Treatment-experienced Research Articles

Cost Effectiveness of Avelumab for Metastatic Merkel Cell Carcinoma.

BackgroundMetastatic Merkel cell carcinoma (mMCC) is a rare and aggressive skin cancer. Until recently, there were no licensed treatment options for patients with mMCC, and prognosis was poor. A cost-effectiveness analysis was conducted for avelumab, a newly available treatment option for mMCC, versus standard care (SC), from a UK National Health Service perspective.MethodsA partitioned survival model was developed to assess the lifetime costs and effects of avelumab versus SC. Data from the JAVELIN Merkel 200 trial (NCT02155647) were used to inform estimates of quality-adjusted life-years (QALYs). Unit costs and associated frequencies of use were informed by published literature and clinical expert opinion. Results were presented as incremental cost-effectiveness ratios (ICERs, i.e. the cost per QALY gained) for treatment-experienced (TE) and treatment-naïve (TN) patients. Uncertainty was explored through a range of sensitivity analyses.ResultsDiscounting costs and QALYs at 3.5% per annum, avelumab was associated with ICERs of £35,274 (TE)/£39,178 (TN) per QALY gained. Probabilistic sensitivity analysis results demonstrated that avelumab was associated with an 88.3% (TE)/69.3% (TN) probability of being cost effective at a willingness-to-pay threshold for end-of-life treatments of £50,000 per QALY gained. Results were most sensitive to alternative survival extrapolations and dosing assumptions.ConclusionsThe analysis results suggest that avelumab is likely to be a cost-effective treatment option for UK mMCC patients. The results for TN patients are subject to some uncertainty, and a confirmatory analysis will be conducted with more mature data.

Effectiveness of ombitasvir/paritaprevir/ritonavir, dasabuvir for HCV in HIV/HCV coinfected subjects: a comprehensive analysis

BackgroundData on the treatment of patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection remains limited. A comprehensive analysis was performed to evaluate the efficacy and safety of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir(r) ± dasabuvir (DSV) ± ribavirin (RBV) for treatment in HCV/HIV coinfected patients.MethodsWe systematically searched and included studies that enrolled patients with HIV/HCV coinfection using the OBV/PTV/r ± DSV ± RBV regimens and reported sustained virological response after 12 weeks (SVR12) end-of-treatment. Heterogeneity of results was assessed and pooled SVR rates were computed with 95% confidence intervals (95%CI). Subgroup analysis and assessment of publication bias through Egger’s test were further performed.ResultsTen studies containing 1358 coinfected patients were included in this study. The pooled estimate of SVR12 was 96.3% (95%CI: 95.1–97.4). Subgroup analysis showed that pooled SVR12 rate was 96.2% (95% CI: 94.8–97.4) for patients with genotype (GT) 1 and 98.8% (95% CI: 95.1–100.0) for those with GT4. The SVR12 rates for the treatment-naïve (TN) and treatment-experienced (TE) patients were 96.8% (95% CI, 94.8–98.5) and 98.9% (95% CI, 96.4–100.0), respectively. Pooled SVR12 rate was 97.8(95%CI: 94.6–99.8) for patients with cirrhosis and 96.7% (95%CI: 95.3–97.8) without cirrhosis. The pooled incidence of any adverse events (AEs) and serious adverse events (SAEs) was 73.9% (95%CI: 38.1–97.6) and 2.7% (95%CI: 0.0–9.5). Publication bias did not exist in this study.ConclusionsThe comprehensive analysis showed high efficacy for the OBV/PTV/r ± DSV ± RBV regimen in patients coinfected with HIV and HCV, regardless of genotypes, history of treatment and the presence or absence of cirrhosis.

Effectiveness of dolutegravir-based regimens as either first-line or switch antiretroviral therapy: data from the Icona cohort.

IntroductionConcerns about dolutegravir (DTG) tolerability in the real‐life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG‐based regimens from a large cohort of HIV‐infected individuals.MethodsWe performed a multicentre, observational study including all antiretroviral therapy (ART)‐naïve and virologically suppressed treatment‐experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG‐based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan–Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation.ResultsAbout 1679 individuals (932 ART‐naïve, 747 TE) were included. The one‐ and two‐year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART‐naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART‐naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART‐naïve (2.1%) and TE (1.7%) patients. In ART‐naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH = 3.30, p = 0.009). TE patients starting a DTG‐based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC‐based triple‐therapies, aHR = 3.56, p = 0.012 for tenofovir‐based) and for toxicity (aHR = 5.26, p = 0.030 for ABC‐based, aHR = 6.60, p = 0.024 for tenofovir‐based). The one‐ and two‐year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group.ConclusionsIn this large cohort, DTG showed excellent efficacy and optimal tolerability both as first‐line and switching ART. The low risk of treatment‐limiting toxicities in ART‐naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice.

Daclatasvir plus Sofosbuvir with or without ribavirin in patients with chronic Hepatitis C genotype 3a in Pakistani population - A real world experience.

Background and Objectives:Pakistan is among leading countries of world in prevalence of chronic hepatitis C Daclatasvir plus sofosbuvir is recommended for treatment of CHC. The purpose of study was to determine the sustained virological response in patients with chronic viral hepatitis C genotype 3a irrespective of previous treatment experience or presence of liver cirrhosis.Methods:Open label observational study was conducted at ABSTH Gujrat from January 2017 to April 2018 using non-probability purposive sampling. Patients chronically infected with hepatitis C virus having genotype 3a irrespective of presence of cirrhosis or previous treatment experience were included. Treatment naive patients without cirrhosis were given 12 weeks regimen of daily daclatasvir 60mg along with daily sofosbuvir 400mg. Patients with either compensated cirrhosis or treatment experienced were given 24 weeks regimen of daily daclatasvir 60mg along with daily sofosbuvir 400mg with weight based ribavirin. Data analysis was done using SPSS 20.0Results:Total 125 patients were included in study out of which 42 (33.6%) were male and 83 (66.4%) were female. Early virological response and end treatment response was achieved by 124 (99.2%) patients. Twenty four patients were lost to further follow-up and SVR24 was available for 101(80.8%) patients out of which 48 were having cirrhosis and 53 were without cirrhosis. SVR24 was achieved by 96 patients (95%). Virological response was better in treatment naive patients and without cirrhosis compared to treatment experienced and those with cirrhosis.Conclusion:Daclatasvir plus sofosbuvir is an effective combination in patients with chronic hepatitis C genotype 3a infection.

New resistance mutations to nucleoside reverse transcriptase inhibitors at codon 184 of HIV-1 reverse transcriptase (M184L and M184T).

Mutations at HIV-1 reverse transcriptase (RT) codon 184 such as M184V confer resistance to two nucleos(t)ide RT inhibitors (NRTI), lamivudine (3TC) and emtricitabine (FTC). The prevalence of mutations at HIV-1 RT codon 184 was evaluated using three independent RT sequence databases from treatment-experienced (TE) and treatment-naïve (TN) individuals. Data were collected retrospectively from three centers: one in Italy and two in France between 1997 and 2016. In order to highlight the role of these mutations in conferring drug resistance, structural and thermodynamic analyses were conducted by means of computational approaches. Among 32,440 RT sequences isolated from TE and 12,365 isolated from TN patients, the prevalence of HIV-1 RT codon 184 substitutions in each group was 31.21% and 0.72%, respectively. The mutations M184L and M184T have been observed only in TE patients. In all cases but four, M184L and M184T mutations were present during NRTI treatment. Molecular recognition studies on M184L and M184T structures showed both FTC and 3TC thermodynamic profiles unfavorable in comparison with the wild-type sequence, corroborated by molecular dynamic simulations (MDS). In this study, we highlighted two new resistance mutations in vivo for NRTI resistance. The low frequency of this pathway can be related to high impairment of replicative capacity mediated by these mutations.

Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study

BackgroundChronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection.MethodsChinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing.ResultsAll 206 enrolled patients achieved SVR12 (100%; 95% CI 98–100%), including 106 treatment-naive patients (100%; 95% CI 97–100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported.ConclusionLedipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.

Effectiveness of Dolutegravir-Based Regimens as Either First Line or Switch Antiretroviral Therapy: Data from the ICONA Cohort

Background We aimed to estimate the risk of discontinuation (TD) and virological failure (VF) of dolutegravir (DTG)-based regimens. Methods We performed a multicentre, observational study including all antiretroviral therapy (ART)-naA¯ve and virologically suppressed treatment-experienced (TE) patients from the ICONA cohort who started DTG for the first time. We estimated time to DTG-TD and VF using Kaplan-Meier curves. We used Cox regression model to assess predictors of DTG-TD. Findings 1,679 individuals (932 ART-naive, 747 TE) included. The one- and two-year probabilities (95% CI) of DTG-TD were 6⋅7% (4⋅9-8⋅4) and 11⋅5% (8⋅7-14⋅3) for ART-naive and 6⋅6% (4⋅6-8⋅6) and 7⋅6% (5⋅4-9⋅8) for TE subjects. In both ART-naive and TE, DTG-TD was mainly driven by toxicity with an estimated risk (95% CI) of 4⋅0% (2⋅6-5⋅4) and 2⋅5% (1⋅3-3⋅6) by one year and 5⋅6% (3⋅8-7⋅5) and 4⋅0% (2⋅4-5⋅6) by two years, respectively. Neuropsychiatric events were the main reason for DTG-TD in both ART-naive (2⋅1%) and TE (1⋅7%) patients. In ART-naive, a concomitant AIDS diagnosis predicted the risk of DTG-TD for any reason (aRH=3⋅38, p=0⋅001) whereas starting DTG in combination with abacavir (ABC) predicted DTG-TD for toxicity (aRH=3⋅30, p=0⋅009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of DTG-TD for any reason (aHR 2⋅50, p=0⋅037 for ABC-based triple-therapies, aHR 3⋅56, p=0.012 for tenofovir-based) and for toxicity (aHR 5⋅26, p=0⋅030 for ABC-based, aHR 6⋅60,p=0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of VF were 1⋅2% (0⋅3-2⋅0) and 4⋅6% (2⋅7-6⋅5) in the ART naive group and 2⋅2% (1⋅0-3⋅3) and 2⋅9% (1⋅5-4⋅3) in the TE group. Interpretation DTG showed excellent efficacy and tolerability both in ART-naive and TE patients. The low risk of toxicities limiting DTG treatment provide reassuring information in the light of the forthcoming transition to DTG-based first-line therapy in resource-limited countries. Funding: Viiv Healthcare International. Declaration of Interest: AM, ACL, AT, FM and FV have nothing to disclose. SR outside the submitted work reports grants personal fees and non-financial support from ViiV Healthcare,Gilead Sciences and Janssen-Cilag, personal fees and non-financial support from Bristol Myers Squibb and personal fees from Merck Sharp and Dohme. FCS outside the submitted work reports personal fees from Gilead Sciences, Bristol Meyers Squibb, Abbvie, Roche Diagnostic, Janssen-Cilag, Abbott Molecular and ViiV Healthcare, grants and personal fees from Merck Sharp and Dohme and grants from Italian Ministry of Instruction University and Research. AC outside the submitted work reports grants and personal fees from ViiV Healthcare and personal fees from Merck Sharp and Dohme and Janssen-Cilag. ADL outside the submitted work reports grants and personal fees from ViiV 331 Healthcare, Merck Sharp and Dohme and Gilead Sciences and personal fees from Janssen-Cilag and Abbvie. GM outside the submitted work reports personal fees from Gilead Sciences and ViiV Healthcare. AA outside the submitted work reports grants, personal fees and non-financial support from Gilead Sciences, ViiV Healthcare and Bristol Myers Squibb, grants and personal fees from Janssen-Cilag, personal fees from Merck Sharp and Dohme and personal fees and non financial support from Abbvie. AdAM outside the submitted work reports grants and personal fees from Gilead Sciences, ViiV Healthcare and Merck Sharp and Dohme and personal fees from Janssen and Bristol Myers Squibb. Ethical Approval: The Icona Foundation study was approved by the Ethics Committee (IRB) of each participating institution. All of the individuals enrolled provided a written informed consent at the time of the enrolment. All procedures of the study were performed in accordance with the 1964 Helsinki declaration and its later amendments.

The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: Role of the treatment regimen

Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon (IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV clinical database. We identified HCC-naïve individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997-2016 resulting in a sustained virologic response. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or 31 January 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free vs. IFN-containing. A total of 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; p = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, p = 0.744). These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. We examined the risk of liver cancer in 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer.

Discrimination and support from friends and family members experienced by people with mental health problems: findings from an Australian national survey.

To investigate the scope and nature of discrimination and positive treatment experienced by adults with mental health problems from their friends and family in a population-based survey. An Australian telephone-survey of 5220 adults included 1381 individuals who reported a mental health problem or scored high on a screening questionnaire. Respondents were interviewed about their experience of discrimination and positive treatment from their friends, spouse and other family members. Descriptions of experiences were content-analysed to identify key characteristics. Mental health diagnoses were primarily depression or anxiety disorders, and just over half had received treatment in the last 12months. Positive treatment from family and friends was far more common than discrimination, reported by 74.1% of respondents. This was primarily characterised by providing emotional support and maintaining contact, as well as checking on their mental health and being a good listener. Nevertheless, discriminatory behaviours from friends and family were reported by 25.8% of respondents, with reducing or cutting contact being by far the most common. Friends and family also commonly dismissed that mental illness was real or caused suffering and showed a lack of understanding about mental health problems or treatments and how they can impact behaviour and functioning. This nationally representative study of real life experiences highlights the potential for harm or benefit from a person's social support network. Despite positive experiences being common, there is an ongoing need to reduce mental illness stigma and improve understanding of how to support a loved one with a mental health problem.

Outcomes of treatment with direct-acting antivirals for infection with hepatitis C virus genotypes 1-4 in an ambulatory care setting.

Outcomes with direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) genotypes 1-4 were determined. A total of 360 patients at 36 clinical sites in Massachusetts with HCV genotypes 1-4 and a prescription for at least one DAA medication between May 2011 and October 2015 were included. The primary investigator completed a retrospective and concurrent chart review, and data were collected through April 2016. A total of 446 patients were assessed for eligibility into the study, with 86 patients excluded. The majority of patients were white males with genotype 1 infection. About half of the patients were treatment naive (TN), and 40% of patients had documented cirrhosis. TN patients without cirrhosis had the highest overall sustained virologic response (SVR) rate at 107 of 109 (98.2%), followed by treatment-experienced (TE) patients without cirrhosis at 59 of 63 (93.7%), TN patients with cirrhosis at 40 of 46 (87.0%), and TE patients with cirrhosis at 64 of 79 (81.0%) when boceprevir- and telaprevir-containing regimens were excluded. A total of 7 of 360 (1.9%) patients reported missing at least one dose of medication. Adverse drug reactions reported in the electronic medical record (EMR) were collected for analysis and included patients who received at least one dose of medication and had adequate EMR documentation. In patients treated with DAAs for infection with HCV genotypes 1-4, variables favoring achievement of SVR included an age of <45 years, a body mass index of <25 kg/m2, absence of cirrhosis, a fibrosis score of 0-2, and being TN.

Phase 3 trial of first generation protease inhibitor therapy for hepatitis C virus/human immunodeficiency virus coinfection.

AIMTo evaluate efficacy/safety of hepatitis C virus (HCV) protease inhibitor boceprevir with pegylated interferon (PEG-IFN) alfa and weight-based ribavirin (RBV) in a phase 3 trial.METHODSA prospective, multicenter, phase 3, open-label, single-arm study of PEG-IFN alfa, weight-based RBV, and boceprevir, with a PEG-IFN/RBV lead-in phase was performed. The HCV/human immunodeficiency virus coinfected study population included treatment naïve (TN) and treatment experienced (TE) patients. Treatment duration ranged from 28 to 48 wk dependent upon response-guided criteria. All patients had HCV Genotype 1 with a viral load > 10000 IU/mL. Compensated cirrhosis was allowed. Sample size was determined to establish superiority to historical (PEG-IFN plus RBV) rates in sustained viral response (SVR).RESULTSA total of 257 enrolled participants were analyzed (135 TN and 122 TE). In the TN group, 81.5% were male and 54.1% were black. In the TE group, 76.2% were male and 47.5% were white. Overall SVR12 rates (HCV RNA < lower limit of quantification, target not detected, target not detected) were 35.6% in TN and 30.3% in TE. Response rates at SVR24 were 28% in TN and 10% in TE, and exceeded those in historical controls. The highest rate was observed in TN non-cirrhotic participants (36.8% and the lowest in TE cirrhotics (26.3%). Cirrhotic TN participants had a 27.8% SVR12 rate and 32.1% of TE non-cirrhotics achieved SVR12. Significantly lower response rates were observed among black participants; in the TE, SVR12 was 39.7% in white participants but only 13.2% of black subjects (P = 0.002). Among the TN, SVR12 was 42.1% among whites and 27.4% among blacks (P = 0.09).CONCLUSIONThe trial met its hypothesis of improved SVR compared to historical controls but overall SVR rates were low. All-oral HCV treatments will mitigate these difficulties.

Experiences of discrimination and positive treatment from health professionals: A national survey of adults with mental health problems.

To systematically investigate the scope and nature of discrimination and positive treatment experienced by adults with mental health problems when using health services in an Australian population-based survey. Australian adults (n = 1381) who reported a mental health problem or scored high on a screening questionnaire were interviewed about their experience of discrimination and positive treatment from healthcare professionals. Descriptions of experiences were content-analysed to identify key characteristics. In all, 11.8% of respondents reported discrimination from a health professional in the past 12 months. The most common types of discrimination included being treated dismissively, being judged and not being listened to, particularly regarding personal history and treatment needs. In contrast, 40.4% reported being treated more positively by their health professional because of their mental health problem. Key types of positive treatment by health professionals were being supportive and understanding and being a good listener. Good quality care approaches were also appreciated, including making a referral, being engaged in the treatment process, regularly checking the status of the person's mental health and providing information. A minority of respondents with mental health problems had experienced discrimination from their healthcare professional, potentially interfering with recovery. Anti-stigma education interventions for healthcare professionals should address how to increase knowledge and understanding of mental health problems, reduce negative attitudes and encourage supportive behaviours.

The combination of daclatasvir and sofosbuvir for curing genotype 2 patients who cannot tolerate ribavirin.

The current standard-of-care for treatment of HCV genotype 2 (GT-2) patients is the combination of sofosbuvir (SOF) with weight-based ribavirin (RBV). Patients with HCV GT-2 infection and ribavirin contraindications require the use of SOF plus NS5A inhibitor daclatasvir (DCV) which is not reimbursed everywhere. We conducted an open-label observational, prospective study on a subgroup of GT-2 patients either naïve or treatment experienced (TE) with contraindications to the use of RBV. Patients with cirrhosis of Child-Pugh-Turcotte (CPT) class A and B or advanced fibrosis with comorbidities were included. They were assigned to receive 12 or 24 weeks of SOF/DCV. The primary end point of the study was sustained virological response (SVR) defined as HCV RNA levels <12 IU/ml, 12 weeks post treatment. Out of 106 patients with GT-2 who received treatment at our unit from July 2014 to June 2015, 20 (18.8%) patients, whose treatment could not be deferred, were ribavirin intolerant; 19 received SOF/DCV combination for 12 or 24 weeks. The majority of the patients was men, 58% had cirrhosis, and 58% were TE. All treated patients achieved SVR regardless of treatment duration. The most common adverse events (AEs) were fatigue, headache and nausea. No discontinuations due to AEs were observed. Two patients had oesophageal bleeding but continued treatment and achieved SVR; one patient developed HCC 12 weeks post treatment, but remained HCV RNA undetectable. This study supports the use of SOF/DCV for 12 weeks in non-cirrhotics or 24 weeks in cirrhotic GT-2 patients who cannot tolerate RBV, including those with decompensated disease.

Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia.

To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

Cost-Effectiveness of Dolutegravir in HIV-1 Treatment-Experienced (TE) Patients in France

ObjectivesTo evaluate the cost-effectiveness of a new generation integrase inhibitor (INI), dolutegravir (DTG), in France, in treatment-experienced (TE) and INI-naïve HIV-infected adults with at least two classes resistance compared to raltegravir (RAL), by adapting previously published Anti-Retroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model.MethodsARAMIS is a microsimulation Markov model with a lifetime time horizon and a monthly cycle length. Health states are defined as with or without opportunistic infection and death. In the initial cohort, efficacy and safety data were derived from a phase III study comparing DTG to RAL. Antiretroviral treatment algorithms, accounting for patient history, were based on French guidelines and experts opinion. Costs are mainly including treatment costs, routine HIV and opportunistic infection care, and death. Utilities depend on CD4+ cell count and the occurrence of opportunistic infections.ResultsThe ARAMIS model indicates in the TE population that DTG compared to RAL over a life time is associated with 0.35 additional quality-adjusted life years (QALY; 10.75 versus 10.41) and additional costs of €7,266 (€390,001 versus €382,735). DTG increased costs are mainly related to a 9.1-month increase in life expectancy for DTG compared with RAL, and consequently a longer time spent on ART. The incremental cost-effectiveness ratio (ICER) for DTG compared with RAL is €21,048 per QALY gained. About 83% and 14% of total lifetime costs are associated with antiretroviral therapy and routine HIV care respectively. Univariate deterministic sensitivity analyses demonstrate the robustness of the model.ConclusionDTG is cost-effective in the management of TE INI naive patients in France, from a collective perspective. These results could be explained by the superior efficacy of DTG in this population and its higher genetic barrier to resistance compared to RAL. These data need to be confirmed with longer-term real life data.

Cost-Effectiveness of Dolutegravir in HIV-1 Treatment-Naive and Treatment-Experienced Patients in Canada.

IntroductionThe Antiretroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to evaluate the cost-effectiveness of dolutegravir (DTG) in Canada in treatment-naive (TN) and treatment-experienced (TE) human immunodeficiency virus (HIV)-1 patients.MethodsThe ARAMIS-DTG model is a microsimulation model with a lifetime analytic time horizon and a monthly cycle length. Markov health states were defined by HIV health state (with or without opportunistic infection). DTG was compared to efavirenz (EFV), raltegravir (RAL), darunavir/ritonavir, rilpivirine (RPV), elvitegravir/cobicistat, atazanavir/ritonavir and lopinavir/ritonavir in TN patients and to RAL in TE patients. The initial cohort, the main efficacy data and safety data were derived from phase III clinical trials. Treatment algorithms were based on expert opinion. Costs normalized to the year 2013 included antiretroviral treatment cost, testing, adverse event, HIV and cardiovascular disease care and were derived from the literature.ResultsDolutegravir was estimated to be the dominant strategy compared with all comparators in both TN and TE patients. Treatment with DTG was associated with additional quality-adjusted life-years that ranged from 0.17 (vs. RAL) to 0.47 (vs. EFV) in TN patients and was 0.60 in TE patients over a lifetime. Cost savings ranged from Can$1393 (vs. RPV) to Can$28,572 (vs. RAL) in TN patients and amounted to Can$3745 in TE patients. Sensitivity analyses demonstrated the robustness of the model.ConclusionsDolutegravir is a dominant strategy in the management of TN and TE patients when compared to recommended comparators. This is mainly related to the high efficacy and high barrier to resistance.FundingViiV Healthcare.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-015-0071-0) contains supplementary material, which is available to authorized users.

OC-115 The use of sofosbuvir based regimens amongst treatment naive and experienced patients with advanced fibrosis/cirrhosis: real world results from a difficult to treat cohort

<h3>Introduction</h3> Patients with cirrhosis account for 17–23% of subjects in Phase 3 trials of Sofosbuvir, however strict inclusion/exclusion criteria may make outcomes less reproducible in routine practice. Data is lacking for GT1 treatment experienced (TE) patients, and data for treating GT3 patients with interferon based regimens limited. We sought to establish the tolerability and effectiveness of Sofosbuvir based regimens in such patients with advanced fibrosis/cirrhosis in routine care. <h3>Method</h3> We analysed the Scottish HCV Database to identify patients with a liver stiffness measurement (LSM) ≥9.5 kPa, starting a Sof based regimen in Glasgow treatment centres between June and October 2014 inclusive. Data were obtained on demographics, LSM, cirrhosis status, treatment status, baseline labs, Child’s score, drug and alcohol use. Data were compared with trial inclusion/exclusion criteria. Baseline viral load, week 4 PCR, EOTR, SVR12 and premature discontinuations were recorded. <h3>Results</h3> 123 patients, were treated with either Sof/IFN/Rib (n = 108) or Sof/Rib (n = 15). Baseline characteristics are summarised in Table 1. 97 (78.9%) patients were cirrhotic (median LSM 20.8 (IQR 14.8–35.5)). The majority were GT3 (68, 55.3%) or GT1 (47, 38.2%). Half (61, 49.6%) were TE, including 9 PI failures. 65 (52.8%) would have failed at least one trial inclusion/exclusion criteria (37 (30.1%) due to baseline labs, 30 (24.4%) recent drug/ alcohol misuse, schizophrenia (1, (0.8%)). At week 4 38/121 (31.4%) patients were undetectable (RealTime HCV, Abbott), 49 (40.5%) detectable &lt;12 IU/ml, and 32 (26.4%) quantifiable (median 23 IU/ml, IQR 15–56). On an ITT basis, 103/114 (90.3%) patients achieved EOTR. 5 discontinued prematurely (including one due to an AE and one death unrelated to treatment), 5 were lost to follow up. 1 patient was detectable (&lt;12 iu/ml) at end of treatment. Per protocol 37/44 (84%) of patients have to date achieved an SVR12. SVR data for the remaining cohort will be presented. <h3>Conclusion</h3> Patients with advanced fibrosis/cirrhosis and unfavourable baseline characteristics can be treated effectively with Sofosbuvir based regimens. High rates of detectable HCV RNA at week 4, did not appear to impact on end of treatment response. Initial SVR12 results are encouraging. <h3>Disclosure of interest</h3> D. Sutherland: None Declared, E. Forrest: None Declared, M. Heydtmann: None Declared, M. Priest: None Declared, P. Mills: None Declared, J. Morris: None Declared, A. Stanley: None Declared, R. Fox Consultant for: Gilead, Janssen, BMS, Abbvie, Speaker Bureau of: Gilead, Janssen, BMS, Abbvie, S. Barclay Consultant for: Gilead, Janssen, BMS, Abbvie, Speaker Bureau of: Gilead, Janssen.

PTU-105 Real world effectiveness, safety and cost per cure in hepatitis C patients treated with protease inibitor based therapy: results from the HCV research UK cohort

Introduction To estimate real world effectiveness, safety and cost per sustained virological response (SVR) of 1stgeneration protease inhibitor (PI)- based therapies for GT1 chronic HCV infection (CHC) in clinical practice in the UK. Method Patients treated with telaprevir (TPV) or boceprevir (BOC) (stratified 2:1), pegylated interferon and ribavirin (PR) with available outcome data were randomly selected from the HCV Research UK database. Healthcare utilisation and adverse events (AEs) requiring intervention were identified from case note review. Cost of drugs, visits, diagnostics, and AE management were estimated from published sources. Causality of treatment regimen in relation to AE was independently assessed by 2 clinicians. Cost per SVR was calculated as total median cost divided by SVR rate. Sensitivity analyses exploring the impact of SVR rate, discontinuations, inclusion of unclassifiable AEs/hospitalisations and PI price on cost per SVR were undertaken. Results 154 patients from 35 UK centres were analysed. Baseline characteristics: median age 50y (IQR 44–56), male 73%, cirrhotic 21%, 52% treatment experienced (TE). Overall SVR was 62.3% (range 25% in cirrhotic prior null responders, to 86.2% in non-cirrhotic prior relapsers). 53/154 (34.4%) patients discontinued therapy prematurely (50.9% physician withdrew, 26.4% patient withdrew, 22.6% failed stopping rules). 36% (55/154) experienced treatment-related AEs requiring intervention, leading to treatment discontinuation in 25.4% (14/55). 8.4% (13/154) patients required hospitalisation for treatment related AEs. Total treatment related costs for cohort were £4,288,802 (PI: 68.3%, PR: 26.3%, AE management and follow-up: 5.4%). Median total cost per cure was £44,852 (range £35,492 TN non-cirrhotic to £107,288 in cirrhotic prior NR). ![Abstract PTU-105 Table 1][1] Abstract PTU-105 Table 1 Conclusion This is the first UK multicentre study estimating outcomes and costs of PI based regimen in clinical practice. There was substantial variation in SVR and cost per SVR among patient subgroups. These cost per SVR estimates are conservative as retreatment costs for patients not achieving SVR are not included. The high discontinuation rate and HCV treatment-related AEs and hospitalisations suggest a substantial additional burden. Disclosure of interest S. Barclay Grant/ Research Support from: Gilead, Janssen, MSD, Consultant for: Abbvie, BMS, Gilead, Janssen, MSD, Speaker Bureau of: Gilead, Janssen, MSD, Roche, G. Cooke Grant/ Research Support from: Janssen, BMS and Gilead, Consultant for: Janssen, BI, Gilead and Merck, W. Irving Grant/ Research Support from: Pfizer, GSK, Gilead; Educational grants: BI, Gilead, Merck, Consultant for: Merk, Novartis, BMS, Speaker Bureau of: Janssen, E. Holtham: None Declared, M. Bec Conflict with: conducted the statistical analyses funded by Gilead, J. Schwarzbard Conflict with: conducted the statistical analyses funded by Gilead. [1]: pending:yes

Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis.

To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.

HIV-1 attachment inhibitor prodrug BMS-663068 in antiretroviral-experienced subjects: week 24 sub-group analysis.

IntroductionBMS-663068 is a prodrug of BMS-626529, an attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into the host CD4+ T-cell. AI438011 is a Phase IIb, randomized, active-controlled trial investigating the safety, efficacy and dose–response of BMS-663068 versus atazanavir/ritonavir (ATV/r) in treatment-experienced (TE), HIV-1-positive subjects.Materials and MethodsAntiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (BMS-626529 IC50 100 nM), were randomized equally to four BMS-663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control group (ATV/r 300/100 mg QD) with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). A sub-group analysis of viral efficacy and immunologic reconstitution is presented.ResultsA total of 251 subjects were treated. Median age was 39 years, 60% were male and 38% were white. Median baseline (BL) viral load (VL) was 4.85 log10 c/mL (43%; 100,000 c/mL) and median CD4+ T-cell count was 230 cells/mm3 (38%; 200 CD4 cells/mm3). Through Week 24, response rates (HIV-1 RNA 50 c/mL) were comparable across all BMS-663068 arms and the ATV/r arm regardless of gender, age and race. Response rates for subjects with BL VL 100,000 c/mL (BMS-663068, 82-96%; ATV/r, 93%) were higher than those for subjects with BL VL ≥100,000 c/mL (BMS-663068, 70-87%; ATV/r, 73%); however, there were no substantial differences in response across the BMS-663068 and ATV/r arms in either sub-group. Response rates for subjects with BL CD4+ cell counts ≥200 cells/mm3 (87-96%) were higher than those for subjects with BL CD4+ cell counts 200 cells/mm3 (62–82%); however, no substantial differences in response were seen across the BMS-663068 and ATV/r arms in either sub-group. Mean changes in CD4+ T-cell counts from BL were similar across all arms regardless of gender, age and BL CD4+ T-cell count.ConclusionVirologic response rates were similar across the BMS-663068 and ATV/r arms in TE subjects, regardless of BL demographic characteristics (gender, race, age), BL HIV-1 RNA, or BL CD4+ T-cell count. Mean increases in CD4+ T-cell counts across the BMS-663068 arms were consistent with ATV/r, regardless of gender, age and BL CD4+ T-cell count. These results support continued development of BMS-663068.NotePreviously submitted at IDWeek, Philadelphia, PA, 8 October 2014.