GS-9669: a novel non-nucleoside inhibitor of viral polymerase for the treatment of hepatitis C virus infection

Hepatitis C virus (HCV) is an RNA virus that chronically infects 2–3% of the world’s population. About 25% of these chronic carriers evolve towards liver cirrhosis, a disease that is significantly associated with reduced survival and quality of life. Antiviral therapy can eradicate the infection ? a process that is associated with a reduced disease progression rate. Several oral direct agents have been developed and tested for the treatment of HCV infection. This review focuses on the mechanism of action, pharmacokinetics, efficacy, safety and resistance of GS-9669, a non-nucleoside inhibitor of viral polymerase, active against HCV genotype 1. In combination with other oral antivirals, GS-9669 results: in very high rates of viral eradication (90–100%) in patients with HCV genotype 1 infection, with a good tolerability and safety profile. In conclusion, GS-9669 is a good candidate to be used in interferon-free combinations for the treatment of chronic HCV infection.     

Que sera,sera: evolution of the swine H1N1 influenza A virus

About 2% of the world’s population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90–100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world.     

Challenges in the treatment of chronic hepatitis C in the HIV/HCV-coinfected patient

Hepatitis C virus (HCV) and HIV are common coinfections that convey a shortened lifespan, mostly related to liver disease. Treatment against HCV in the coinfected patient is notoriously more complex and challenging. There are no optimal treatment algorithms for HIV/HCV coinfected patients as efficacy of approved anti-HCV therapies is low with relevant side effects. The use of direct-acting antivirals for anti-HCV therapy has the potential to improve therapeutic efficacy, but also increase side effects and drug–drug interactions. In spite of all of this, the most important and significant fact is that chronic hepatitis C is potentially curable, and the eradication of the HCV infection is a crucial outcome in this population. The establishment of a productive collaboration among the regulatory agencies, the medical community and the pharmaceutical industry could lead to faster access to more effective HCV therapies for the coinfected patient and eventually stop the progression of liver disease in these patients.     

Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection

Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.     

Hepatitis and transfusions.

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are major causes of liver disease. Chronic infection with these viruses often leads to chronic liver disease, including cirrhosis or primary hepatocellular carcinoma (HCC). Concern is growing among patients and health care workers about possible transmission of bloodborne pathogens during medical procedures. This fear has primarily been focused on nosocomial transmission of human immunodeficiency virus (HIV), but other bloodborne infectious agents may also be transmitted during procedures. Chief among these are the hepatitis viruses, particularly HBVand HCV, both of which are significantly more widespread than HIV Circumstantial evidence suggests that hemodialysis, per se, is an important risk factor for infection with HCV.     

Current treatment for hepatitis C virus/human immunodeficiency virus coinfection in adults

Hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection is a major problem among HIV-infected patients, resulting in increased morbidity and mortality rates due to the acceleration of liver fibrosis progression by HIV, leading to liver cirrhosis and hepatocellular carcinoma. Although the efficacy of direct-acting antiviral therapy in patients with HIV/HCV coinfection and HCV monoinfection are similar in terms of sustained virologic response rate, there are some additional complications that arise in the treatment of patients with HIV/HCV coinfection, including drug-drug interactions and HCV reinfection due to the high risk behavior of these patients. This review will summarize the current management of HIV/HCV coinfection.     

Treatment options for nonresponders and relapsers to initial therapy for hepatitis C

As treatment for chronic hepatitis C virus (HCV) infection has advanced over the past decade, efforts have evolved to retreat patients who did not achieve a sustained virologic response to previous antiviral regimens. Retreating nonresponders to interferon alfa monotherapy with a combination of interferon and ribavirin yields a sustained virologic response in 9% to 32% of patients, whereas retreatment with peginterferon alfa plus ribavirin yields a sustained virologic response in up to 30% to 40% of patients. Sustained virologic response is more likely in retreated patients with HCV genotype 2 or 3, low serum HCV RNA levels, and lack of response to prior interferon monotherapy. Retreatment of nonresponders to interferon-ribavirin combination therapy is associated with lower response rates (< or = 20%). Despite treatment advances, the efficacy of current antiviral regimens for nonresponders remains inadequate. The next few years will see more-targeted antiviral regimens for these patients and therapies focused on slowing the progression of liver disease rather than viral eradication.     

Effects of alcohol consumption on viral hepatitis B and C

The liver is the main target organ for hepatitis viruses and the vital organ for alcohol metabolism. These two factors of viral hepatitis and alcohol abuse in combination can exert dual harmful actions, leading to enhanced damage to the liver. Epidemiological studies have revealed a higher prevalence of hepatitis C virus (HCV) infection among alcoholics than the general population. The interaction of alcohol with viral hepatitis [e.g., hepatitis B virus (HBV), HCV] and the underlying mechanisms are not fully understood. The effects of alcohol on viral hepatitis include promoted viral replication, weakened immune response, and increased oxidative stress. Clinically, alcohol abuse is correlated with an increased risk of developing end-stage liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B and C, suggesting that the combination of alcohol and HBV/HCV lead to more severe liver damage. The influence of mild to moderate alcohol drinking on the HBV-induced liver fibrosis, cirrhosis, and hepatocellular carcinoma among patients infected with HBV remains unclear. Unlike HBV infected patients, no safe level of alcohol intake has been established for patients with HCV. Even light to moderate alcohol use can exert a synergistic effect with viral hepatitis, leading to the rapid progression of liver disease. Furthermore, interferon-based therapy is less effective in alcohol drinkers than in control patients, even after abstinence from alcohol for a period of time. Therefore, abstaining from alcohol is highly recommended to protect the liver, especially in individuals with HBV/HCV infection, to improve the clinical efficacy of antiviral treatment and prevent the rapid progression of chronic viral hepatitis.     

Early antiviral treatment of hepatitis C virus recurrence after liver transplantation in HIV-infected patients

OBJECTIVE: To investigate the efficacy of early antiviral treatment for hepatitis C virus (HCV) recurrence in HIV/HCV-coinfected patients undergoing liver transplantation for end-stage liver disease. METHODS: Open prospective trial of early treatment of HCV recurrence in consecutive HIV/HCV-coinfected patients transplanted at a tertiary hospital in Barcelona between 2002 and 2004. All patients had indication for liver transplantation, no previous CDC class C HIV-associated opportunistic events, a CD4+ T-cell count >100cells/microl, and undetectable plasma HIV RNA on highly active antiretroviral therapy. Treatment with pegylated interferon-alpha2b (1.5 microg/kg/week) and ribavirin (800-1000 mg/day) was given for 24 to 48 weeks, as soon as HCV recurrence was histologically documented. RESULTS: Of six patients who underwent transplant, five patients surviving the early post-transplantation period developed HCV recurrence, presenting as severe cholestatic hepatitis in three, and were started on antiviral treatment a median of 12 weeks (range: 5-31) after transplantation. After a median follow-up of 24 months all treated patients were alive. Biochemical response was achieved in all patients, although only one achieved a sustained virological response. Mild rejection before HCV recurrence occurred in two cases. Treatment was well tolerated with no episodes of rejection or mitochondrial toxicity. No patient required modification of the antiretroviral regimen. Liver biopsies performed in patients without virological response, 12-34 months after transplantation, showed cirrhosis in two and moderate chronic active hepatitis in the remainder. CONCLUSIONS: Despite early antiviral treatment, severe HCV recurrence after liver transplantation may compromise long-term survival in HIV-infected patients. Improved treatment strategies for these patients are urgently required.     

Standard interferon-alpha in combination with ribavirin for hepatitis C patients with advanced liver disease and thrombocytopenia

BACKGROUND AND AIM: Patients with advanced liver disease due to thrombocytopenia and chronic infection with hepatitis C virus (HCV) are difficult to treat in view of concerns about the efficacy and safety of interferon-based therapy. Nevertheless, antiviral therapy might have a substantial benefit in these patients as it potentially minimizes disease progression and prevents recurrence after liver transplantation. We evaluated the safety, efficacy and tolerability of standard interferon-alpha in an accelerating dose regimen in combination with ribavirin in patients with HCV-induced liver cirrhosis and thrombocytopenia. PATIENTS: Nine patients (M=8, age: 48.4 +/- 9.9, mean +/- SD) with HCV-related advanced liver disease and thrombocytopenia were prospectively investigated. The Child-Pugh stage was A in six patients and B in three, the MELD score was 11 [6-17] (median [range]). Four patients were interferon naive. HCV-genotype distribution was 1b (n=3), 3a (n=4) and 4 (n=2). The patients received 1-1.5 MU/d standard interferon-a2b with increasing dose regimen and weight-based ribavirin for 48 weeks (genotype 1), or 24 weeks (genotype 3), or until liver transplantation, respectively. RESULTS: The baseline platelet count was 64.3 +/- 8.7 (G/l, mean +/- SD) and remained remarkably stable during treatment (58.0 +/- 12.4 G/l at week 4, 51.7 +/- 20.5 G/l at week 8, P=0.1). All patients had adverse events such as weight loss, fever and anorexia. Hospitalization because of decompensation or infection was necessary in three patients. Three patients underwent liver transplantation. A virological response on treatment was achieved in eight patients and sustained in three (33.3%) patients. CONCLUSION: Treatment with standard interferon-alpha2b/ribavirin could be of benefit in patients with advanced liver cirrhosis and thrombocytopenia however, a vigilant monitoring of these high risk patients is mandatory.     

Hepatitis C virus infection and long-term survivors of childhood cancer: Issues for the pediatric oncology nurse

Infection with hepatitis C virus (HCV) represents a major public health concern today because of its prevalence in the United States. Acute HCV is commonly asymptomatic and often results in chronic disease. However, symptoms related to chronic disease may not appear for decades. Patients with HCV have a broad spectrum of symptoms, which vary from elevated liver function test results to cirrhosis, liver cancer and end stage liver disease. Past treatment therapies have not been highly effective; however, a new treatment is currently available. Today, many high-risk activities are associated with HCV infection. Blood transfusions are no longer a risk factor. However, 20% of individuals who received transfused blood products contracted hepatitis C nearly two decades ago. Therefore, cancer survivors who received blood products to combat chemotherapy induced anemia and thrombocytopenia before 1980 represent a population at risk. It is important that nurses caring for these patients understand the pathophysiology, etiology, transmission, and course of HCV. This knowledge will enable nurses to encourage serological testing to identify infected individuals. Once identified, patients with hepatitis C can receive social support and appropriate referrals to help them deal with the psychosocial issues related to long-term effects and secondary illnesses.     

Chronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapy

HIV-infected patients are living longer since the introduction of highly active antiretroviral therapy. However, coinfection with the hepatitis C virus (HCV) leads to increased morbidity from liver disease and higher overall mortality. The prevalence of chronic hepatitis C among patients with HIV/AIDS ranges from 7% (sexual transmission of HIV) to >90% (injection drug use). Uncontrolled HIV infection seems to accelerate the progression of HCV-induced liver fibrosis. Forty-eight weeks of combination therapy with pegylated interferon alpha (2a or 2b) plus ribavirin achieves a sustained viral response in coinfected individuals in up to 38% with HCV genotype 1 and up to 73% with genotypes 2 or 3. The safety profile of this treatment is similar to therapy in HCV-monoinfected patients with influenza-like symptoms, cytopenia and neuropsychiatric symptoms dominating. However, HIV/HCV-coinfected patients who also take zidovudine develop more profound anaemia than those on other HIV nucleoside analogue therapy. Didanosine and stavudine are associated with rare but serious mitochondrial toxicity, such as pancreatitis or lactic acidosis. It does not appear that the addition of ribavirin increases that risk. There is currently no evidence that in HIV/HCV coinfection one pegylated interferon product is superior to the other. Contrary to common perception, it is also unproven that HIV/HCV-coinfected patients respond less well to therapy with peginterferon alpha plus ribavirin than HCV-monoinfected patients. Given the safety and efficacy of combination therapy with peginterferon plus ribavirin and the deleterious effects of chronic hepatitis C, all HIV/HCV-coinfected patients should be evaluated for therapy.     

Long-term outcome of chronic hepatitis C virus infection in primary hypogammaglobulinaemia

The clinical course of HCV infection in patients with primary hypogammaglobulinaemia appears to be more severe than in immunocompetent patients. We studied the long-term course of chronic HCV infection in 20 Norwegian hypogammaglobulinaemia patients with a 13-15 year known history of HCV infection. Twelve of 20 patients developed cirrhosis during the observation period (1984-1999), and the remaining eight also had chronic liver disease verified by liver biopsy in the majority of the cases. Eleven of the 20 patients are dead. Two died following liver transplantation for HCV cirrhosis. Five died due to terminal liver failure without receiving a liver allograft. Two patients died from other causes, but with advanced liver disease contributing to the outcome, while two deaths were unrelated to the HCV infection. Among patients with common variable immunodeficiency (CVI), five out of six are dead. Two patients cleared the hepatitis C virus 3 years following interferon monotherapy, while three patients achieved a sustained response to combination therapy with interferon and ribavirin. Viral load did not seem to have a major impact on disease progression. Our results emphasize the severity of hepatitis C virus infection in patients with hypogammaglobulinaemia. Patients with CVI appear to have the poorest prognosis.     

Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure,an expert review

Hepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct – acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA – Dasabuvir, a non – nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated with less than 1 % of patients permanently discontinuing treatment and 2% of patient experiencing a serious adverse reaction. It is contraindicated in patients with known hypersensitivity to ritonavir (e.g. Steven – Johnson syndrome) and strong inducers of CYP3A and CYP2CB.     

Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) are present in the peripheral blood and liver of chronically infected patients. The current study was performed to study the relationship between the strength of the CTL response, liver disease severity, and viral load. The results may be summarized as follows: first, using CTL precursor frequency (CTLpf) analysis to quantitate the peripheral blood CTL response, chronically infected patients were less strongly sensitized to a panel of well-defined HCV epitopes than they were to an epitope within the influenza matrix protein. Second, HCV-specific CTLpf did not correlate with disease activity or viral load in the majority of patients on a cross-sectional basis, although it did increase in three patients concomitant with sharp increases in liver disease. Finally, interferon therapy did not enhance the CTLpf against the HCV epitopes studied in these patients, indicating that its antiviral effect is independent of the CTL response. Since the HCV-specific CTLpf in the blood is actually quite low, the CTL may contribute to ongoing liver disease in these patients while being quantitatively inadequate to destroy all of the infected hepatocytes, thereby facilitating HCV persistence and contributing to chronic liver disease.     

Worse quality of life in volunteer blood donors with hepatitis C

BACKGROUND: Health-related quality of life (HRQOL) encompasses many different aspects of health perceived by the individual, and its alterations in patients with hepatitis C virus (HCV) have been recently reported. The objective was to study a population of volunteer blood donors at different stages of HCV liver disease. STUDY DESIGN and METHODS: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), a generic tool, was used to evaluated HRQOL. The SF-36 scores of HCV patients were compared with those of matched healthy blood donors and at the sixth month in those who were submitted to antiviral treatment. Sex, drug use, and alcohol consumption were also evaluated. A total of 120 HCV chronic carriers were divided into three groups: 1) patients with no indication for liver biopsy (n = 37); 2) patients submitted to liver biopsy with mild liver disease (n = 40); and 3) patients with moderate to severe liver disease submitted to interferon plus ribavirin treatment (n = 43). RESULTS: HCV patients had significantly lower SF-36 scores when compared with matched healthy blood donors. There was no correlation between SF-36 scores and history of intravenous and/or inhaled drug use or alcohol consumption. Women had lower SF-36 scores than men in six domains. At the sixth month of treatment, patients who continued to be positive for the presence of HCV RNA (nonresponders) had lower quality of life than those who became HCV RNA-negative. CONCLUSION: Healthy blood donors with HCV showed significantly reduced HRQOL that was more marked in women. The presence of the virus is one of the possible explanations for the reduced HRQOL.     

Recent trends in the therapy of hepatitis C

The treatment of HCV correlated hepatitis is an important argument, because of the great incidence and prevalence of this disease. At the end of the Eighties, the IFN was the first substance used for HCV correlated hepatitis therapy. The IFN monotherapy with a dose of 3-6 MU for 6-12 months eradicates the infection in the 15% of cases, and cause an histological temporary improvement in a variable number of patients that keep the infection. In the following years, the research on evaluation of the efficacy of the recombinant interferons or interferons made with genetics engineering (IFN alpha 2a, IFN alpha 2b and IFN Consensus) has given results comparable with the results obtained with IFN alpha. Later, it started the experimentations with IFN associated to other substances, for example IFN-ribavirin combination therapy. The treatment IFN-Ribavirin eradicates the infection in 30% of the patients with the genotype 1b and in 60% with the genotype 2 or 3, while this treatment is less efficacious in the patients with the genotype 4. Recently, it started to use the PEG IFN. The pegylation is the combination of a polietylen-glicole molecule with the IFN molecule, so as to prolong its half-life and reduce the dose only one a week, with reduction of the collateral effects. Some studies has shown that the use of PEG-IFN in monotherapy could help the patients with advanced liver complaint. Successive studies are directed to show the efficacy of the PEG-IFN and ribavirin combination therapy. Recent researches put in evidence new substances, that could represent the future for HCV correlated hepatitis therapy. Between these substances we have to highlight the interleukin, the inhibitors of the viral multiplication and the inhibitors of IMPDH (Inosine monophosphate dehydrogenase). At the beginning of 2002 has made the improvement of HCV vaccine known. Actually, in the USA there are in progress human experimentations, and the production of gamma-globuline, that could be effective to prevent the infection.     

Response to combined interferon and ribavirin is better in patients infected with hepatitis C virus genotype 6 than genotype 1 in Hong Kong

Data on the treatment efficacy of interferon (IFN)-alpha and ribavirin in patients with chronic hepatitis infected with hepatitis C virus (HCV) of genotype 6 are lacking. A study has been reported from Hong Kong which compared the treatment efficacy of IFN-alpha and ribavirin in the treatment of chronic HCV infection with genotypes 1 and 6. Twenty-four patients with HCV genotype 1 and 16 patients with HCV genotype 6 were studied. The baseline demographic data including median age, gender ratio, alanine aminotransferase levels, bilirubin levels, HCV RNA levels and histological scores were comparable between the two groups of patients. All patients received IFN-alpha 5 million units three times per week and ribavirin (1,000 mg for those weighing 75 kg) for 1 year. Patients infected with HCV genotype 6 achieved virological response significantly higher than those with HCV genotype 1 (67 vs. 33% at week 24, p = 0.02; 75 vs. 42% at the end of treatment, p = 0.05; 63 vs. 29% at 6 months after completion of treatment, p = 0.04). Histological improvement in inflammatory activity and fibrosis in the liver were observed in 25% and 25% of patients infected with HCV genotype 6 in contrast to only 13 and 8% in patients infected with HCV genotype 1; however, the differences were not statistically significant. In conclusion, patients with HCV genotype 6 gain a better response to combined treatment with IFN-alpha and ribavirin than those with HCV genotype 1 and achieve a significantly higher rate of sustained virological response.     

Involvement of TAP2 and LMP7 gene polymorphisms in HCV infection

We aimed to study whether TAP and LMP polymorphisms could influence the severity of liver disease or the response to IFN treatment in patients with chronic HCV infection. TAPZ*0103 gene frequencies in carriers with normal ALT was significantly higher than that in CLD patients. As for the results of IFN responses, LMP7-K gene frequency in sustained-responders was higher than that in non-responders. Multivariate analysis revealed that LMP7-K and HCV RNA quantity were independent factors influencing the outcome of IFN therapy. Furthermore, among patients with a low viral load, the LMP7-K positive patients had a significantly higher ratio of sustained response compared to those without LMP7-K. The TAP2 polymorphism may be closely associated with low hepatitis activity, whereas the LMP7 polymorphism influences the efficacy of IFN treatment and can be a useful predictive parameter in HCV patients with a low viral load.     

Hepatitis C infection: a clinical review

Nearly three million persons in the United States are viremic with hepatitis C (HCV). Despite a decreasing incidence of HCV in this country, the prevalence of HCV-related chronic liver disease is increasing. Most infections in the United States are acquired by intravenous drug use. The chronicity rate of HCV is high, reaching 85% in some populations, and the risk of progression to advanced liver disease is as high as 20% within twenty years of infection. Host factors like alcohol use accelerate the rate of progression. The enzyme immunoassay is the preferred initial test for diagnosis; the third generation assay has greater than a 99% specificity in immunocompetent patients. Barring contraindications, the standard of care for treatment of chronic HCV has become pegylated interferon and ribavirin. With this therapy, the cure rate for treatment-na?ve patients is about 55%, but rates are higher in certain groups. Common side effects of therapy include neuropsychiatric symptoms, influenza-like symptoms and hematological abnormalities.