HCV New Drugs

Saturday, July 28, 2012

Hepatitis C Therapy in Non-genotype 1 Patients: The Near Future

From Journal of Viral Hepatitis

Hepatitis C Therapy in Non-genotype 1 Patients
The Near Future

Full Text @ Medscape

C. Wartelle-Bladou; G. Le Folgoc; M. Bourlière; L. Lecomte Authors and Disclosures Posted: 07/27/2012; J Viral Hepat. 2012;19(8):525-536.
© 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Summary. Worldwide, 50–70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations.

Introduction
There are approximately 170–200 million people chronically infected with hepatitis C virus (HCV) worldwide. Chronic hepatitis C can lead to cirrhosis and its subsequent complications such as hepatocellular carcinoma with more than 350 000 people dying each year from hepatitis C–related liver disease. Clearance of the virus is associated with improved histological outcomes, morbidity and mortality. The therapeutic goal is therefore to achieve a sustained virological response (SVR) defined as undetectable HCV RNA 6 months after cessation of therapy. Among the six identified HCV genotypes, genotype 1 (GT-1) is the most prevalent and was, until the approval in 2011 of two-first-generation NS3/4A protease inhibitors (PIs) in combination with pegylated interferon (PEG-INF)-α and ribavirin, the most difficult to cure. The launch in 2011 of boceprevir and telaprevir was a major landmark in the management of GT-1-infected patients. In association with PEG-INF and ribavirin, these two drugs increase the chances of cure by 30% with SVR rates in the range of 66–75% in naïve patients.^[1–3] The benefit appears to be even more important in treatment-experienced patients in whom the chances of cure increase by 50–60% in relapsers, 40–45% in partial responders and 25% in null responders.^[4,5]

However, this major advance benefits only GT-1 patients while there remains worldwide 50–70 million subjects infected with an HCV genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin (PR) remains the currently approved standard-of-care treatment (SOC). HCV genotypes present specific geographical distribution (Fig. 1), leading to a quasi-mono-genotypic HCV infection in some parts of the world such as Egypt, where the HCV infection prevalence reaches 15% in the general population with an almost exclusive GT-4 distribution. In such a country, chronic hepatitis C will exert an increasing substantial disease burden without more effective treatments.

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The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A PIs, nucleos(t)ide (NIs) and non-nucleoside inhibitors (NNIs) of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-proteins-directed antiviral agents are cyclophilin inhibitors and silibinin. Several drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds.

Current Standard-of-care Treatment Treatment Results in Non-GT-1 HCV Infection
The recommended first-line treatment for non-GT-1 chronic hepatitis C is based on the use of any of the two pegylated IFN-α available administered weekly subcutaneously and daily oral ribavirin.^[6] PEG-IFN-α2a should be used at a dose of 180 μg once per week, whereas PEG-IFN-α2b should be used at a weight-based dose of 1.5 μg/kg per week. The ribavirin dose depends on the HCV genotype. Patients infected with GT-4, GT-5 or GT-6 should receive a weight-based dose of ribavirin of 15 mg/kg body weight per day. Patients infected with GT-2 or GT-3 can be treated with a flat dose of 800 mg of ribavirin daily; however, those with baseline factors predictive of a low responsiveness should receive a weight-based dose of ribavirin similar to GT-4, GT-5 and GT-6. Although initially the duration of treatment was fixed, 24 weeks for GT-2 and GT-3 and 48 weeks for GT-4, GT-5 and GT-6, the treatment duration should now be tailored to the on-treatment virological response in most non-GT-1 HCV patients.

Patients infected with GT-2 or GT-3 are not a homogenous population. There is now mounting evidence that these two genotypes should be distinguished from one another and not be anymore labelled together as the 'easy-to–treat' group. Indeed, SVR rates with a SOC 24-week treatment range from 75% to 97% and 62% to 92% in GT-2 and GT-3 patients, respectively.^[7] Shortening the duration of treatment without compromising the chances of cure has been investigated in GT-2/GT-3 patients with conflicting results. A meta-analysis concluded that in rapid virological responders (RVR, defined as undetectable HCV RNA at 4 weeks), shortening of treatment duration to 16 weeks is possible in GT-2 patients or in GT-3 patients with an optimal weight-based ribavirin dose. Whatever the genotype, shortening of treatment duration is not recommended in cirrhotic patients. Extension of the treatment to 48 weeks is suggested in the absence of an RVR and/or in the presence of predictive factors of lower SVR such as advanced liver fibrosis or high BMI.^[6] The impact of the IL28B polymorphism is unclear in GT-2/GT-3 patients. While some studies have failed to demonstrate any clear association between IL28B polymorphism and SVR,^[8,9] others have reported a positive association between the favourable rs12979860 CC or rs8099917 TT genotype, respectively, with RVR, but not SVR,^[10] suggesting an increased rate of relapse in this population along with higher pretreatment viral loads and ALT levels. Finally, two European studies showed that CC genotype is associated with SVR.^[11,12] In an Italian study, IL28B CC genotype is highly predictive of SVR among non-RVR patients.^[12]

In patients infected with GT-4, despite the lack of data validating the response-guided therapy concept, it has been suggested by an international panel that a response-guided approach similar to the one used in GT-1 patients may be considered.^[13] Thus, RVR are highly likely to achieve SVR and are candidate to 24-week regimens in the absence of poor baseline predictive factor of response. Patients with RVR and pejorative predictive factors and complete early virological responders (EVR defined as undetectable HCV RNA at week 12) should be treated for 48 weeks. Patients with partial EVR (detectable HCV RNA but >2 log₁₀ drop at week 12 and undetectable HCV RNA at week 24) may be considered for treatment prolongation to 72 weeks.^[13] IL28B polymorphism is an important baseline predictive factor of response in GT-4 patients. Genotype CC in the SNP rs12979860 is associated with SVR but not with liver severity in these patients.^[14,15] However, its predictive weight is lower than in GT-1 patients, and RVR remains the strongest predictive factor of response.^[14]
In patient infected with GT-6, two studies evaluated response-guided therapy in a pilot trial and a randomized trial.^[16,17] They demonstrated that patients with RVR could be treated for 24 weeks. However, those without RVR had very low SVR.^[16] In GT-5-infected patients, there are no data on response-guided therapy, and 48-week regimens should therefore be recommended.

Apart from clinical trials, observation cohorts provide us with real-life results. In the PROPHESYS cohort, 37% of the 7163 patients included were infected with a non-GT-1 HCV. The observed SVR rates after SOC treatment were of 41%, 61%, 68% and 71% in GT-4, GT-3, GT-5/GT-6 and GT-2 patients, respectively.^[18] In the German cohort, which included 23 893 patients, 39 patients were infected with GT-5 and 39 patients with GT-6. SVR after 48 weeks of treatment was 58% and 59% for GT-5 and GT-6, respectively.^[19]

Current results of SOC treatment in non-GT-1 patients are not optimal especially in GT-4 and GT-3 patients.

Standard-of-care treatment will not be successful in 30–60% of patients. A second course of PEG-INF and ribavirin for a longer duration with an optimal dose of ribavirin is currently the only available option. This leads to unsatisfactory results with poor SVR rates ranging from 19% to 34% in previous nonresponders to 46% in relapsers.^[6] Therefore, new treatments are urgently needed in this population.

Telaprevir and Boceprevir in Non-genotype 1 Hepatitis C Virus Infection
Telaprevir and boceprevir are orally available, first-generation PIs. Combined with PEG-IFN and ribavirin, both drugs have recently been approved for the treatment of naïve and treatment-failure GT-1-infected patients.

The antiviral activity of telaprevir against GT-2 and GT-3 HCV was investigated in a randomized, partially blinded study. The study design allowed evaluation of the intrinsic antiviral potency of the drug in the 9 GT-2 patients and 8 GT-3 patients randomized to an initial 2-week course of telaprevir monotherapy. A significant reduction in the HCV viral load (median HCV decrease – 3.27 log₁₀ IU/L) was observed at day 3 in GT-2 patients compared with SOC. However, a virological breakthrough was observed in six of the nine patients within 15 days. Telaprevir monotherapy had no activity in GT-3 patients, with only a slight decrease in the HCV RNA levels (−0.54 log₁₀ IU/L at day 3 and 15, respectively).^[20] Triple therapy with telaprevir for 2 weeks induced a greater reduction in HCV RNA level compared with the SOC arm in GT-2 patients, but not in GT-3 patients.^[20] Boceprevir monotherapy was evaluated in a phase I study in 40 GT-2/GT-3 patients in a 2-week dosing period. The maximum decrease in the viral load during the treatment period was observed in the 400 mg q.8 h arm in GT-3 patients with a mean – 1.71 log₁₀ UI HCV RNA from baseline comparable with the viral drop seen in GT-1 patients.^[21]

In a phase IIa study conducted in 24 GT-4 patients, triple therapy with telaprevir for 2 weeks induced a greater reduction in the HCV RNA level compared with the SOC arm. However, following triple regimen, PR for 46 weeks did not lead to a greater SVR compared with PR (62% in both groups).^[22]
While telaprevir in association with PR demonstrated antiviral effectiveness in GT-2 patients, leading to an ongoing phase III trial in treatment-experienced patients, triple regimen with first-generation PI elicits no or limited antiviral effectiveness in GT-3 and GT-4 chronic hepatitis, confirming the need for more potent combinations.

Beyond Triple Therapy with First-generation Protease Inhibitors
The main compounds in clinical stage development for non-GT-1 HCV infection comprise DAAs, host-targeting antiviral agents and PEG-INF-λ.

Most second-wave PIs are macrocyclic. Their antiviral potency is similar or slightly better than first-generation PIs, but they exhibit a more favourable resistance profile and are easier to administrate.^[23] TMC-435 inhibits HCV replication across all genotypes in preclinical protease biochemical assays, with an IC₅₀ value below 13 nm except for GT-3a protease.^[24] Danoprevir (DNV) has equipotent activity against HCV genotypes 1, 4 and 6 in vitro.^[23] MK 5172 is a highly effective second-generation PI with subnanomolar in vitro IC₅₀ values across all HCV genotypes. It is effective in vitro against the majority of first-generation PI resistance–associated variants and is the first pan-genotypic PI.^[25] The safety profile of both second-wave and second-generation PIs appears to be good so far.

NS5B polymerase inhibitors comprise nucleoside(-tide) inhibitors (NIs) and non-nucleotide inhibitors (NNIs).^[26] NIs binds to the NS5B active sites, causing chain termination and/or an increased number of errors when incorporated into a growing RNA chain. The NS5B's active site being well conserved, NIs tend to have a similar efficacy across all genotypes and present the highest barrier of resistance of all DAAs to date. In contrast, NNIs have shown a restricted spectrum of activity against the various HCV genotypes. They are mainly active against HCV GT-1 and present the lowest barrier of resistance. NS5B NIs appear therefore to be among the most promising pan-genotypic drugs.
Hepatitis C virus NS5A is a critically important viral protein in the virus replication, whose function is still not clearly elucidated.^[27] BMS-790052 (Daclatasvir) is a first-in-class NS5A inhibitor which potently inhibits replicons representative of all six major genotypes with EC50 of <1 nm without overt cytotoxicity to host cells.^[28]

Drugs targeting host proteins essential for the HCV replication may provide a greater barrier to resistance than DAAs. The first host-targeting compounds to emerge were the cyclophilin inhibitors, cyclophilin A being the putative protein involved. Debio 025 (alisporivir, ALV) is a selective cyclophilin inhibitor whose antiviral activity against HCV GT-1, 3 and 4 was demonstrated in a proof-of-concept study with no overt sign of upcoming resistance.^[29] Seven-day intravenous treatment (20 mg/kg/day) with silibinin, whose mechanism of action is not yet completely understood, resulted in a mean decrease of 3 log₁₀ IU/mL in HCV RNA in GT-1 patients. No data are available on the specific antiviral activities for non-GT-1 genotypes.^[30]

Pegylated interferon lambda is a type III interferon with a marked antiviral C activity and a restricted distribution of receptors, mostly in the liver, leading to less hematopoietic side effects than PEG-IFN-α This was confirmed in a phase 2b study in terms of reduction in side effects, even in cirrhotic patients.^[31–33] A recent study suggested that vitamin D could increase the response to PR treatment in HCV GT-1 patients.^[34] This should be confirmed in other trials and in other HCV genotypes.

Where Are We Now in Clinic With New Compounds?

Genotype 2 and Genotype 3 Future Treatment

Second-Wave and Second-Generation Protease Inhibitors
TMC 435 monotherapy 200 mg daily for 7 days was investigated in GT-2–6 patients in a phase IIa study. The study confirmed the absence of activity observed in vitro in GT-3 infection and demonstrated a weak activity of the compound against GT-2.^[35] In a phase 1 study with MK-5172 monotherapy 400 mg daily for 7 days, a maximum mean HCV RNA reduction from baseline of 5.4 and 3.98 log 10 UI/mL was observed in GT-1 and GT-3 patients, respectively.^[36] Studies assessing MK-5172 with PR for 12 or 24 weeks are currently ongoing in GT-2/GT-3 patients (Table 1).

NS5B Nucleos(t)ide Inhibitors
Mericitabine (RG7128) is a nucleoside analogue, whose antiviral activity was demonstrated in vitro across HCV genotypes. Mericitabine was evaluated in GT-2/GT-3 treatment-failure patients. After a 4-week triple combination, RG7128 1500 mg bid was discontinued and PR resumed for 20–44 weeks. Week 4 RVR rate was 95% in RG7128-treated patients vs 60% in the PR arm, demonstrating the antiviral potency of the molecule. In the absence of an RVR, no patient presented SVR whereas 68% of RVR patients were cured. SVR rates were less impressive, due to the short duration of the triple regimen (4 weeks), and did not differ among GT-2 and GT-3 RG7128 treated patients: 63% and 67%, respectively.^[37] In patients treated with RG7128, SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%).^[37]

PSI-7977 (now GS-7977) is a pyrimidine nucleotide analogue with a high antiviral activity across all genotypes and a high genetic barrier to resistance. It is safe, well tolerated and administrated once daily. PSI(GS)-7977 was evaluated in 25 naïve GT-2/GT-3 patients in the PROTON study. A 12-week triple combination of PSI(GS)-7977 400 mg once daily plus PEG-INF and weight-based ribavirin yielded a 100% SVR rate 24 weeks after the end of therapy.^[38] Furthermore, in the ELECTRON study, an 8-week triple combination of PSI(GS)-7977 400 mg/day plus PEG-IFN and weight-based ribavirin yielded a 100% SVR rate 12 weeks after the end of therapy in the 10 treatment-naive GT-3 patients included.^[39] Combination of PSI(GS)-7977 with ribavirin was further evaluated in the ELECTRON study with a 12-week treatment duration. The trial conducted in 40 treatment-naïve GT-2/GT-3 patients comprised one triple regimen arm, two INF-sparing arms and one INF-free arm.^[40] SVR rates 12 weeks after cessation of treatment were 100% in all arms. Ten patients were enrolled in an additional 12-week PSI(GS)-7977 monotherapy. Whereas the EOT rate was 100%, four patients relapsed within the month following cessation of therapy, outlining the importance of ribavirin. There was no virological breakthrough identified and no premature discontinuation of treatment due to adverse events.^[40] In subsequent arms of the ELECTRON study, 25 treatment-experienced GT-2/GT-3 patients were treated for 12 weeks with PSI(GS)-7977 and ribavirin. Whereas the EOT rate was 100%, three patients relapsed within the month following cessation of therapy, and SVR rates 4 weeks after cessation of treatment was 80%.^[39] Other potent guanosine nucleotide polymerase inhibitors INX-189, active against GT-1, GT-2 and GT-3, are currently beginning phase II trial in naive GT-2 or GT-3 patients.

NS5A Inhibitors (NS5A Is)
Daclatasvir (BMS-790052) is, in vitro, a potent inhibitor of viral replication in all six major genotypes. There are two ongoing phase II studies in GT-2/GT-3 patients. The first one conducted in naive patients assesses the benefit of a triple regimen with daclatasvir 60 mg daily plus PR given for 16 or 24 weeks. The second study is being conducted in treatment-experienced patients and evaluates the benefit of a quadruple regimen comprising daclatasvir 60 mg daily, asunaprevir (NS3/4 PI) and PR given for 24 weeks (Table 1).

Cyclophilin Inhibitors
Alisporivir (Deb025) was investigated in GT-2/GT-3 naïve patients in a double blind, placebo controlled escalating dose-ranging with or without PEG-INF for 29 days in a phase II study.^[41] HCV RNA levels at week 4 were reduced by −5.91 and −5.89 log₁₀ IU/mL in the 600 and 1000 mg combination arms, respectively. Five of six patients in both groups had undetectable HCV RNA at the end of treatment, and one patient had a SVR after 28 days of Deb025.^[41,42] In the phase II VITAL study, 346 GT-2/GT-3 naïve patients were randomized in five groups: (1) ALV 1000 mg qd; (2)ALV 800 mg qd + RBV 800 mg/day; (3) ALV 600 mg qd + RBV 800 mg/day; (4) ALV 600 mg qd + PEG-INFα-2a 180 μg/week; and (5) PEG-IFNα-2a 180 μg/week + RBV 800 mg/day.^[43] All treatments were given for 24 weeks. In all ALV arms, patients received a leading dose of ALV 600 mg bid during the first treatment week. In each arm, in the absence of an RVR, patients were treated from week 6 to week 24 with a triple regimen ALV 600 mg qd + PEG-IFNα-2a 180 μg/week + RBV 800 mg/day. Whatever the ALV dose, SVR rates 12 weeks after the end of therapy were significantly higher in ALV-treated patients ranging in ITT analysis from 77% to 83%vs 58% in the control arm. Among the three IFN-free arms, 22%, 23% and 34% of patients in ALV 1000, 600 and 800 mg arm, respectively, reached RVR and were therefore maintained on the IFN-free regimen until week 24. The SVR rate 12 weeks after cessation of treatment was 82%, 93% and 91% in ALV 1000, 600 and 800 mg groups, respectively.^[43] However, despite those encouraging results, the development of the molecule wad stopped due to the occurrence of six cases of acute pancreatitis including one fatal case.

IFN-free Regimen With Direct Antiviral Agents Combination With or Without Ribavirin
The ELECTRON study has demonstrated that a 12-week IFN-free regimen with PSI(GS)-7977 + RBV was able to cure ten naive GT-2/GT-3 patients without advanced disease. Moreover, the same regimen was able to cure '80% (SVR4)' of a larger cohort of treatment-experienced GT-2/GT-3 patients again without advanced fibrosis.^[39]

The second IFN-free regimen phase II trial assessed the antiviral efficacy of daclatasvir (NS5A. I) in combination with GS-7977 (NS5B. NI) with or without ribavirin for 24 weeks in naive GT-2/GT-3 patients without advanced fibrosis.^[44] There were three arms: (i) a first week of GS-7977 followed by 23 weeks of daclatasvir in combination with GS-7977, (ii) 24 weeks of daclatasvir and GS-7977 combination, (iii) 24 weeks of triple combination of daclatasvir, GS-7977 and ribavirin 800 mg/day. Combination was well tolerated, and early SVR rate 4 weeks after the end of therapy was 91% (40/44 patients). Two patients were lost to follow-up, one patient had a breakthrough and one patients relapsed 4 week after the end of therapy.

A third ongoing IFN-free regimen phase II trial assesses the antiviral efficacy of a regimen associating ABT-267 (NS5A. I) and ABT-450r, a ritonavir-boosted protease inhibitor, with or without ribavirin in naive GT-2/GT-3 patients (Table 1).

Interferon Lambda
Final data for GT-2/GT-3 patients of the EMERGE phase II study suggest a beneficial impact of PEG-INF-λ in GT-3 patients.^[45] There were 60 GT-2 and 58 GT-3 patients enrolled in this trial evaluating different doses of PEG-IFN-λ (120, 180 and 240 μg) in association with RBV for 24 weeks. Whatever the PEG-IFN-λ dose, SVR rates 24 weeks after the EOT were numerically greater in GT-3 patients receiving PEG-INF-λ compared with the control SOC group (PEG-INFα-2a 180 μg plus ribavirin). SVR rates in GT-2 patients were similar in PEG-INF-λ and control arms. Flu-like symptoms, myalgia and pyrexia were significantly lower in PEG-INF-λ-treated patients. No reduction in the dose of ribavirin was needed in the PEG-INF-λ 180 μg group vs 23% in those treated with PEG-INFα-2a 180 μg.^[45]

In Summary
The recently reported clinical results suggest that (i) an oral 'PEG-INF-free' 12-week treatment (GS-7977 with ribavirin for 12 weeks) can lead to definitive clearance of the virus in most naive and treatment-experienced GT-2/GT-3 HCV infection with mild or moderate fibrosis; (ii) ribavirin still matters in combinations including a single DAA; (iii) an oral, 'IFN-free', 'RBV-free' DAAs combination (daclatasvir and GS-7977 for 24 weeks) may achieve eradication of the virus in more than 90% of naive GT-2/GT-3. The high SVR rate, 4 weeks after EOT, needs to be confirmed with a longer follow-up, particularly in the absence of ribavirin in the regimen. Moreover, all these very encouraging results for IFN-free regimens need to be confirmed in patients with more advanced fibrosis and in null-responders to SOC. Meanwhile, triple regimen with GS-7977 plus PEG-IFN and ribavirin for 12 weeks appears to be conclusive, but must be confirmed in the most-difficult-to-treat patients. Candidate compounds, currently available for an oral, IFN-free combination in this population, are second-generation PI (MK-5172) as second-wave PI exerts no efficacy on GT-3, NS5A inhibitors, NS5B nucleoside or nucleotide inhibitors (Mericitabine, GS-7977) and cyclophilin inhibitors (ALV); however, this last compound is on hold due to toxicity. The association would ideally comprise at least one compound with a high barrier to resistance.
Several therapeutic combinations (triple combinations with PR, INF-free combinations and INF-free, ribavirin-free DAAs combinations) are currently evaluated both in naïve and in prior nonresponders GT-2/GT-3 patients (Table 1). Those studies need to address more rapidly the most-difficult-to-treat population.

Finally, switching from PEG-INFα to PEG-INF-λ may be an interesting alternative in GT-2/GT-3 patients. The lesser hematopoietic side effects with no need for RBV dose reduction may be of particular interest in GT-3 patients as an optimal dose of RBV appears essential in this subgroup to prevent relapse.

Genotype 4

Second-Wave and Second-Generation Protease Inhibitors
TMC 435 was investigated in 8 GT-4 patients during an 11-day monotherapy course. Mean viral decrease was −3.43 log10 UI/mL at day 3 and −3.52 at day 8.^[35] A phase III study assessing the efficacy of triple regimen with TMC435 150 mg qd plus PR for 12 weeks fallowed by 12 or 24 weeks of PR is ongoing in naive and treatment-experienced GT-4 patients.

Danoprevir is also active against GT-4. Different doses of DNV boosted with ritonavir (DNVr 200/100, 100/100, 50/100 mg bid) for 24 weeks and DNVr100/100 for 12/24 weeks (response-guided arm) were evaluated in combination with PR in the DAUPHINE trial.^[46] Thirty-three GT-4 patients were enrolled in this open-label, active-controlled phase IIb study. All DNVr-treated GT-4 patients achieved an SVR12, independently of the DNVr dose and the treatment duration. There were no DNVr-related grade 3/4 AE. Diarrhoea was the only side effect that occured in all DNVr arms with an 10% higher incidence than in the control group.

Asunaprevir, a second-wave PI, is studied in an ongoing trial in combination with PR for various duration – 24 to 48 weeks – in naïve GT-4 patients.
Lastly, among PIs, second-generation PI (as MK-5172) may be a good candidate for triple therapy; however, studies are pending.

NS5B Nucleos(t)ide Inhibitors
Mericitabine was evaluated in the 28 naive GT-4 patients who were included in the PROPEL study. This phase II, controlled trial evaluated an initial 8- or 12-week triple combination of mericitabine with PR followed by 12–36 weeks of PR. RVR and cEVR were higher among patients treated with mericitabine, but SVR and relapse rates were comparable to the PEG-IFN and ribavirin control arm.^[47] This is due to the short duration of triple regimen. In the JUMP phase 2b study, five naive GT-4 patients alongside 166 GT-1 naive patients were randomized to SOC for 48 weeks or to triple therapy with mericitabine during 24 weeks, followed by 24 weeks of PR in those without eRVR.^[48] In this study SVR rate was always superior in triple regimen arms compared with SOC. However, the 57% SVR rate is lower to what we reach with other triple regimens. Therefore, mericitabine may be more interesting as a compound used in a DAAs association than in a triple regimen with PEG-IFN and ribavirin.

GS-7977 in combination with PEG-IFN and ribavirin exhibits a rapid and drastic viral decay within the first 4 weeks of treatment similar across all genotypes.^[49] Eleven GT-4 patients were included in the ATOMIC study and treated with GS-7977 400 mg once daily plus PEG-IFN and ribavirin for 24 weeks. All 11 patients were HCV RNA undetectable at week 4. At interim analysis, the eight patients evaluable 12 weeks post-treatment (three patients pending) had remained HCV RNA negative.^[50]

NS5A Inhibitor Daclatasvir (BMS-790052) is, in vitro, a potent inhibitor of viral replication in all six major genotypes. Daclatasvir in association with PEG-IFN and ribavirin was evaluated in 30 GT-4 patients. Preliminary data reported that all 12 patients in the daclatasvir 60 mg qd arm had undetectable HCV RNA at week 12 compared with 58% in the 20 mg arm and 50% in the placebo arm.^[51]

Cyclophilin Inhibitor (CI) our naïve GT-4 patients presented a viral decay of more than 2 log10 UI at week 4 in a phase 2a dose-ranging study of 29 days of the cyclophilin inhibitor ALV.^[41] This weak antiviral activity preclude further study; however, due to this different mode of action, CI could be part of DAAs combination regimen. Unfortunately, the molecule was on hold due to toxicity.

Direct Antiviral Agents Combination With PEG-IFN and Ribavirin here are two ongoing studies evaluated in treatment-experienced GT-4 patients: the combination of daclatasvir (NS5A inhibitor) plus asunaprevir (PI) and PEG-IFN plus ribavirin for 24 weeks in the first study; and ritonavir-boosted DNV (PI) plus mericitabine (NS5B NI) and PEG-IFN plus ribavirin for 24 weeks in the second study (Table 1).

Nitazoxanide
Nitazoxanide (NTZ) is an antiparasitic drug efficient against cryptosporidium, giardia Lamblia and clostridium difficile. The postulated antiviral C mechanism of NTZ is believed to be through selective induction of a host protein kinase.^[52] The STEALTH C trial was conducted in 96 GT-4 patients in two Egyptian centres. The SVR rate increased from 50% in the control SOC 48 weeks group to 79% in patients receiving 12 weeks lead-in phase of NTZ 500 mg twice daily followed by 36 weeks of triple combination.^[53] Although these results are promising, the number of patients was small and the percentage of patients with advanced liver disease was low. Thus, further studies are needed to investigate NTZ in GT-4.

In Summary
Clinical results with DAAs are sparse for GT-4 patients, mostly derived from trials enrolling GT-1–4 patients with small numbers of GT-4 subjects included. However, the reported results are promising, demonstrating: (i) 100% RVR rates with a triple combination (GS-7977 + PR); (ii) high SVR rates with short 12-week combination regimens (GS-7977 + PR, DAN/r + PR). (iii) The efficiency of second-wave PIs in GT-4 HCV infection.
Potential INF-free therapeutic options consist in a combination of GS-7977 with RBV or a combination of two DAAs with or without ribavirin. Candidate DAAs are second-wave (DNV/r, TMC 435) and second-generation PIs (MK-5172), NS5A inhibitor (daclatasvir), NS5B NIs (mericitabine, GS-7977) and new cyclophilin inhibitor if available.

Genotype 5 and 6
Clinical results of the use of DAAs for GT-5 and GT-6 HCV infection are limited.
TMC 435 monotherapy induced a significant mean viremia decrease of −4.35 log₁₀ UI/mL after 8 days in the GT-6 patients studied whereas the mean change was only – 2.19 in GT-5 patients (−2.71 at day 3).^[35]

Five GT-6 patients were included in the ATOMIC study and treated with GS 797 400 mg once daily plus PEG-INF plus ribavirin for 24 weeks. The RVR rate at week 4 and the SVR rate 12 weeks after the end of the treatment were both 100%.^[50]

Conclusion
Current results of SOC treatment in non-GT-1 patients are not optimal, especially in GT-4 and GT-3 patients.

New treatments are urgently needed in this subgroup. While telaprevir in association with PR has demonstrated antiviral effectiveness in GT-2 patients, the current available first-generation PIs (telaprevir and boceprevir) are not active against non-GT-1 HCV infection.

Evaluation of many promising molecules such as second-generation PIs, NS5A I and NS5B NIs, some with pan-genotypic activity, have begun, demonstrating potent viral efficacy with good safety profile in easy-to-treat patients. An all-oral PEG-INF-free regimen for 12 weeks was able to cure nearly all naive and treatment-experienced GT-2/GT-3 HCV infection with mild or moderate fibrosis. IFN- and RBV-free DAAs combination also appears very efficient in this population. These data need to be confirmed in treatment-experienced and advanced liver fibrosis populations.

Meanwhile, triple regimens with DAAs plus PEG-IFN and ribavirin appear to be very conclusive although results must be confirmed in difficult-to-treat patients. Whether or not PEG-IFN and/or ribavirin will remain in some patients the backbone of future DAAs combinations remains an open and unsolved issue.

References

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Bacon BR, Gordon SC, Lawitz E et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207–1217.
Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–2428.
EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55: 245– 264.
Di Martino V, Richou C, Cervoni JP et al. Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized, controlled trials and implications for the future. Hepatology 2011; 54: 789–800.
Rauch A, Kutalik Z, Descombes P et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138: 1338–1345, 45.
McCarthy JJ, Li JH, Thompson A et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology 2010; 138: 2307–2314.
Moghaddam A, Melum E, Reinton N et al. IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection. Hepatology 2011; 53: 746–754.
Sarrazin C, Susser S, Doehring A et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 2011; 54: 415–421.
Mangia A, Thompson AJ, Santoro R et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology 2010; 139: 821–827, 7.
Khattab MA, Ferenci P, Hadziyannis SJ et al. Management of hepatitis C virus genotype 4: recommendations of an international expert panel. J Hepatol 2011; 54: 1250–1262.
Stattermayer AF, Stauber R, Hofer H et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2011; 9: 344–350.
Asselah T, De Muynck S, Broet P et al. IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol 2012; 56: 527– 532.
Pham TTT, Ho TD. An optimal duration of treatment for chronic hepatitis C genotype 6 patients. Hepatology 2011; 54(Suppl.): 810A– 811A.
Tangkijvanich P, Komolmit P, Mahachai V, Poovorawan K, Akkarathamrongsin S, Poovorawan Y. Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study. J Viral Hepat 2012; 19: 423–430.
Marcellin P, Cheinquer H, Curescu M et al. Worldwide experience treating chronic hepatitis C with peginterferon alfa/ribavirin: final results from 7163 naive mono-infected patients enrolled in the large multinational PROPHESYS cohort study. Hepatology 2011; 54(Suppl.): 824A.
Mauss S, Berger F, Vogel M et al. Treatment results of chronic hepatitis C genotype 5 and 6 infections in Germany. Z Gastroenterol 2012; 50: 441–444.
Foster GR, Hezode C, Bronowicki JP et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141: 881–889.
Silva M, Kasserra C, Gupta A, Treitel M, Hughes E, O_Mara E. Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3. APASL Feb 17–20, 2011. Available at: http://www.natap.org/2011/APSL/APSL_03.htm.
Benhamou Y, Moussalli J, Ratziu V et al. Activity of telaprevir or in combination with peginterferon alfa-2a and ribavirin in treatment naive genotype 4 hepatitis C patients. Final results of study C210. Hepatology 2010; 52(Suppl.): 719A–720A.
Gottwein JM, Scheel TK, Jensen TB, Ghanem L, Bukh J. Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology 2011; 141: 1067–1079.
Lin TI, Lenz O, Fanning G et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother 2009; 53: 1377– 1385.
Barnard RJ, Graham D, AcostaAet al. MK-5172, a next generation HCV NS3/4A protease inhibitor is active against common resistance associated variants (RAVS) and exhibits cross genotype activity. Global Antiviral Journal 2011; 7(Suppl. 1), HEP DART 2011; Abstract 108: 99.
Membreno FE, Lawitz EJ. The HCV NS5B nucleoside and non-nucleoside inhibitors. Clin Liver Dis 2011; 15: 611–626.
Gish RG, Meanwell NA. The NS5A replication complex inhibitors: difference makers? Clin Liver Dis 2011; 15: 627–639.
Gao M, Nettles RE, Belema M et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465: 96–100.
Paeshuyse J, Kaul A, De Clercq E et al. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006; 43: 761–770.
Ferenci P, Scherzer TM, Kerschner H et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135: 1561–1567.
Zeuzem S, Arora S, Bacon B et al. Pegylated interferon lambda shows superior viral response with improved safety and tolerability versus PegIFN alfa-2A in HCV patients (G1/2/3/4): EMERGE phase IIB through week 12. J Hepatol 2011; 54: S538–S539.
Everson GT, Gray TE, Hillson JL et al. Pegylated interferon lambda ameliorates ribavirin-induced anemia in HCV patients by maintaining compensatory erythropoiesis: analysis of emerge phase 2B results through week 12. Hepatology 2011; 54: 993A–994A.
Rodriguez-Torres M, Hillson JL, Bacon BR et al. Safety and efficacy of pegylated interferon lambda compared to pegylated interferon alfa-2A in HCV-infected patients G1/2/3 with compensated cirrhosis: EMERGE phase 2b efficacy and safety results through week 12. Hepatology 2011; 54: 994A.
Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. World J Gastroenterol 2011; 17: 5184–5190.
Moreno C, Berg T, Tanwandee T et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study. J Hepatol 2012; 56: 1247–1253.
Peltry AS, Fraser IP, O_Mara E et al. Safety and antiviral activity of MK-5172, a next generation HCV NS3/4A protease inhibitor with a broad HCV genotypic activity spectrum and potent activity against known resistance mutants in genotype 1 and 3 HCV infected patients. Hepatology 2011; 54(Suppl.): 531A.
Gane EJ, Rodriguez-Torres M, Nelson DE et al. Sustained virologic response following RG7128 1500mg BID/PEG-IFN/RBV for 28 days in HCV genotype 2/3 prior non responders. J Hepatol 2010; 52: S16.
Lalezari J, Lawitz E, Rodriguez-Torres M et al. Once daily PSI-7977 plus PEGIFN/RBV in a phase 2B trial: rapid virologic suppression in treatment-naive patients with HCV GT2/GT3. J Hepatol 2011; 54: S28.
Gane EJ, Stedman CA, Hyland RH et al. ELECTRON: once daily PSI-7977plus RBV in HCV GT1/2/3. J Hepatol 2012; 56: S438–S439.
Gane EJ, Stedman C, Hyland RH et al. Once daily PSI-7977 plus RBV: pegylated interferon alfa not required for complete rapid viral response in treatment naive patients with HCV GT2 or GT3. Hepatology 2011; 54: 377A.
Flisiak R, Feinman SV, Jablkowski M et al. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology 2009; 49: 1460–1468.
Patel H, Heathcote EJ. Sustained virological response with 29 days of Debio 025 monotherapy in hepatitis C virus genotype 3. Gut 2011; 60: 879.
Pawlostky JM, Sarin SK, Foster G et al. Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-GT2or GT3 patients: SVR12 results from VITAL-1 phase 2b study. J Hepatol 2012; 56: S553.
Sulkowski M, Gardiner D, Lawitz E et al. Potent viral suppression with the all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (nucleotide NS5B inhibitor +/) ribavirin in treatment-naive patients with chronic HCV GT1,2, or 3. J Hepatol 2012; 56: S560.
Zeuzem S, Arora S, Bacon B et al. Peginterferon lambda-1A compared to peginterferon alfa-2A in treatment-naive patients with HCV genotypes 2 or 3: first SVR 24 results from EMERGE phase IIB. J Hepatol 2012; 56: S5.
Everson G, Cooper C, Hezode C et al. Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/PEGIFN alfa-2A/RBV in HCV genotype 1 or 4 patients: DAUPHINE week 12 interim analysis. J Hepatol 2012; 56: S466.
Wedemeyer H, Jensen D, Herring Jr R et al. Efficacy and safety of mericitabine in combination with PEGIFN alfa-2A/RBV in G1/4 treatment naive HCV patients: final analysis from the PROPEL study. J Hepatol 2012; 56: S481.
Pockros P, Jensen D, Tsai N et al. SVR-12 among G1/4 treatmentnaive patients receiving mericitabine in combination with PEG-IFN alfa-2A/RBV: interim analysis from the JUMP-C study. J Hepatol 2012; 56: S477–S478.
Hassanein T, Nelson DR, Lawitz E et al. PSI-7977 with PEG/RBV elicits rapid declines in HCV RNA in patients with HCV GT-4 and GT-6. GAJ 2011; 7: 57.
Kowdley KV, Lawitz E, Crespo I et al. ATOMIC: 97% RVR for PSI-7977+PEG/RBV · 12 week regimen in HCV GT1: an end to response-guided therapy? J Hepatol 2012; 56: S1.
Hezode C, Hirschfield GM, Ghesquiere W et al. BMS-790052, A NS5A replication complec inhibitor combined with peginterferon alfa 2a and ribavirin in treatment naive HCV-genotype 1 or 4 patients: phase 2B AI444010 study interim week 12 results. Hepatology 2011; 54: 474A.
Ahn J, Flamm SL. Hepatitis C therapy: other players in the game. Clin Liver Dis 2011; 15: 641–656.
Mederacke I, Wedemeyer H. Nitazoxanide for the treatment of chronic hepatitis C new opportunities but new challenges? Ann Hepatol 2009; 8: 166–168.

Source - http://www.medscape.com/viewarticle/767510

World Hepatitis Day 2012

World Hepatitis Day

There are 500 million people currently infected with chronic hepatitis B or C worldwide, with approximately 150 million people infected with hepatitis C. Individuals with chronic hepatitis C are at increased risk of developing serious complications such as cirrhosis, hepatocellular carcinoma (HCC) (with US-based studies clearly showing that up to 51%–55% of HCC patients have anti-HCV antibodies), and end-stage liver disease.

The most common viral infections leading to liver transplantation are hepatitis B and C. In the United States, HCV-related end-stage liver disease is the most common, while hepatitis B is the most common cause of ESLD worldwide.

The symptoms of hepatitis C manifest very slowly and are not always recognized, at least in the early stages of infection. This explains why an estimated 75% of infections remain undiagnosed in the United States.

People aged 40–49 years account for 66% of Americans infected with HCV. This "baby boomer" generation is particularly susceptible to blood-borne HCV transmission as a result of an increased lifetime risk of injection drug use (IDU), and blood transfusion before 1992.

In May the CDC announced the first ever national hepatitis testing day and proposed that all baby boomers be tested once for hepatitis C.

In 2012 we have new drugs to treat HCV and increased awareness for viral hepatitis through campaigns implemented by the World Hepatitis Alliance, and the World Health Organization

Today, July 28, 2012 people around the world will raise awareness for viral hepatitis as World Hepatitis Day begins.

World Hepatitis Day 2012 Campaign Video

World Hepatitis Day is an annual event that each year provides international focus for patient groups and people living with hepatitis B and C. It is an opportunity around which interested groups can raise awareness and influence real change in disease prevention and access to testing and treatment.

Visuals for the video have been based on the metaphor of a falling piano, highlighting that around the world hepatitis is being ignored, playing with the slogan for World Hepatitis Day 2012 'It's closer than you think' and encouraging everyone to confront it!

For more information visit http://www.worldhepatitisalliance.org/en/Home.aspx

Friday, July 27, 2012

ALF- New HCV Website and Adds HCV Specialist To HelpLine

NEW HEPATITIS C TOOLS AVAILABLE - HELPING YOU GET TO A CURE

July 28th marks the second World Hepatitis Day. As part of the activities surrounding this important day of awareness about viral hepatitis, the American Liver Foundation will launch its new hepatitis C information and education support program titled, “Hepatitis C: Diagnosis, Treatment, Support.”

With the introduction of two new treatments for hepatitis C, this is a disease that can be cured. The goal of the Hepatitis C: Diagnosis, Treatment and Support program is to provide the necessary information so those individuals considering treatment have answers to their questions, can identify the resources available to them and look at avenues of support.

New Hepatitis C Website to Be Launched

The Hepatitis C: Diagnosis, Treatment, Support website is about to be launched. This will be the most comprehensive place on the web to find information for those who are diagnosed with hepatitis C and looking for information on treatments. The website will be found at www.hepc.liverfoundation.org.

American Liver Foundation HelpLine Service Adds a Dedicated Hepatitis C Specialist and Expands Hours

1-800-GOLIVER (1-800-465-4837

After receiving a diagnosis of hepatitis C, everyone has questions. And there are times you need someone to help sort through those questions and provide information.

To answer this need, the American Liver Foundation has added a hepatitis C specialist and expanded the HelpLine hours.

Callers can now reach someone at the Helpline from 9:00 AM to 7:00 PM Eastern time, Monday – Friday. In addition, questions sent on e-mail to info@liverfoundation.org will be promptly answered.

07/2012 Digital Liver Disease Journal: HCV In Children, After Liver Transplantation,Cirrhosis, HIV, and More

July 2012

Volume 1, Issue 3

Pages 63–97

Digital Liver Disease Journal - "Clinical Liver Disease" Third Issue Is Out

The journal is an official digital educational resource from the American Association for the Study of Liver Diseases.

Visitors are able to view videos, full data, and download files in either HTML or PDF formats

The July issue is open access, article topics and links are provided below

You have free access to this content
Hepatitis C viral infection in difficult-to-treat populations: An overview (pages 63–64)
Nezam H. Afdhal
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.57
Watch the interview with the author

You have free access to this content
Hepatitis C viral infection in patients with cirrhosis (pages 65–68)
Ranjeeta Bahirwani and K. Rajender Reddy
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.43
Watch the interview with the authors

Watch the video presentation of this article

You have free access to this content
Hepatitis C genotype 1 infection in HIV–Infected patients in the era of direct-acting antiviral therapy (pages 69–72)
Mark S. Sulkowski
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.51
Watch the interview with the author

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Hepatitis C viral infection after liver transplantation (pages 73–76)
Elizabeth C. Verna and Robert S. Brown Jr
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.62
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Watch the video presentation of this article

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Hepatitis C viral infection in children (pages 77–80)
Douglas Mogul and Kathleen B. Schwarz
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.64

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Hepatitis C viral infection in drug users (pages 81–83)
Diana L. Sylvestre
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.72

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Hepatitis C viral infection in incarcerated patients (pages 84–86)
John Rice, Lisa Cervantes and Michael R. Lucey
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.47
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Access to care: Management of hepatitis C viral infection in remote locations (pages 87–90)
Sanjeev Arora, Karla Thornton and Andrea Bradford
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.46
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Hepatitis C viral infection in patients with chronic kidney disease (pages 91–94)
Andres F. Carrion and Paul Martin
Article first published online: 23 JUL 2012 | DOI: 10.1002/cld.55
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Hepatitis C viral infection in patients with hemophilia and hemolytic disorders (pages 95–97) Eric S. Orman and Michael W. Fried
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Thursday, July 26, 2012

HCV Weekly Rewind:Gilead Begins Single Pill Hepatitis C Study For 2014 Approval

Hello folks,
Welcome to HCV rewind, a weekly digest of news, research and a look at today's headlines.

This week we've been given a glimpse into research on liver cancer, HCV drugs in development (Gilead single pill study), disease progression, disease mortality, diabetes, and news coming from the International AIDS Conference. Also in the media, the number of states linked to the suspect in hepatitis C outbreak at Exeter hospital continues to rise. Last but not least, the US district court in Washington DC, rules a controversial stem cell therapy offered at US clinics should be regulated.

We begin with a disturbing, but significant hepatitis C study published in the Journal of Infectious Diseases. According to the paper the overall mortality from liver related disease and non-liver conditions - including some cancers- was found to be significantly increased in people with chronic hepatitis C. The Full text is available to the public through open access, and includes an accompanying editorial.

In The News

19/07/2012

Hepatitis C may increase deaths from both liver-related and other diseases

In a long-term study of people infected with the hepatitis C virus (HCV), researchers found increased deaths from both liver-related and non-liver related diseases in patients with active infections who had not cleared their infection.

The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.

HCV infects more than 170 million people globally and has been shown to cause such liver diseases as cirrhosis and hepatocellular carcinoma. Many infected patients have no symptoms and are not aware of infection until after irreversible liver disease has occurred. In addition, several diseases not related to the liver have been linked to HCV. However, nearly two-thirds of patients can be cured of their HCV infection with currently available antiviral therapy.

Chien-Jen Chen, ScD, and researchers from the Genomic Research Center in Taipei, Taiwan, enrolled more than 23,000 adults in Taiwan in their study and followed them from 1991 to 2008. Blood samples were collected at study entry and at follow-up health examinations. Researchers found increased mortality from liver- and non-liver-related diseases—including cancers of the esophagus, prostate, and thyroid, as well as circulatory and renal diseases—among those infected with HCV. Mortality was higher in HCV-infected participants with detectable serum levels of HCV RNA, indicating they had active infections; subjects with previous infections who only had HCV antibodies, but not HCV RNA, in their blood did not have increased mortality on follow-up.

According to Dr. Chen, "The findings implied that the serum HCV RNA level is an important marker for clinical decisions in the management of HCV-infected patients." Dr. Chen suggested that HCV-infected patients may benefit from treatment with antiviral and immunomodulating agents to promote viral clearance.

The investigators concluded that their findings have significant implications for clinical practice and public health—namely, that individuals seropositive for HCV RNA should be followed intensively and urged to be evaluated for antiviral therapy. In addition, they noted, testing to determine serum HCV RNA level by a sensitive assay is essential for clinical management of HCV-infected patients.

Dr. Chen and his colleagues cautioned that some non-liver-related diseases are too rare to accurately determine their risk in connection with HCV infection. They suggested that a collaborative study with a large sample size would be needed in order to further investigate the full spectrum of diseases associated with HCV.

In an accompanying editorial, Kenrad E. Nelson, MD, of Johns Hopkins University in Baltimore, noted that overall mortality was significantly increased from liver-related and other causes compared to uninfected patients from the same communities in the study. The findings indicate that, although some who are infected with HCV can cure their infection without treatment, most people who are infected and who have no symptoms develop chronic infections and are at increased risk of death from HCV, Dr. Nelson said.

Many patients with HCV infection go undiagnosed, and among those whose infection is detected, "few are medically evaluated and effectively treated," Dr. Nelson added. Although treatment for HCV infection is improving dramatically, he noted, a significant reduction in HCV-related mortality will require that screening measures are greatly expanded.

Fast Facts:

Overall mortality in patients infected with hepatitis C virus (HCV) was significantly increased from both liver-related and other diseases compared to uninfected patients from the same communities.
Compared to people who had never been infected with HCV, mortality was higher in HCV-infected patients with detectable levels of HCV RNA in their blood on follow-up, but not in patients with inactive infections—those who were positive for HCV antibodies but whose blood was free of HCV RNA.
Diseases not related to the liver that were observed in this study included cancers of the esophagus, prostate, and thyroid, and circulatory and renal diseases.
Most people with chronic HCV infection don't know they are infected because the infection is often without symptoms. However, chronic HCV can be curable with treatment, so people should be screened and considered for treatment if they have chronic HCV infection.

Liz Highleyman, Editor-in-Chief and Publisher at HIV and Hepatitis, examines the study results in detail:

Hepatitis C Raises Risk of Both Liver-Related and Non-Liver Deaths

Published on Tuesday, 24 July 2012 00:00

Over years or decades, chronic hepatitis C can progress to serious liver disease including cirrhosis, hepatocellular carcinoma, and end-stage liver failure. But the effect of HCV infection on non-liver-related illness and death has not been extensively studied.

Mei-Hsuan Lee from Academia Sinica in Taipei, Chien-Jen Chen from the Genomic Research Center, and fellow investigators with the R.E.V.E.A.L.-HCV Study Group looked at associations between HCV infection and liver-related and non-liver deaths...
Continue reading...

Exeter Hospital Hepatitis C Outbreak -More States Linked To Suspect

.
Suspect in hepatitis C outbreak was fired in Ariz.

By Holly Ramer on July 26, 2012 @ Bloomberg

CONCORD, N.H. (AP) — A dozen hospitals in seven states are scrambling to identify people who might have been infected with hepatitis C by a traveling medical technician who was charged a week ago with causing an outbreak in New Hampshire.

With details of David Kwiatkowski's resume still emerging, a hospital official in Arizona said he had been fired from her facility in April 2010, after he was found unresponsive in a men's locker room with syringes and needles. Kwiatkowski was treated at the hospital, and tests showed he had cocaine and marijuana in his system, said Monica Bowman, chief executive officer of the Arizona Heart Hospital...

In Michigan, officials at Oakwood Annapolis Hospital in Wayne noted that there was no indication that Kwiatkowski had hepatitis C when he was employed there from January to September 2007, and that he passed at least two drug tests during that time. State health officials said they are still looking into other locations where Kwiatkowski worked and what steps, if any, they need to take....

Twenty-five former patients at St. Francis Hospital in Poughkeepsie, N.Y., where Kwiatkowski worked for three months in late 2007 and early 2008, have been asked to get tested. In Kansas, state health officials are sending letters to about 460 patients who were treated at the cardiac catheterization lab at Hays Medical Center from May 24, 2010, to Sept. 22, 2010. The state also is setting up an informational website, and the hospital has set up a telephone hotline...

In Maryland, hundreds of patients are being contacted by the four hospitals where Kwiatkowski worked between May 2008 and March 2010. None of the four, which include The Johns Hopkins Hospital and a Veterans Affairs hospital in Baltimore, reported that Kwiatkowski was fired or that his behavior raised red flags...

At Houston Medical Center in Warner Robins, Ga., CEO Cary Martin the identification process hasn't been completed yet. Kwiatkowski worked in the cardiac cath lab there from October 2010 to March 2011 but did not have access to the hospital's medication system, he said....

Continue reading at Bloomberg

Contributing to this report were Associated Press writers Felicia Fonseca and Paul Davenport in Arizona, Kate Brumback in Atlanta, Ben Nuckols in Washington, David Runk in Detroit, John Hanna in Topeka, Kan., and JoAnn Loviglio in Philadelphia.

Video - Jul. 26, 2012

US Attorney: Hepatitis C Case 'Unprecedented'

A federal prosecutor said Tuesday he expects to bring more charges against a traveling medical technician accused of infecting 30 patients with hepatitis C in New Hampshire.(AP)..

View video here...

Learning About HCV

This week Clinical Care Options released "part one" of an online quiz containing 35 questions on treating hepatitis C, answered by nine world-renowned hepatology experts, to review the quiz and links, click here. When CCO goes live with part two and three, I'll be sure to post a link.

July Issue Of CDL

Digital Liver Disease Journal - "Clinical Liver Disease" Third Issue Is Out

07/2012 Digital Liver Disease Journal: HCV In Children, After Liver Transplantation, Cirrhosis, HIV, and More
The journal is an official digital educational resource from the American Association for the Study of Liver Diseases.

Visitors are able to view videos, full data, and download files in either HTML or PDF formats

Disease Progression In hepatitis C

NIH scientists identify likely predictors of hepatitis C severity
Scientists at the National Institutes of Health have identified several factors in people infected with the hepatitis C virus that may predict whether the unusually rapid progression of disease from initial infection to severe liver conditions, such as cirrhosis, will occur. Knowing whether a patient's condition is likely to deteriorate quickly could help physicians decide on the best course of treatment.
Continue reading...

Pharmaceuticals

Gilead Begins Single Pill Hepatitis C Study For 2014 Approval

By Michelle Fay Cortez and Ryan Flinn on July 27, 2012

Gilead Sciences Inc. (GILD) said it plans to start a combination study of two drugs in a single pill to treat hepatitis C by the end of the year, putting it on track to request U.S. regulatory approval for the medicine in 2014.

Gilead, which spent $10.8 billion to acquire one of the medicines, GS-7977, plans to combine it with another, GS-5855, in a trial of 800 patients starting in the fourth-quarter, said Norbert Bischofberger, chief medical officer of the Foster City, California-based company, in a conference call yesterday. If the combination is effective, the company could apply for regulatory approval in the middle of 2014, Bischofberger said.

Gilead is among several drugmakers racing to develop new hepatitis C treatments that act more quickly with fewer side effects than the current standard of care. The goal is to provide doctors and patients with simpler, more effective treatments, Bischofberger said.

The company aims for a therapy that “will clearly be a one pill, once daily, maybe a 12 week course,” for patients with all different types of hepatitis C, Bischofberger said. “That’s our goal. We are very close.”

Continue reading @ Bloomberg

Gilead Sciences' Stock Rises on Prospects for Hepatitis C Pill
By Brett Chase Jul 27, 2012 12:15 pm

Some analysts say Gilead is now clearly in the lead for a better hepatitis drug.

MINYANVILLE ORIGINAL Shares of Gilead Sciences rose as much as 6% Friday on sentiment, once again, that the biotech company is in the lead position for a better hepatitis C treatment.

Gilead is performing multiple studies to test an experimental drug, but the trial that is possibly the most intriguing looks at a combination therapy that rolls two medicines into a single pill. Gilead hopes to advance tests of its lead hepatitis drug GS-7977 in a combination with another company medicine, GS-5885. Wall Street analysts and investors are excited about the potential for this combination as a highly effective, safe, single pill. If all goes well in studies, the company may apply for US approval by 2014.

“This probably puts them in the lead,” ISI Group analyst Mark Schoenebaum says.

Hepatitis C is a liver-wasting virus that affects millions of people. Gilead is in a highly competitive race for a better hepatitis treatment with rivals such as Bristol-Myers Squibb (BMY), Abbott Laboratories (ABT), Merck (MRK), Vertex Pharmaceuticals (VRTX), Idenix Pharmaceuticals (IDIX), and Roche (RHHBY).

Shares of Gilead were up 5% to $54.41 in late-morning trading. The stock is up 33% this year.

Pressure is on the company to prove that its almost $11 billion acquisition of Pharmasset will pan out. Gilead acquired GS-7977 in that takeover, which was completed earlier this year. (See Gilead Plans $11 Billion Takeover of Pharmasset to Gain Hepatitis Drugs.)

The company is likely to apply for US approval of GS-7977 next year. But the combo pill with the two drugs signals potential for an even more superior treatment compared with the current standard of care. Currently, medicines are taken with an injection of interferon, an immune booster that can have nasty side effects. The goal of all the next-generation hepatitis drug programs is to develop a treatment that doesn’t require interferon. A single pill to treat the virus would be a real breakthrough.

“It’s the ultimate frontier in (hepatitis) therapy,” Gilead’s chief scientific officer Norbert Bischofberger told investors on a conference call late-day Thursday. “That’s what we want to pursue.”

Bristol-Myers CEO Lamberto Andreotti has said Gilead should test GS-7977 with his company’s drug, daclatasvir. Like GS-5885, daclastasvir is among a class of drugs called NS5A inhibitors. GS-7977 is known as a nucleotide polymerase inhibitor.

Gilead execs say they want to go forward with their own drug rather than testing with Bristol-Myers.

Source-MINYANVILLE

Gilead Sciences Management Discusses Q2 2012 Results - Earnings Call Transcript

Before we begin our formal remarks, we want to remind you that we will be making forward-looking statements that contains certain assumptions, risks and uncertainties that are beyond our control.

These risks include the possibility that our actual financial results may differ materially from the revised guidance we are presenting today.

The possibility of unfavorable results from our clinical studies, including those evaluating the GS 7977, and GS 5885 in various patient populations and the possibility that we may be unable to compete our clinical studies and regulatory filings or obtain regulatory approvals in currently anticipated timelines.

A description of these risks can be found at our latest SEC disclosure documents in our recent press releases. Gilead does not undertake any obligation to update these forward-looking statements made during this call.

Continue reading @ Seeking Alpha

Related@ Gilead Sciences-Second Quarter 2012 Financial Results
.
FDA grants fast track designation for Idenix HCV therapy
The US Food and Drug Administration (FDA) has granted fast track designation for Idenix Pharmaceuticals' IDX719 to treat chronic hepatitis C infection (HCV).

IDX719 is an NS5A inhibitor that demonstrated pan-genotypic activity in a recent proof-of-concept clinical trial in genotypes 1-4, treatment-naive HCV patients.

Idenix president and chief executive officer Ron Renaud said the receipt of fast track designation from the FDA for IDX719 reflects the critical need for new treatment regimens to address HCV infection.

"As previously reported, we are on track to initiate a phase II combination study of IDX719 with IDX184, our other lead HCV product candidate, by the end of this year," Renaud added.

The fast track program allows a company to file a new drug application on a rolling basis, which permits the FDA to review the filing as it is received, rather than waiting for the entire submission prior to commencing the review process.
Source

Related- IDX719-Idenix hepatitis C drug Receives Fast Track Designation

Idenix: New HCV Treatment Could Be A Game Changer

July 24 - Investing Commentary

Author's Profile

Idenix Pharma (IDIX): New HCV Treatment Could Be A Game Changer

Excerpt:

The company's candidate IDX184 is the principle value driver at this point. Although IDX184 is considered to be less potent than the leading HCV nuclear clinical candidate (Gilead Sciences' GS-7977), the available data suggest that IDX184 would be successfully developed, thereby unlocking significant value in Idenix shares...

"While the wholly-owned key asset IDX184 is not a best-in-class nucleotide ("nuc") polymerase inhibitor, we think its high barrier to resistance will confer value in alternative DAA combos, with data in 2013 driving estimates higher and solidifying its scarcity among late-stage nucs," UBS analyst Matthew Roden wrote in a note to clients...

Idenix has the only unencumbered nuc in late-stage clinical development, as well as IDX719, a potentially best-in-class pan-genotypic NS5a inhibitor in phase-1 trials as well. IDX719 targets the HCV non-structural 5A (NS5A) protein presents a second clinical stage asset, and could be differentiated among the NS5a class in terms of potency and pan-genotypic activity.

The company has also planned to begin trials with a combination of IDX 719 and IDX 184 towards the end of this year. "Given the potential for both classes to become backbone therapies in HCV (and potentially form an all-IDIX pan-genotypic combo), we believe the Idenix pipeline has considerable scarcity value, and will attract large pharma or biotech partners," the analyst noted. In addition, Idenix holds significant intellectual property in nuc chemistry, and may have rights to other nucs in HCV.....

Continue Reading....

Related - Published July 14 at gurufocus.com
IDX184-Idenix Pharmaceuticals Lagging Behind In Breakthrough Hepatitis C Drug Development

GSK wins FDA priority review for Promacta supplemental new drug application to treat thrombocytopenia in adult patients with chronic hepatitis C virus infection

July 26

GlaxoSmithKline (GSK), Ligand Pharmaceuticals' partner, has gained FDA priority review status for the supplemental new drug application for Promacta to treat thrombocytopenia in adult patients with chronic hepatitis C virus infection.

Eltrombopag, known by the brand name Promacta in the US and Revolade in the European Union and other countries, is indicated for thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia.

The risks associated with Promacta include hepatotoxicity, bone marrow reticulin formation and risk for bone marrow fibrosis, thrombotic/thromboembolic complications, hematologic malignancies, and cataracts

A priority review designation is given to drugs that are considered to offer major advances in treatment or provide a treatment where no adequate therapy exists, if approved.

Under the Prescription Drugs User Fee Act, the goal for completing a priority review is six months.

Ligand is a biopharmaceutical company with a business model that is based upon the concept of developing or acquiring royalty revenue generating assets and coupling them to a lean corporate cost structure.
Source

Liver Cancer

Medscape published data on the importance of early diagnoses of HCC, and the excellent survival rate for patients who underwent curative treatments. View Full Text @ Medscape, or click here to read only the discussion/conclusion.

Survey: Surgeons Play to Strengths in Early Hepatocellular Cancer
Therapy for early HCC with well-compensated cirrhosis is controversial; there is little agreement on when resection, transplantation, or radiofrequency ablation becomes the best approach. Choice of therapy for early HCC often depends on the surgeon’s repertoire of techniques and the therapeutic services the hospital offers, based on the findings of a web-based survey of centers that had at least five HCC cases per year..Continue reading..

Liver Cancer - Clinical Trials

Jennerex begins Phase 2 HCC trial of JX-594
PBR Staff Writer Published 26 July 2012
Jennerex has treated the first patient in a Phase 2 clinical trial of intravenous treatment with JX-594 for patients with advanced hepatocellular carcinoma (HCC) who have not received treatment with sorafeni.

The multinational, single-arm, open-label study of JX-594 is administered weekly by intravenous infusions in sorafenib-naive patients with advanced HCC. The trial will be conducted in South Korea, US and Europe.

The radiographic response rate based on modified RECIST and modified Choi criteria is the primary objective of the study and the patients will subsequently be followed for progression-free survival and overall survival.

Jennerex research and development president and chief medical officer David Kirn said unlike other treatments in the class, JX-594 can be administered intravenously, and it has the ability to target tumors systemically and, therefore, has the potential to impact both metastatic and primary tumors.

"In our previously reported randomized Phase 2 dose-ranging study in HCC with intratumoral delivery, we showed a statistically significant benefit in overall survival in the high dose group, which we believe was due, in large part, to the systemic delivery of JX-594 at that dose level," Kirn added.
Source

Failures

Combination of Tarceva, Nexavar fails to meet main goal of Phase III liver cancer study
Bayer, Onyx Pharmaceuticals and Astellas announced Monday that a late-stage trial investigating the combination of Tarceva (erlotinib) and Nexavar (sorafenib) failed to meet the main goal of a late-stage trial in patients with unresectable hepatocellular carcinoma (HCC).

Hepatocellular carcinoma - Brivanib Phase III Does Not Meet Overall Survival Primary Endpoint
Bristol-Myers Squibb Company today reported the result of the phase III BRISK-FL clinical trial of the investigational agent brivanib versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (HCC; liver cancer). The study did not meet its primary overall survival objective based upon a non-inferiority statistical design

Worth A Click

For the savvy HCV patient who strives to stay abreast of the latest research, Healio offers news and education in the field of gastroenterology, hepatology, infectious disease and more. The site alleviates the daunting task of breaking down either full text articles or abstracts found in medical journals online by publishing the same research in easy to comprehend articles. Here are a few articles offered at Healio this week.

July 25-26, 2012
Chronic HCV can increase mortality risk from hepatic, extrahepatic diseases
Liver transplant may be an option for some patients with unresectable HCC
Patients with HCV may not benefit from HAV vaccination

**After visiting the site a few times free registration is required

Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch
The in depth report includes the following topics; HCV drug resistance, DAA drug-drug interactions, nucleosides and nucleotide polymerase inhibitors, HCV protease inhibitors, the next generation of drugs, HCV quad therapy, treating genotypes 1-4, SVR-4 ,SVR-12, interferon free therapy and much more....
Click here to read the article....

HCV Awareness

Just In July 27-
ALF- New HCV Website and Adds HCV Specialist To HelpLine

World Hepatitis Day
On 28 July 2012 people around the world will come together to mark World Hepatitis Day and raise awareness of viral hepatitis. Coordinated by the World Hepatitis Alliance since 2007, World Hepatitis Day was officially recognised by the World Health Organization on May 2010 and it’s now one of only four disease related official days.

Hepatitis kills around one million people every year. Millions more suffer immediate sickness or long-term ill health. World Hepatitis Day provides an opportunity to recognise viral hepatitis as a major global health problem in order to advance prevention and control.

Hepatitis C: A “silent killer”
Encourage patients to get tested for World Hepatitis Day, July 28

The liver disease hepatitis C is a major health issue in the United States—as much as 5 million Americans have hepatitis C, approximately four times the amount of people with HIV. It’s the leading cause of liver cancer and the most common reason for liver transplantation in the country. What’s more surprising is that 75% of people with hepatitis C don’t know it yet.

Hepatitis C has been called a “silent epidemic” in a Department of Health & Human Services report because it often has no symptoms and can go decades without detection. In the meantime, serious liver damage or even liver cancer may occur.

Recent CDC studies have reported that deaths from hepatitis C are on the rise. In 2007, there were more than 15,000 deaths in the United States from hepatitis C, surpassing the 13,000 deaths from HIV/AIDS in the same year.

People born from 1945 through 1965 have a greater prevalence of hepatitis C than the general population. In fact, 82% of people with the disease in the country are members of the baby boomer generation, and 73% of the deaths from hepatitis C occur in this group.

Those at increased risk for hepatitis C include people who had blood transfusions before 1992, people with tattoos, people who used I.V. drugs even once, and those who work in a health care setting. Certain populations, including African Americans and Hispanics, are also affected by hepatitis C at a significantly higher rate than the general population.

The good news is that for many patients, hepatitis C can be cured, unlike other chronic diseases such as hepatitis B and HIV/AIDS.

Screening for hepatitis C is not currently part of routine testing. Many patients who think they have been tested have not. CDC recently released draft guidelines recommending that all baby boomers have a simple, one-time antibody test to screen for hepatitis C. According to a CDC-sponsored study, such age-based screening could identify more than 800,000 additional cases of chronic hepatitis C infection and, when followed by treatment, could reduce the number of deaths by an additional 121,000 over risk-based screening.

Posted by Alex Egerváry
July 26, 2012
Read more here....

UK - Hepatitis C hospital cases soar

(UKPA)–14 hours ago

Around 216,000 people in the UK are chronically infected with hepatitis C.

A Health Protection Agency (HPA) annual report into the infectious disease revealed an increase in hospital admissions and deaths for End Stage Liver Disease (ESLD) and liver cancer - both of which are related to hepatitis C.

In 2010 there were 1,979 hospital admissions, compared with 612 in 1998, while deaths have risen from 98 in 1996 to 323 in 2010.

In 2011, 9,908 new diagnoses of hepatitis C were reported to the HPA in England, up from 7,892 cases in 2010, however the HPA said the rise is thought to be due to changes in laboratory reporting.
The report, Hepatitis C in the UK, looks at the future burden of hepatitis C-related infections and national progress in tackling the infection. It was produced to coincide with World Hepatitis Day on July 28.

Dr Helen Harris, a hepatitis expert at the HPA, said: "Many of the 216,000 people who are chronically infected with the virus are unaware of their infection. Therefore, it is vital that we continue to monitor the true burden of infection to help focus public health action on getting these people diagnosed and into treatment.

"Although our latest report shows that we are having a number of successes in our fight against hepatitis C, many people continue to become seriously ill from this preventable infection, which is usually treatable if caught early enough.

"We must therefore redouble our efforts and continue to develop new schemes to raise awareness in at-risk communities and ensure that individuals who may have been exposed to the virus are tested, diagnosed and treated early, before they become seriously ill."

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV). The virus causes inflammation of the liver and, when left untreated, can result in chronic liver disease, liver failure, or death. Because the liver is able to work even when damaged, many people are unaware they have the disease at first because they have no symptoms. It is only when the liver becomes seriously damaged that symptoms occur and people report to their doctor.

Charles Gore, chief executive of The Hepatitis C Trust, said: "Hepatitis is closer than you think In the UK, a 'see no evil, hear no evil, speak no evil' attitude prevails and many people are needlessly dying. We simply must increase testing."
Read more...

Bristol-Myers Squibb Foundation Marks World Hepatitis Day 2012 with New Grants Focused on Hepatitis B and Hepatitis C Patient Empowerment in China and India
Foundation's Delivering Hope(TM) program wins Asia's Best CSR Practices Award
NEW YORK, Jul 26, 2012 (BUSINESS WIRE) -- The Bristol-Myers Squibb Foundation has awarded four new grants totaling US $1.69 million to improve prevention, care and support of hepatitis B (HBV) and hepatitis C (HCV) in China and India as part of its Delivering Hope(TM) program. The grants, announced to coincide with World Hepatitis Day on July 28, support initiatives to empower hepatitis patients to take an active role in disease management and advocacy. This focus on patient empowerment recognizes the significant health disparities that exist in these countries but also the progress that has been made to address them through disease awareness efforts and education targeted to the health care community.
Continue reading @ Bristol-Myers Squibb

Health Check: Hepatitis C testing

By: Barbara Morse Silva | NBC 10
Published: July 25, 2012

WHO-Prevent hepatitis C: Avoid unsafe injections , use of illicit drugs, tattoos, piercings, acupuncture performed with contaminated equipment
Hepatitis C is a contagious liver disease that results from infection with the hepatitis C virus. It can range in severity from a mild illness lasting a few weeks to a serious, lifelong illness.
The hepatitis C virus is usually spread when blood from an infected person enters the body of a susceptible person. It is among the most common viruses that infect the liver.
Every year, 3–4 million people are infected with the hepatitis C virus. About 150 million people are chronically infected and at risk of developing liver cirrhosis and/or liver cancer. More than 350 000 people die from hepatitis C-related liver diseases every year.

Related-WHO: Four ways to reduce hepatitis infections in people who inject drugs

HIV/AIDS

Two More Men with HIV now Virus-Free. Is This a Cure?
Two men unlucky enough to get both HIV and cancer have been seemingly cleared of the virus, raising hope that science may yet find a way to cure for the infection that causes AIDS, 30 years into the epidemic....

Study finds gaps in services for heterosexual men with HIV
July 27- Study finds heterosexual men feel existing HIV-related programs and services don't meet their needs and are geared primarily or exclusively toward gay men and heterosexual women who are living with the virus...

XIX International AIDS Conference
22-27 July 2012 Washington D.C., USA

View Conference Coverage @ NATAP and HIV and Hepatitis

Conference website
The entire AIDS 2012 programme is available online through the Programme-at-a-Glance (PAG). Links to abstracts, slide sets with audio, rapporteur reports and e-posters will be added as they are available.

Source: DGDispatch @ Doctors Guide

Low-Level Viraemia on Antiretroviral Therapy Should Not Be Sole Indicator of Virologic Failure: Presented at AIDS 2012
Kidney Function Declines With Use of Tenofovir Plus Protease Inhibitors as Treatment for HIV: Presented at AIDS 2012

Gilead HIV drug as good as Merck's Isentress: study
Gilead Sciences Inc said its elvitegravir, a component of the company's important four-drug Quad HIV treatment currently awaiting an approval decision, demonstrated similar efficacy and tolerability to Isentress in difficult-to-treat patients...Continue reading...

Stem Cells

The US district court in Washington DC, rules a controversial stem cell therapy offered at clinics should be regulated...

Ruling frees FDA to crack down on stem cell clinics

Excerpt - New Scientist

Peter Aldhous, San Francisco bureau chief

It's official: stem cells are drugs. At least, that's the opinion of the US district court in Washington DC, which has ruled that the Food and Drug Administration (FDA) has the authority to regulate clinics offering controversial stem cell therapies...

Treatments in which stem cells are harvested from bone marrow and injected straight back into the same patient are deemed part of routine medical practice - not regulated by the US government. But if the cells are subjected to more than "minimal manipulation", the FDA maintains that the therapy becomes a "drug", which must be specifically approved for use...

Full Article at New Scientist

Read more @ New Scientist , Scope, Nature and Knoepfler Lab Stem Cell Blog.

Diabetes

FDA staff say Roche drug helped diabetics see

A U.S. Food and Drug Administration advisory panel recommended Roche Holding AG's Lucentis eye drug for treatment of diabetic macular edema, a leading cause of vision loss among working-age people.

The FDA advisory committee of outside experts on Thursday recommended both 0.3 milligram and 0.5 milligram doses of the drug after reviewing clinical research showing it clearly helps diabetic patients who suffer from the vision-robbing condition.

However, some panel members expressed concern about evidence linking higher doses of the drug to adverse events including death....Continue reading..

Healthy You

Coffee: The Original Wonder Drug?

Medscape Features A Slideshow On The Benifits Of Coffee, published July 24, 2012
The best part of waking up...is reducing your risk of neurodegeneration. And depression, and cancer, and cardiovascular disease... It's becoming increasingly clear that coffee is more than just a morning routine. The body of data suggesting that the world's most widely used stimulant is beneficial in a variety of mental and medical conditions is growing at a staggering rate. A recent study published in the New England Journal of Medicine found that coffee consumption lowered all-cause mortality by over 10% at 13-year follow-up.^[1] Based primarily on recent Medscape Medical News coverage, the following slideshow reviews the potential medical and psychiatric benefits of coffee consumption.

Liver Disease
The liver might help break down coffee, but coffee might protect the liver (in some cases). Evidence suggests that coffee consumption slows disease progression in patients with alcoholic cirrhosis and hepatitis C and reduces the risk of developing hepatocellular carcinoma.^[30-33] A 2012 study reported that coffee intake is associated with a lower risk for nonalcoholic fatty liver disease (NAFLD),^[34] while other recent work found that coffee protects against liver fibrosis in those with already established NAFLD.
Click here to view the slide presentation

Minority Women: Latinas' Cirrhosis and Liver Disease Rates High
July 26
In the United States, the most common causes of cirrhosis are drinking too much alcohol and hepatitis. Although Latinas have lower rates of alcohol use than other groups of women, they still have high rates of cirrhosis. This may be explained, in part, by nonalcoholic fatty liver disease (NAFLD), which is common in Latinos and can cause cirrhosis. NAFLD is a buildup of fat in the liver in people who drink little or no alcohol. Ethnicity may play a role in the tendency of Latinos to develop NALFD. This group also has high rates of obesity and diabetes, which are among the risk factors for NAFLD.
Continue reading.....

Health Care Reform

How will the Affordable Care Act affect your health care?

Posted on July 27, 2012 by admin @ Project Inform

In 2010, President Obama signed the Affordable Care Act (ACA) into law. Commonly known as health care reform, the ACA provides new insurance coverage for millions of uninsured Americans.

The ACA also puts strong patient protections into place and provides tools to help citizens understand their health care options. Many protections and reforms have already been put into place. Most of the large coverage expansions will take place in 2014.

The law is generally meant to ensure that many more Americans will be able to have secure and affordable health insurance. It will also mean that people will have clearer information about their insurance choices, and insurance companies will be held more accountable for delivering quality health care.

As soon as the ACA was signed into law, people who oppose it started to challenge the law in the courts and through media. One of the lawsuits made its way to the Supreme Court and in late June 2012, the Court delivered its decision.

The Supreme Court decision

The Supreme Court reviewed the ACA and upheld most parts of it. The part that requires all Americans to get health insurance (called individual mandate) was found to be constitutional. However, the court found that the penalty for not having insurance must be imposed as a tax.

Before the ACA was signed into law, insurance companies could deny coverage to someone on the basis of pre-existing conditions like HIV or hepatitis C and gender. They could also raise premiums based on age and where someone lives. Now, because the individual mandate was upheld, these types of insurance discrimination are no longer in danger of being stripped from the law.

The Supreme Court also upheld the Medicaid expansion part of the ACA. This will provide federal funding to help states expand their Medicaid programs to serve all adults under 138% of the federal poverty level (FPL), or about $15,000 per year for one person.

However, the Supreme Court did not uphold the part that says Congress could withhold funding if states refuse to expand their Medicaid programs. Although it doesn’t make sense for a state to refuse these large amounts of funding (100% in the first three years), unfortunately several governors have already said they will not expand their Medicaid programs.

The problem with this is that about half of all people who would get new coverage under health care reform (including people with HIV) will rely on Medicaid. If a state refuses this federal funding, its low-income individuals would continue to be unable to access health insurance coverage, which is exactly what health care reform is trying to address.

The Supreme Court decision and people with HIV

The decision to uphold the individual mandate is a victory for people living with HIV and others who have been shut out of the health insurance market. The ban on insurance discrimination against adults with pre-existing conditions will begin in 2014. This means that people living with HIV and/or hepatitis C will be able to get affordable, quality health care and specialized treatment.

As for Medicaid, the good news is that many states will expand their programs, allowing people with HIV to get Medicaid coverage sooner. (Currently, most people have to become disabled to use it.) The bad news is that people with HIV who live in states that don’t expand their Medicaid will continue to be unable to afford health insurance and forced to rely on insufficient health care services. Estimates indicate that 50–70% of uninsured people with HIV will depend on Medicaid expansion and will continue to get suboptimal or no health care without those services.

Currently, only about half of Americans with HIV regularly see their doctors and only 1 out of 4 are taking HIV medications. Medicaid expansion would allow low-income people with HIV to find the quality health coverage they need in order to ensure continuous care. Research shows that early access to treatment gives people the opportunity to stay healthier and reduce the likelihood of transmitting HIV to others.

What to expect as we move towards 2014

Learning about these changes in health care programs may seem overwhelming to you. And rightly so. Changes will differ quite a bit state by state, and much of how your health care will look is being decided at the state level. Health care providers, advocacy organizations, and even state and local governments are all struggling to prepare for these transitions in HIV care.

We are all in this learning process together. We can assume that there will be hiccups along the way. Below are links to two different timelines of the changes that we can expect. It will also be important to check at your state level for the timeline in your own state.

www.healthcare.gov/law/timeline/http://healthreform.kff.org/Timeline.aspx

Keep in mind these are beneficial changes

Although these changes can be difficult to understand, the ACA will solve many issues that people living with HIV currently face. People with incomes above 138% FPL (about $15,000 per year) who have had problems getting insurance will be able to purchase it through a new market place called an Exchange.

The Exchange will be a place where people can compare plans and choose the one that is best for them. If an individual’s income is below 400% FPL (about $44,500 per year), they will receive financial help from the federal government to buy their insurance.

People with incomes below 138% FPL will be eligible for Medicaid. For the first time everyone will be eligible regardless of disability status. Also people will be allowed to have a savings account of any amount and still qualify. As of now, it is unclear what will happen if there are states that do not choose to expand their programs.

It is very important to note that health care reform does nothing to help people with HIV who are undocumented. It does not end the five-year Medicaid waiting period for most new immigrants. However, new immigrants will be able to purchase insurance coverage in the Exchanges. We will all have to continue advocating for quality care for immigrants living with HIV in the US.

We don’t expect these transitions to occur without any problems. And we all have a lot of work to do to ensure that implementation of the ACA meets the needs of people with HIV. Despite these expected challenges, health care for people with HIV will be strengthened after full implementation of health care reform.

How can I begin to prepare for changes?

Here is a list of things you can do to start to prepare for changes over the next couple of years:

Begin to educate yourself about where you currently get your health care coverage.
Find out if you will experience any changes in coverage; many will not but many others will.
Begin to educate yourself about the insurance coverage you think you will gain. People with HIV have been historically shut out of health care coverage and have much to learn about these new systems.
Stay involved with the implementation of health care reform by joining www.hivhealthreform.org and the monthly webinars offered there.
Begin to find out if there is anyone planning for changes for people with HIV at your local or state level. Check your local HIV planning council or contact local, regional or state HIV agencies.
Keep talking to your provider, clinic and/or doctor about their plans for health care reform.
Stay involved in what is going on. If you come across an unfavorable change in your care or notice something that could use improvement, contact organizations or officials to make your voice heard.

What resources can I refer to?

www.hivhealthreform.org
www.kff.org
www.familiesusa.org/health-reform-central
www.taepusa.org
www.healthcare.gov

Learn More @ Project Inform

Off Topic

'Cannibal' bath salt drugs as 'addictive as cocaine'

Wednesday Jul 25 2012

The former legal high mephedrone, also known as meow meow, is as ‘addictive as cocaine’ reported the Mail. The effects of the drug, which the paper says has been blamed for a series of ‘cannibal attacks’ have recently been studied in mice…Continue reading..

Contact hcvnewdrugs@gmail.com

Helpful Links
HCV Education
Research Articles
Fibrosis
Cirrhosis
Liver Cancer
Liver Transplants
Fatty Liver Disease
HCV-elderly
Possible Side Effects Of HCV Therapy
Other Conditions Related To HCV
HCV Genotypes/treatment
HCV Newsletters
Premier Hepatitis C Websites

The above links offer data about interferon-free regimens approved to treat HCV, with learning activities, editorials, and tips from patient bloggers who understand the ups and downs of liver disease, in addition to a list of outstanding hepatitis C websites, blogs and support forums.

On Twitter
I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading articles about the treatment and management of hepatitis C.

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Latest Update Feb 12, 2019

Lancet Study:

Direct-acting antivirals reduce risk of premature mortality and liver cancer for people with chronic hepatitis C

These findings firmly counter those of a Cochrane review of direct-acting antiviral treatment trials that could neither confirm nor reject if direct-acting antivirals had an effect on long-term HCV-related morbidity and mortality. They also provide the best evidence to date to support guidance documents that recommend direct-acting antiviral treatment for all patients with chronic HCV infection.

The Controversy
Rebuttal over Cochrane Review of DAAs
A systematic review published by the Cochrane Collaboration suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits. View each rebuttal and all ongoing media coverage.

Risk Of Developing Liver Cancer After HCV Treatment