Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine medical practice.

BACKGROUND: Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions. AIM: To assess the comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV) vs. ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ± RBV in genotype 1 HCV patients treated in routine medical practice. METHODS: Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response (SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment. RESULTS: 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59-0.86, P < 0.001), body mass index (BMI) > 30 kg/m(2) (OR 0.73, 95% CI 0.60-0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49-0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48-0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11-1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors. CONCLUSIONS: In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer significant, when limited to patients completing a 12-week course.

Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans.

BACKGROUND: Real-world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. AIM: To assess sustained virological response (SVR) of sofosbuvir (SOF)-based regimens in routine medical practice. METHODS: Observational, intent-to-treat cohort analysis of genotype 1 and 2 HCV-infected veterans initiating SOF-based regimens with recommended treatment duration of 12 weeks. RESULTS: Four thousand and twenty-six veterans with genotype 1 (N = 3203) and genotype 2 (N = 823) comprise the cohort. SVR rates for genotype 1 were 66.8% for SOF + peginterferon + ribavirin (RBV), 75.3% for SOF + simeprevir (SIM), 74.1% for SOF + SIM + RBV and for genotype 2 were 79.0% for SOF + RBV. Genotype 1 patients were less likely to achieve SVR with BMI ≥30 (OR 0.64, 95% CI 0.49-0.84, P < 0.001), a history of decompensated liver disease (OR 0.51, 95% CI 0.36-0.71, P < 0.001), treatment experience (OR 0.58, 95% CI 0.48-0.71, P < 0.001), APRI >2 (OR 0.44, 95% CI 0.36-0.55, P < 0.001) and with SOF + PEG + RBV compared with SOF + SIM (OR 0.50, 95% CI 0.40-0.62, P < 0.001). Age, sex, race/ethnicity, diabetes and genotype subtype did not predict SVR. Odds of achieving SVR with SOF + SIM + RBV did not differ compared with SOF + SIM (OR 1.03, 95% CI 0.75-1.44, P = 0.86). Genotype 2 patients were less likely to achieve SVR with prior treatment experience (OR 0.55, 95% CI 0.35-0.88, P = 0.009) and APRI >2 (OR 0.39, 95% CI 0.25-0.62, P < 0.001). CONCLUSIONS: In this real-world cohort, SVR rates were lower than in clinical trials. Genotype 1 and 2 HCV-infected patients with advanced liver disease by APRI >2 or FIB-4 > 3.25 were significantly less likely to achieve SVR. For genotype 1, a SOF + SIM ± RBV regimen was associated with a higher likelihood of SVR.

Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort.

BACKGROUND: Limited data exist on the effectiveness of boceprevir and telaprevir in routine practice. AIM: To assess the comparative effectiveness of boceprevir and telaprevir regimens. METHODS: In this observational, intent-to-treat cohort analysis of hepatitis C genotype 1-infected veterans initiated on peginterferon/ribavirin and boceprevir (n = 661) or telaprevir (n = 198), we determined sustained virological response (SVR), treatment discontinuation rates and adverse haematological events. Inverse probability-of-treatment weighting (IPTW) was used to estimate the effect of one drug over the other, with matched pairs and unweighted logistic regression on the entire cohort for comparison. RESULTS: Of 835 veterans, SVR occurred in 50% and 52% receiving boceprevir- and telaprevir-based treatment, respectively (P = 0.72). No significant differences occurred among subgroups: cirrhotics (37% vs. 39%, P = 0.94), null responders (23% vs. 18%, P = 0.81), partial responders (39% vs. 58%, P = 0.15) and relapsers (60% vs. 77%, P = 0.11). Early discontinuation rates for boceprevir and telaprevir, respectively, were 31% and 28% by week 24 (P = 0.46) and 54% and 45% by 48 weeks (in those completing at least 28 weeks) (P = 0.14). Choice of telaprevir over boceprevir was significantly associated with SVR in multivariate models (IPTW OR: 1.57, 95% CI: 1.10-2.25, P = 0.01; matched-pairs OR: 1.91, 95% CI: 1.23-3.00, P = 0.004; unweighted OR: 1.50 95% CI: 1.05-2.14, P = 0.02). Rates of haematological adverse events in boceprevir- and telaprevir-treated patients were as follows: anaemia 59% vs. 51%, P = 0.30, thrombocytopenia 41% vs. 48%, P = 0.26, neutropenia 41% vs. 27%, P = 0.04. CONCLUSIONS: Sustained virological response was more likely with telaprevir-based regimens compared with boceprevir-based regimens in routine medical practice, after accounting for patient differences. Early discontinuation and haematological events, however, were similar.

Implications of rapid virological response in hepatitis C therapy in the US veteran population.

BACKGROUND: Early predictors of response to hepatitis C virus (HCV) therapy, such as rapid virological response, are valuable for the identification of patients with a higher likelihood of treatment success. AIM: To identify predictors of rapid virological response in a real world setting. METHODS: Using the VA Clinical Case Registry, we identified patients with HCV mono-infection, without liver transplantation, who initiated peginterferon (PEG-IFN) and ribavirin (RBV) in 2007 or 2008 and had HCV RNA testing for RVR. Significant baseline characteristics from genotype specific univariate analyses were used in backwards stepwise models to identify significant independent predictors of RVR. RESULTS: The final cohort consisted of 2424 patients with genotype 1 (G1), 666 patients with genotype 2 (G2), and 419 patients with genotype 3 (G3). Rapid virological response rates were 15% for G1, 71% for G2 and 57% for G3. Sustained virological response rates were significantly higher in patients with rapid virological response than without, increasing from 18% to 52% in G1, 39% to 71% in G2, and 40% to 60% in G3 (P < 0.0001). A baseline HCV RNA < 500,000 IU/mL positively predicted RVR across all genotypes studied. In addition, for G1, Black race, Hispanic ethnicity, aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≥ 0.6, ferritin ≥ 350 ng/mL, LDL< 100 mg/dL and diabetes; for G2, BMI ≥ 30 kg/m(2), platelets < 150 K/µL, LDL< 100 mg/dL and the use of PEG-IFN alfa-2b; and for G3, AST/ALT ≥ 1.0, all negatively predicted rapid virological response. CONCLUSION: We found several novel independent predictors of rapid virological response, including BMI, AST/ALT ratio, ferritin, platelets, LDL, diabetes and type of PEG-IFN prescribed, which may be useful in guiding treatment decisions in routine medical practice.

Trends in uptake of recently approved antiretrovirals within a national healthcare system.

OBJECTIVE: The aim of the study was to describe Veterans Healthcare Administration (VHA) system-wide uptake of three HIV protease inhibitors: atazanavir, darunavir and tipranavir. METHODS: This retrospective cohort study evaluated VHA uptake of three target antiretrovirals and lopinavir/ritonavir in each complete 90-day quarter since approval to December 2007 using VHA HIV Clinical Case Registry data. We assessed uptake using number of new prescriptions, number of providers and facilities prescribing target agents, provider type, clinic type, facility size and location within four US regions. RESULTS: Overall, 6551 HIV-infected veterans received target antiretrovirals. Uptake was generally greatest within the first year after Food and Drug Administration (FDA) approval, and then slightly declined and plateaued. Geographically, early adoption of new antiretroviral drugs tended to occur in the Western USA, as evidenced by comparison of uptake patterns of new antiretrovirals to use of all antiretroviral agents. A small percentage of prescribers of all antiretrovirals were responsible for new prescriptions for target medications, particularly for darunavir and tipranavir. Providers at almost 50% of VHA facilities were prescribing these agents within the first year. CONCLUSIONS: Uptake of new antiretrovirals in the VHA generally reflected overall prescribing of all antiretrovirals, suggesting a lack of VHA impediments to new antiretrovirals in the healthcare system. Some regional variation in uptake among the targeted antiretrovirals occurred over time but tended to resolve after the first several months. Providers responsible for early prescribing of the target medications were limited to a fraction of providers who tended to be physicians who practised in infectious disease (ID) clinics at medium-sized facilities.

Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus.

The US Department of Veterans Affairs (VA) cares for many human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients. VA treatment recommendations indicate that all HIV/HCV-coinfected patients undergo evaluation for HCV treatment and list pretreatment assessment tests. We compared clinical practice with these recommendations. We identified 377 HIV/HCV-coinfected veterans who began HCV therapy with pegylated interferon and ribavirin and 4135 HIV/HCV-coinfected veterans who did not but were in VA care at the same facilities during the same period. We compared laboratory and clinical characteristics of the two groups and estimated multivariate logistic regression models of receipt of HCV treatment. Overall, patients had high rates of receipt of tests necessary for HCV pretreatment assessment. Patients starting HCV treatment had higher alanine aminotransferase (ALT), lower creatinine, higher CD4 counts and lower HIV viral loads than patients not starting HCV treatment. In the multivariate model, positive predictors of starting HCV treatment included being non-Hispanic whites, having higher ALTs, lower creatinines, higher HCV viral loads, higher CD4 counts, undetectable HIV viral loads and receiving HIV antiretrovirals. A history of chronic mental illness and a history of hard drug use were negative predictors. Most HIV/HCV-coinfected patients received the necessary HCV pretreatment assessments, although rates of screening for hepatitis A and B immunity can be improved. Having well-controlled HIV disease is by far the most important modifiable factor affecting the receipt of HCV treatment. More research is needed to determine if the observed racial differences in starting HCV treatment reflect biological differences, provider behaviour or patient preference.

Low-income Californians' experiences with health insurance and managed care.

California is rapidly implementing mandatory managed care for most of its Medicaid (Medi-Cal) beneficiaries. To assess the impact of this delivery system change, the authors analyzed a 1996 statewide population-based random-sample telephone survey of 3,563 adults between the ages of 18 and 64. Respondents with Medi-Cal managed care and Medi-Cal fee-for-service rated access to care and quality of care significantly higher than uninsured respondents yet lower than low-income privately insured individuals. While the authors did not find a difference in health care access and quality among Medi-Cal managed care enrollees compared with Medi-Cal fee-for-service enrollees, they also did not find that managed care provided any observed advantages to Medi-Cal recipients.

Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function.

Further investigation of the in vivo pharmacological properties of the putative 5-HT1A antagonist, BMY 7378.

The present study examined the actions of the putative 5-HT1A antagonist BMY 7378 on central pre- and postsynaptic 5-HT1A function in the rat in vivo. Unlike the direct acting 5-HT1A agonist 8-hydroxy-2-(di-n-pro-pylamino)tetralin (8-OH-DPAT), BMY 7378 (0.25-5 mg/kg s.c.) did not induce the full postsynaptically mediated 5-HT behavioural syndrome (forepaw treading, head weaving, flat body posture hindlimb abduction). Indeed, the maximal 5-HT behavioural syndrome scores of BMY 7378 were about 10% of those for 8-OH-DPAT. Following pretreatment, however, BMY 7378 dose dependently (0.25-5 mg/kg s.c.) reduced to undetectable levels forepaw treading and head weaving induced by 8-OH-DPAT (0.75 mg/kg s.c.). BMY 7378 also inhibited stereotypy and locomotor activity induced by 0.5 mg/kg apomorphine although this effect was only statistically significant at the highest dose tested (5 mg/kg). In contrast to its apparent 5-HT1A antagonist properties in the behavioural experiments, BMY 7378 caused a marked and dose-dependent (0.01-1.0 mg/kg s.c.) decrease of 5-HT release in ventral hippocampus of the anaesthetized rat as detected by brain microdialysis. This effect of BMY 7378 had a similar onset and duration of action but with slightly reduced efficacy compared to that previously described for 8-OH-DPAT. As with 8-OH-DPAT, the inhibitory effect of BMY 7378 on 5-HT release was attenuated by pretreatment with the 5-HT1 receptor/beta-adrenoceptor antagonist pindolol (8 mg/kg s.c.) but not its counterpart propranolol (20 mg/kg s.c.). Pretreatment with a combination of the beta 1- and beta 2-adrenoceptor antagonists metoprolol (4 mg/kg s.c.) and ICI 118 551 (4 mg/kg s.c.), respectively, did not alter the 5-HT response to BMY 7378. From these data we conclude that BMY 7378 is a mixed agonist/antagonist at central 5-HT1A receptors.

Novel GABA agonists depress the reward effect of lateral hypothalamic stimulation in rats.

Rats were given systemic injections of one of a series of novel GABA compounds which can penetrate the blood-brain barrier to release GABA into the brain. They were then tested on lateral hypothalamic self-stimulation behavior using a rate-frequency paradigm to discriminate effects on reward from those on motor/performance. Both reward and, to a lesser extent, motor/performance impairments were found with all GABA compounds. In more extensive testing with one compound, LG2, no differences in the effects of three salts (acetate, ascorbate, and tartarate) were found except that the tartarate salt effects decayed more rapidly.