremia (9/51, 17.6%), it was also present in 7 of 157 women with undetectable serum viral loads (4.5%), p = 0.005.ConclusionsARV single tablet regimens are associated with adherence. Detectable HIV-1 may be present in the genital secretions of women with undetectable viremia which means there is potential for HIV transmission in adherent individuals with serologic suppression.

Sofosbuvir\u2013velpatasvir single-tablet regimen administered for 12 weeks in a phase 3 study with minimal monitoring in India

Background and aimsIn clinical studies, sofosbuvir–velpatasvir has demonstrated high cure rates and favorable tolerability in patients chronically infected with chronic hepatitis C virus (HCV) of any genotype. We evaluated the effectiveness and safety of sofosbuvir–velpatasvir administered with minimal medical monitoring to patients in India.MethodsAt 16 sites in India, 129 adult patients with chronic HCV infection of any genotype initiated 12 weeks of once-daily sofosbuvir–velpatasvir (400–100 mg). Patients with compensated cirrhosis or prior treatment experience could be included in the study. Study drug was dispensed monthly, but there were no on-treatment study assessments. The primary efficacy endpoint was rate of sustained virologic response (HCV RNA < 15 IU/mL) 12 weeks after treatment (SVR12), which was compared to a pre-specified performance goal of 85%.ResultsThe majority of patients had HCV genotype 3 infection (70%), followed by HCV genotype 1 (22%). The SVR12 rate was 93% (120/129; 95% CI, 87% to 97%) (p = 0.009 compared with the 85% performance goal). Of the nine patients who did not achieve SVR12, 1 experienced virologic failure, 2 relapsed after treatment, 1 withdrew consent after treatment, and 5 were lost to follow-up (1 during and 4 after treatment). Sofosbuvir–velpatasvir was well-tolerated, and no patients discontinued treatment because of an adverse event. The most frequently reported adverse events were headache (3% of patients), upper abdominal pain (2%), and pyrexia (2%).ConclusionsIn this study conducted at multiple sites in India, sofosbuvir–velpatasvir administered without genotype restriction or on-treatment safety assessments was well-tolerated and highly effective.

Dolutegravir-Rilpivirine, Dual Antiretroviral Therapy for the Treatment of HIV-1 Infection

Objective: To review the efficacy and safety of dolutegravir (DTG) with rilpivirine (RPV) as a dual therapy regimen in the treatment of HIV-1 infection. Data Sources: A literature search was performed using PubMed (1966 to January 2019) and Google Scholar (2014 to January 2019) with the search terms dolutegravir, rilpivirine, dual, and switch. Other resources included review articles and the manufacturer product label. Study Selection and Data Extraction: All relevant English-language articles of studies assessing the efficacy and safety of switch therapy to DTG with RPV and review articles were included. Data Synthesis: The fixed-dose combination tablet of DTG and RPV is the first dual therapy approved for the treatment of HIV-1 infection in adult patients who have achieved virological suppression for least 6 months on current antiretroviral therapy. This single-tablet regimen is dosed once daily and has been compared with standard triple therapy antiretroviral regimens for safety and efficacy. The dual therapy regimen demonstrated comparable maintenance of virological suppression evaluated up to 100 weeks, with low rates of virological failure. Common adverse effects include headache and diarrhea. Relevance to Patient Care and Clinical Practice: This dual therapy represents an attractive option with a high barrier to resistance in patients without hepatitis B coinfection with adverse effects or significant drug-drug interactions on current therapy, polypharmacy, or end-stage renal disease, who are controlled on triple therapy. Conclusions: This dual therapy combination of DTG-RPV provides maintenance of virological suppression as a switch strategy with few drug interactions and positive effects on lipids and renal and bone health.

Experience with Voluntarily De-Simplifying a Single-Tablet ART Regimen

Very long-term use of effective (but expensive) single-tablet regimens (STRs) has led to consideration of safe (but less expensive) alternative

Health-related quality of life among HIV-infected patients initiating treatment in Brazil in the single-tablet regimen era

ABSTRACTHealth-related quality of life (HRQoL) is a multidimensional concept involving an individual’s self-perception about how a disease or treatment impacts their daily life. In this study, we evaluated the HRQoL and factors associated with this outcome in 366 patients initiating combination Antiretroviral Therapy (cART) in Belo Horizonte, Brazil.We measured HRQoL using the EuroQoL-5D 3 level (EQ-5D) and the HIV instrument of the World Health Organization (WHOQOL-HIV BREF) and identified factors associated with HRQoL using multilevel linear regression. Participants had been on cART treatment a median of 65.5 days at the time the instruments were completed. The median HRQoL of patients on the single-tablet regimen containing efavirenz/ tenofovir/ lamivudine and the multi-tablet regimen containing dolutegravir and tenofovir/ lamivudine were high, with no significant difference between groups. Factors consistently associated with lower HRQoL were being single (unmarried), having a lower educational level, recent cigarette smoking, recent signs and symptoms of anxiety or depression, comorbid disease and the occurrence of adverse drug reactions. We observed high levels of HRQoL in cART-treated people and no differences between dolutegravir and efavirenz-based regimens. This study provides inputs to future economic analysis and identifies opportunities to increase the HRQoL of patients by targeting modifiable factors.

Modelling the Impact and Cost-effectiveness of Extended Hepatitis C Virus Screening and Treatment with Direct-acting Antivirals in a Swiss Custodial Setting.

Hepatitis C virus (HCV) among people living in detention (PLD) is typically high in many countries including Switzerland, where it is estimated that the HCV prevalence rate is between 5.7% and 6.2%. In Switzerland, the existing screening strategy involves routine screening of PLD who indicate they are from HCV high-risk populations based on questionnaire responses upon entry to the detention center, rather than an offer to screen all PLD. A cost-effectiveness analysis from a Swiss healthcare provider perspective was conducted by combining a 5-year decision tree screening model with results from a Markov model of HCV treatment outcomes. This model explored the cost-effectiveness of increased HCV screening to cover all PLD compared to the current approach, using a standard test package and subsequent treatment with a single-tablet regimen in Swiss custodial settings. Sensitivity and scenario analyses examined the uncertainty of results. At the willingness-to-pay threshold of 100 000 Swiss Francs (CHF) per quality-adjusted life-year (QALY), comprehensive general screening was cost-effective compared to current risk-based screening, with a base case incremental cost-effectiveness ratio of CHF 14 312 per QALY. The net monetary benefit of screening the whole PLD population was CHF 23 298 046 and CHF 4298 per person. The proportion of PLD tested was predicted to increase from 13.6% to 67.0% under comprehensive screening. The results showed that comprehensive screening strategies in detention centers in Switzerland can be cost-effective, with the probabilistic sensitivity analysis estimating an 82.3% probability of cost-effectiveness.

Tolerability of Current Antiretroviral Single-Tablet Regimens

The advent of protease inhibitors (PI) in the mid-nineties and its use as part of triple combinations revolutionized the management of HIV infection. Since then, progression to AIDS and AIDS-related deaths can be prevented. However, antiretroviral therapy based on PI has been discouraged for a while given its lower tolerability compared to alternative options; and only recent improvements in pharmacotherapy have renewed the interest for the newest agents within this class. First, the tolerability of the latest PI darunavir (DRV) and atazanavir is much better than for older PI, such as indinavir or lopinavir. Second, metabolic abnormalities and/or drug interactions associated to ritonavir boosting have been ameliorated using cobicistat. Third, adding safer accompanying nucleos(t)ides, such as tenofovir alafenamide (TAF), have minimized further toxicity concerns of PI. Finally, the unique barrier to resistance and new single-tablet regimen (STR) presentation makes DRV, especially attractive for long-term therapy. The recent coformulation of DRV, cobicistat, TAF, and emtricitabine (DRV/c/TAF/FTC) within a single pill to be given once daily (Symtuza®) has positioned PI again at the frontline of HIV therapeutics. In this review, we discuss the results of studies that have assessed the efficacy and safety of the newest STR. In view of the current data, it seems worthy expanding the consideration of Symtuza® for a wider range of clinical scenarios, beyond the treatment of antiretroviral failures including first-line therapy and switching of otherwise virologically suppressed patients. The good tolerability and robust resistance profile should reward Symtuza® and position it among the preferred contemporary STRs.

A Comprehensive Development Agenda on Tenofovir Alafenamide in Clinical Practice.

The introduction of tenofovir (TFV) alafenamide (TAF) into clinical practice will be a further revolution in antiretroviral therapy. Currently available HIV-1 regimens are wide enough to allow diversified usage in different settings. Despite the fact that TAF is not capillary accessible, even in industrialized countries, ultimate International Guidelines have already included TAF in backbone or in single-tablet regimens. Due to a better safety profile, TAF will progressively replace TFV disoproxil fumarate, both in naïve and experienced patients. However, therapeutic innovations have to deal with budget constraints and different global spending-review patterns. The aim of this article is to give a comprehensive agenda of TAF use in naïve and experienced HIV-1 infected patients, providing a full review of the studies present in the literature and contextualizing these findings into daily clinical practice.

New Dual Combination of Dolutegravir-Rilpivirine for Switching to Maintenance Antiretroviral Therapy.

Advances in antiretroviral therapy have led to dramatic improvements in survival of HIV-infected persons. However, HIV cure remains elusive and lifelong treatment is needed. Attempts for reducing long-term drug exposure, toxicities, and cost, while maintaining viral suppression, have led to explore whether maintenance strategies with less than triple therapy could be feasible using the newest more potent antiretrovirals. While monotherapies have failed to do so with selection of drug resistance, some dual combinations have proven its efficacy when used sequentially in patients with viral suppression under standard triple regimens. Furthermore, the advent of coformulations makes easier long-term drug adherence. Herein, we review the current experience with the new single tablet regimen of dolutegravir (DTG) and rilpivirine (RPV) (Juluca®). It is the first approved two-drug single-tablet regimen and the first dual nuc-sparing coformulation. Two randomized, non-inferiority clinical trials (SWORD-1 and -2) and five observational studies have evaluated DTG-RPV in treatment-experienced patients. Despite distinct inclusion criteria, more than 95% of patients kept plasma HIV-RNA undetectable for at least 48 weeks. Along with virological efficacy being non-inferior to triple regimens, the tolerance of DTG-RPV was good, being discontinuations due to adverse events only 0.8-7.9%. Moreover, improvements were seen in lipid profiles in patients switched from protease inhibitors, and in renal and bone biomarkers in those switched from tenofovir disoproxil fumarate. Finally, resistance is rare failing on DTG-RPV. In summary, DTG-RPV is a novel two-drug coformulation that can be effectively and safely used in treatment-experienced patients with viral suppression if the virus is fully susceptible to both drugs. Its unique features make this drug one of the best options as long-term regimen or lifelong maintenance HIV therapy.

Bictegravir in a fixed-dose tablet with emtricitabine and tenofovir alafenamide for the treatment of HIV infection: pharmacology and clinical implications

ABSTRACTIntroduction: Current antiretroviral therapy is more effective and simpler than in previous times due to the development of new drugs with improved pharmacokinetic and pharmacodynamic profiles and the advent of single pill regimens with low toxicity that facilitate long-term adherence. The recent approval of the novel potent integrase strand-transfer inhibitor bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide (TAF) in a fixed daily dose pill, B/F/TAF, adds to the list of single-tablet regimens available to treat HIV infection.Areas covered: This review provides an overview of the pharmacological and clinical information obtained from MEDLINE/PubMed publications and the latest international conferences.Expert opinion: BIC is a potent antiretroviral with an improved resistance profile over previous integrase inhibitors. Its combination with the new tenofovir prodrug TAF and FTC creates an effective regimen B/F/TAF for treatment-naïve patients and for those switching from another successful combination. B/F/TAF’s favorable pharmacokinetic profile, simple dose, low pill burden, and few drug-drug interactions or treatment-related adverse events, will make it one of the preferred regimens in the future.