Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial.

BACKGROUND & AIMS: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis. METHODS: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. RESULTS: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. CONCLUSIONS: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03089944. LAY SUMMARY: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir With or Without Ribavirin in Patients With Chronic Hepatitis C Virus Genotype 1 Infection Receiving Opioid Substitution Therapy: A Post Hoc Analysis of 12 Clinical Trials.

BACKGROUND: We evaluated the impact of opioid substitution therapy (OST) on the completion, adherence, efficacy, and safety of the 3-direct-acting antiviral regimen of ombitasvir, paritaprevir (identified by AbbVie and Enanta) co-dosed with ritonavir, and dasabuvir ± ribavirin among patients infected with hepatitis C virus (HCV) genotype (GT) 1, with or without compensated cirrhosis. METHODS: Data were pooled from GT1-infected patients enrolled in 12 phase II/III/IIIb clinical trials and categorized by use of OST. Patients with ongoing drug use were excluded. HCV treatment completion, treatment adherence (≥90%), sustained virologic response at post-treatment week 12 (SVR12), and adverse events were assessed. RESULTS: Of 4747 patients, 3% (n = 149) received OST. Among patients receiving OST vs those not receiving OST, 82% (n = 122) vs 52% (n = 2409) had GT1a infection; 76% (n = 113) vs 61% (n = 2792) were treatment naïve; and 17% (n = 25) vs 18% (n = 830) had cirrhosis, respectively. The proportion of patients completing HCV treatment did not differ between those receiving and not receiving OST (97% [n = 144] vs 98% [n = 4510], respectively), whereas adherence to treatment was reduced in patients receiving vs those not receiving OST (88% [n = 105] vs 97% [n = 4057], respectively). SVR12 was similar between patients receiving and not receiving OST (94% [n = 140] vs 96% [n = 4405], respectively; P = .273). Treatment was well tolerated. CONCLUSIONS: Although treatment adherence was lower in patients receiving OST vs those not receiving OST, treatment completion and SVR12 were similar between groups. These data support the use of direct-acting antiviral therapies in patients receiving OST.

Trends and projections of hepatitis C virus epidemiology in Latin America.

BACKGROUND AND AIM: The purpose of the present investigation is to provide an analysis of previous works on the epidemiology of the hepatitis C virus (HCV) infection from six countries throughout Latin America, to forecast the future HCV prevalence trends in Argentina, Brazil, Mexico and Puerto Rico, and to outline deficiencies in available data, highlighting the need for further research. METHODS: Data references were identified through indexed journals and non-indexed sources. Overall, 1080 articles were reviewed and 150 were selected based on their relevance to this work. When multiple data sources were available for a key assumption, a systematic process using multi-objective decision analysis (MODA) was used to select the most appropriate sources. When data were missing, analogues were used. Data from other countries with similar risk factors and/or population compositions were used as a proxy to help predict the future trends in prevalence. RESULTS: The review indicates that the dominant genotype is type 1. HCV prevalence in the analysed countries ranges from 1 to 2.3%. The Latin American countries have been very proactive in screening their blood supplies, thus minimizing the risk of transmission through transfusion. This suggests that other risk factors are set to play a major role in continued new infections. The number of diagnosed and treated patients is low, thereby increasing the burden of complications such as liver cirrhosis or hepatocellular carcinoma. The HCV prevalence, according to our modelling is steady or increasing and the number of infected individuals will increase. CONCLUSIONS: The results herein reported should provide a foundation for informed planning efforts to tackle hepatitis.

Sustained virologic response among Latino veterans; does it represent the cure of chronic hepatitis C infection?

OBJECTIVE: Short-term benefits of achieving sustained virologic response (SVR) to treatment for hepatitis C virus infection (HCV) have been well established. However long-term data on benefits of achieving SVR has just begun to emerge. The purpose of this study was to determine whether SVR truly represents long- term viral eradication in a Latino veteran population and document clinical and biochemical outcomes in this group. METHODS: This was a two-phase study, which consisted of a single center retrospective study followed by a cross-sectional analysis which includes a single clinic visit. The first phase of the study consisted of a retrospective record review of all HCV patients treated at the VA Caribbean Healthcare System from 1990 to 2006. Records were reviewed to identify patients who had completed therapy, had documented SVR and at least 12 months of time elapsed since end of therapy. The second phase of the study entailed a single appointment to the gastroenterology research clinics, for blood testing and a short risk factor questionnaire. RESULTS: Sixty four patients were enrolled; mostly males with a mean age at time of enrollment of 54.3 years (range 37-72). One hundred percent of subjects self reported their ethnicity as Hispanic, born in Puerto Rico. Most of our population had HCV genotype 1. Forty seven of 64 (73.4%) patients were naive to therapy while 4 (6.3%) were previously treated. In 13 (20.3%) patients, the prior treatment status could not be clearly established. Regarding therapy used to achieve SVR, 32 (50.0%) patients received interferon (IFN) and ribavarin, 28 (43.8%) peginterferon (PEG) and ribavarin and 4 (6.3%) IFN monotherapy. There was no statistical difference in long-term SVR among these 3 three treatment alternatives. A pre-treatment biopsy specimen was available on 37/64 (57.8%) of our subjects. Marked fibrosis and/or cirrhosis was present in 14/37 (37.8%) subjects who had a pre-treatment biopsy. At the time of the study visit mild elevation of aspartate aminotransferase (AST) was identified only in 5 (7.8%) patients. Alanine aminotransferase (ALT) and bilirubin were normal. Only 3/64 (4.7%) had elevations in alkaline phosphatase. None (0/58) of the patients who presented with normal enzymes had detectable viral load, whereas 20% (1/5) of those with elevated liver function tests had evidence of viremia (p < 0.001). Overall, only 1 (1.6%) patient of our study group had evidence of virological relapse after having achieved SVR, which was documented 30 months after the end of therapy. No identifiable risk factors for re-infection were identified. CONCLUSION: In conclusion, in this Latino veteran population, achievement of (SVR) is a good predictor of clinical outcomes and long-term (HCV) eradication. Altered liver function tests seems to be the best predictor of relapse and should prompt the clinician to investigate for recurrence. For those that after achieving SVR maintain normal liver enzymes, routine follow up viral load demonstrates to have a very low yield and may not be required.

Sexual activity as a risk factor for hepatitis C in Puerto Rico.

BACKGROUND: Hepatitis C (HCV) is a blood born infection that affects millions of people worldwide. Although IV drug use (IVDU) and blood transfusions have been clearly defined as transmission risk factors for HCV, the role of sexual transmission is still not clearly defined. AIMS: To define the role of sexual transmission among Puerto Ricans HCV+ patients, and to determine if there is an association between sexual, and non-sexual risk factors, genotypes and viral load. METHODS: A cross-sectional epidemiological IRB approved study was performed among patients with HCV+ enrolled from Nov-2001 to May-2002. The Puerto Rico Gastroenterology Association sponsored this study. Five hundred subjects completed a risk-factor study questionnaire. Blood samples were drawn to determine HCV genotype and viral load. RESULTS: A male predominance was found (68%). Most patients (70%) were between 45-65 years old. The most common genotype was 1 (82%). Reported sexual risk factors were: sex with a drug user (30.3%), multiple sexual partners (>10) (28.9%), sex with an HCV infected partner (9.0%), and homosexuality (8.3%). Most common non-sexual risk factors were: blood transfusion (30.2%) and intravenous drug use (IVDU) (46.8%). Illicit drug users (IDU) reported having sex at a younger age (15.5 y/o), than those non-IDU (18.9 y/o) p=0.015. IDU reported both, a higher frequency of homosexual encounters than non-IDU (10.8% vs. 1.5%) p<0.0001, as well as having sex with another IDU (47.8% vs. 11.3%) p<0.0001. Those patients who reported sex with an HCV infected partner and were non-IDU had fewer partners than those who were IDU (1-2 vs. >20 partners) p<0.001. As a group, homosexuals had sex at a younger age, had multiple partners (> 20) and a higher proportion of sex with IVDU. After adjusting for age, gender, and risk factors, no significant association was found between genotype and sexual variables. The difference noted between groups in viral load had no statistical significance. CONCLUSIONS: Our data supports that sexual risk factors are common in HCV infected patients. High risk sexual practices such as early sexual intercourse, homosexuality and multiple sexual partners are the most common in patients with hepatitis C with use of illicit drugs as a risk factor also. The role of sexual transmission in this group cannot be clearly established. No significant relationship was found between genotype, viral load and sexual transmission. Patients with illegal drug use (IDU) showed significant difference from non users in regard to the age of the first sexual intercourse, the number of sexual partners and the practice of sex with other illicit drug users or partners of the same sex. When parenteral transmission is excluded, practicing sex with a HCV infected partner was the only identified risk factor in 6.5% of the studied population.

Hepatocellular carcinoma: ten years experience among veterans in Puerto Rico.

PURPOSE: The aim of our study is to determine the characteristics of hepatocellular carcinoma (HCC) as well as risk factors, demographics, survival rates and the use of diagnostic and therapeutic modalities among veteran patients in Puerto Rico. METHODS: A retrospective study of 114 patients with Hispanic background and biopsy-proven HCC diagnosed at the VA Caribbean Healthcare System from 1992 to 2002 was performed. Demographics data, Child-Turcotte-Pugh (CTP) score, presence of cirrhosis, viral serology, alcohol and/or other liver diseases history, diagnostic modalities, lesion size, therapy, and overall survival were examined. RESULTS: The mean age was 66.6 years old. 82% had known underlying cirrhosis. 60% had alcoholic liver disease (ALD), 33% positive serology for hepatitis C (HCV) and 21% both. 5.3% had chronic hepatitis B virus (HBV) infection. Additional causes were not present. CTP classification was: A (42%), B (44%) and C (14%). Abdominal CT scan demonstrated most of the lesions, while ultrasound only 57%. Alfa-fetoprotein was diagnostic in 32%. Mean survival was 10.3 months, better for those with CTP score A. Only 42% of the patients received any kind of therapy. CONCLUSIONS: ALD is the principal underlying liver disease in our HCC patients, closely followed by chronic HCV infection. Less than half of our patients received treatment mainly due to advanced disease for which the over survival was less than a year. HCC continues to be a dreadful disease with poor prognosis for which aggressive screening should be considered for all patients with cirrhosis and advanced liver disease regardless of the cause.

Prevalence of chronic hepatitis C virus genotypes among patients between 21 to 65 years old in Puerto Rico.

OBJECTIVES: This is the first study done in Puerto Rico to estimate the prevalence of hepatitis C virus (HCV) genotype distribution in patients with chronic infection and to determine the statistical association between the genotype and variables such as age, sex, HCV risk factors, and viral load. METHODS: Chronic HCV infected patients diagnosed with ELISA, RIBA or PCR from 1990 to 2002 who were under follow up with members of the Puerto Rico Gastroenterological Association were asked to participate. Eligible patients were those without evidence of HIV or other viral hepatic infection; had no previous antiviral treatment or if previously treated, therapy ended at least six months prior to their participation in the study; had no history of organ transplant and were willing to participate. All study subjects completed a study questionnaire and had blood samples taken to determine HCV genotype and viral load. RESULTS: 500 patients were recruited. Most of the study subjects were males (68%); 70% were 45 to 65 years old. The principal reported risk factors were: surgeries (75.5%), drug use (46.8%), sexual relationships with intravenous/intranasal drug users (30.3%), blood transfusions (30.2%), multiple sex partners (28.9%), tattoos (22.0%), needle accidents (12.7%), and sexual relationships with an HCV infected partner (9.0%). Most patients had multiple risks factors for infection, only 3.4% (17/500) reported a single risk factor whereas 2.0% (10/500) reported none. 33% of the patients were previously treated (non-responders or relapsers) while 67% were naive. In general, 82% of the HCV patients had genotype 1, while 18% had non-1 genotypes. Among genotype 1 subtypes, genotype la (39.8 %) was more common than 1b (27%). The most common non-1 genotype was genotype 2 of which 2b represented 9.8% of the study population. Similar distribution was observed within the categories of the HCV risk factors, with the exception of those who reported sex with an infected partner (p=0.018), sex with multiple sexual partners (p=0.049) and IVDU (p=0.006). For patients in which the viral load was 2 million IU/ml or less, the genotype la (41%) predominates, followed by 1b (29%) and 1a/1b (9%); patients with viral load was greater than 2 million IU/ml, the genotypes distribution was 1a (38%), 1b (24%), and 2b (12%). After adjusting by type of patients (naive and treated), age and gender, no significant association (p<0.05) were found between two-categories of genotype (1 vs. non-1) and HCV risk factors. CONCLUSION: This cross-sectional epidemiological study demonstrated that the most frequent genotype found in Puerto Rican HCV infected patients is genotype 1. The principal risk factors associated in our population were: surgeries, drug use, blood transfusions, sexual relationships with IVDU, and multiple sex partners. The statistical evidence showed that the genotype distribution is not affected by the HCV risk factor, after adjusting by type of patients (naive and treated), age, gender or geographical area.

Steatosis as a predictive factor for treatment response in patients with chronic hepatitis C.

BACKGROUND: Hepatic steatosis has been described in 31-72% of chronic hepatitis C virus (HCV) liver biopsies. Steatosis has been related to disease progression and suggested as a predictor of treatment response in chronic HCV. This study aims to evaluate the presence and degree of steatosis in liver histology of patients with chronic HCV prior to combination therapy with interferon (INF) and ribavirin (RBV), and how it influences treatment response. METHODS: The medical charts of patients with chronic HCV who received treatment at the San Juan Veterans Affairs (VA) Medical Center from 1998 to 2002 were reviewed. Selected patients completed therapy, had a pre-treatment liver biopsy, genotype determination, and pre and post treatment HCV-RNA levels. Patient's age, sex and body mass index (BMI) were determined. Pre-treatment liver biopsy slides were reviewed and graded for steatosis by a hepatopathologist blinded to the treatment outcome. Steatosis was graded by the presence of fat in total biopsy area as: mild (<33%), moderate (33-66%), severe (>66%) or absent. Treatment response was defined as virological clearance measured by HCV RNA at the end of treatment and 24 weeks after completion of treatment. The presence of steatosis was compared to BMI, HCV genotype and treatment response. RESULTS: 46 patients met the inclusion criteria. All patients were male of Hispanic origin. Mean age: 52.7 years (range: 40-68). Mean BMI: 27.5 kg/m2 (range: 21.1-35.9). HCV genotype 1 was present in 67% of patients. 82.6% (38/46) of the patients had hepatic steatosis: 29 (63%) mild, 7 (15%) moderate and 2(4%) severe. 16.6% (8/46) of the biopsies did not show steatosis. Overall, the response rate for those with steatosis was 31.6% (12/38): 10/29 (34.5%) mild, 1/7 (14.3%) moderate and 1/2 (50%) of severe. 75% (6/8) of those without steatosis responded to treatment. This difference (31.6% vs. 75%) was statistically significant (p=.042). The mean BMI of both groups was similar (27.7 kg/m2 for those with steatosis and 26.6 kg/m2 for those without steatosis). This difference was not statistically significant (p=.308). CONCLUSIONS: The results of our study show a high prevalence of steatosis in the liver histology of patients with chronic HCV. The presence and degree ofsteatosis in our HCV patients appears to be unrelated to either genotype or BMI. Furthermore, the response to therapy is negatively influenced by the presence of steatosis regardless of genotype. Hepatic steatosis, mild, moderate or severe, appears to be an independent predictor of poor response to therapy.

Does Silybum marianum play a role in the treatment of chronic hepatitis C?

OBJECTIVES: The recent boom in patient education on chronic hepatitis C has resulted in a worldwide increase in the diagnosis of this condition. Available treatment is expensive and associated with significant side effects; therefore, many patients seek for alternative medicine. Silybum marianum is a natural herb known to mankind for over 2,000 years that has been used as a liver-protecting agent due to its antioxidant properties. The objective of this study is to evaluate the safety profile and the effects of this herb, using a commercially available extract; in the liver chemistry and viral load of hepatitis C in chronically infected patients. METHODS: Patients aged 21-65 years old with a diagnosis of chronic hepatitis C who were not using antiviral therapy were asked to participate. Patients were randomized to treatment with S. marianum 160 mg orally three times a week for four weeks or to no-treatment (control). Blood tests for viral load and liver enzymes (ALT and AST) were done at randomization and at the end of treatment. Paired-t test was used to measure differences between baseline and week 4 values for ALT, AST and viral load. The percent change for ALT, AST and viral load of both groups was analyzed using the Mann Whitney statistical test. RESULTS: 34 patients were enrolled. Men and women were equally distributed. Mean age was 50 years old. Mean baseline measurements of AST, ALT and viral load in the treatment group were 85 +/- 12.41 IU/ml, 120 +/- 20.57 IU/ml and 8.77 +/- 4.12 copies x 10(6)/ml while for the no-treatment group were 71 +/- 9.46 IU/ml, 97 +/- 15.35 IU/ ml and 1.8 +/- 0.62 copies x 10(6)/ml respectively. For treated subjects the mean values of AST, ALT and viral load demonstrated a decrease from baseline values, but this difference was not statistically significant. For control patients the values of ALT (p= .049), AST (p = .005) and viral load (p = .005) showed a statistically significant increase at week 4. Week 4 measurement changes from baseline values were calculated for each participant. The percent change for ALT (p = .014), AST (p = .002) and viral load (p = .326) were compared between the treated and control group demonstrating a statistically significance difference for ALT and AST, but not for viral load. No side effects were reported using the herb extract. CONCLUSION: Sylibum marianum is a well-tolerated plant extract associated with a decrease in liver chemistries but with no apparent effect on viral load when given for 4 weeks. These results suggest that S. marianum may have a protective effect in the inflammatory response to HCV, but no role as an antiviral agent. Further investigations may consider using this plant extract for a longer period of time or as adjuvant to the standard therapy of chronic hepatitis C.