Hepatitis C Virus Infection: Looking for Interferon Free Regimens

The Scientific World Journal
Volume 2013 (2013), Article ID 825375, 11 pages
http://dx.doi.org/10.1155/2013/825375

Review Article

J. González-Moreno and A. Payeras-Cifre

Internal Medicine-Infectious Diseases Department, Hospital Son Llàtzer, Carretera de Manacor, Km 4, 07198 Palma de Mallorca, Spain

Received 7 February 2013; Accepted 4 March 2013

Academic Editors: H. C. Lin and S.-N. Lu

Copyright © 2013 J. González-Moreno and A. Payeras-Cifre. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Recent developments of new drugs' combinations are changing the treatment paradigm in hepatitis C virus infection. Due to the side effect profile of pegylated interferons, interferon-sparing regimens have become the main target in chronic hepatitis C treatment research. Recent proofs of concept studies have suggested that cure of chronic hepatitis C can be achieved without interferon. The purpose of this paper is to provide an overview of the clinical results recently reported for the treatment of hepatitis C virus infection with interferon-free regimens, focusing on the most promising new compounds and combinations.

1. Introduction

Hepatitis C virus (HCV) is a leading cause of liver failure, hepatocellular carcinoma and the most common reason for liver transplantation and infects about 3% of the population worldwide (approximately 170 million people chronically infected) [1]. The epidemic of injection drug use in the 1970s and 1980s and transmission via blood transfusions before 1992 are the main causes of disease expansion. The effect of longstanding infection and the aging process has been a significant increase in HCV-related cirrhosis and premature deaths over the past decade despite the decreasing incidence of new infections [2]. Recent development of new direct-acting antivirals (DAA) and preliminary results of trials using new treatments have opened up a new perspective in HCV therapy. When assembling optimal treatment combinations, factors that are important include the safety and tolerability profile of each agent, compatible pharmacokinetic profiles, and a low potential for unfavourable drug-drug interactions. It is know that interferon (IFN) has major common adverse effects and a bad security profile. That is why IFN-free regimens have become one of the priorities of researchers.

2. Natural History of Infection and Development of Actual Standard Therapy

Currently, the primary causes of HCV transmission are intravenous drug use and, less frequently, unsafe medical or surgical procedures. The risk of vertical perinatal transmission is low (up to 5%) [3]. Although infrequent, some data suggest sex transmission in male who have sex with male. However, up to 44% of patients with acute HCV infection have no obvious risk factors [4].

Up to 75–85% of persons with acute HCV will develop chronic viral infection and between 5 and 25% will progress to cirrhosis over the following decades [5, 6]. The speed of histological deterioration is independent of viral genotype and viral load (VL), but is related to host factors such as male gender, obesity, age >40 at exposure, presence of concomitant liver disease unrelated to HCV as hepatitis B virus (HBV) infection, coinfection with human immunodeficiency virus (HIV) and life style aspects (daily intake of alcohol >50 g) [7, 8].

HCV has six different genotypes (GT) and more than 11 subgenotypes, in which genotype 1, with its subgenotypes 1a and 1b, is the most prevalent [10].

Initially the treatment for HCV was IFN monotherapy, administered daily. Soon it was found that the addition of ribavirin (RBV), an oral nucleoside analogue dosed twice a day, significantly increased viral responsiveness [11]. In the late 1990s, the advent of a pegylated form of IFN (pegIFN) allowed a weekly injection with sustained serum levels and a decrease in adverse effects. In the early 2000s, the efficacy of pegIFN alfa-2a and pegIFN alfa-2b when given with RBV was demonstrated, and this dual therapy (pegIFN-RBV) quickly became standard of care [12]. Although some clinical trials suggest the superiority of pegIFN alfa-2a over pegIFN alfa-2b, others found that both agents are equally effective, and no conclusive evidence supports the preferential use of either pegIFN [13, 14].

Cure in the setting of HCV pharmacotherapy is defined by sustained viral response (SVR), defined as the lack of HCV RNA in the serum 24 weeks after completion of antiviral therapy. Some predictors of SVR are well described and are summarized in Table 1. One of the most important pretreatment predictors of virologic response is the IL-28B polymorphism, described by Ge et al., in 2009 [15]. It is a single-nucleotide polymorphism, rs12979860 on chromosome 19, which represents the interferon lambda 28-B gene encoding IL-3.

 

Table 1: Some classical of predictors of sustained viral response (SVR).

Positive predictors for SVR HCV-related factors Genotypes 2 and 3 Subgenotypes 1a and 2a Low pretreatment VL RVR, eRVR, EVR Host-related factors Young age Absence of advanced liver fibrosis Caucasians IL28B CC genotype Treatment-related factors No RBV dose reduction ( mg/kg per day) Good adherence

eRVR: extended rapid virological response (undetectable HCV RNA at treatment week 4 and week 12); EVR: early virological response (HCV RNA detectable at week 4 but undetectable at week 12, maintained up to the end of treatment); HCV: hepatitis C virus; IL28B: interleukin 28B; RBV: ribavirin; RVR: rapid virological response (absence of measurable HCV RNA at week 4 of treatment); VL: viral load.

Overall SVR rates achieved with pegIFN-RBV were clearly suboptimal at 40–50% for GTs 1 and 4. They were better for GTs 2 and 3 (more than 80%) [16]. Furthermore, this dual treatment has major common adverse effects, particularly hemolytic anemia with RBV and a wide spectrum of effects like neuropsychiatric symptoms or flulike fatigue and neutropenia with IFN, representing major impediments to adherence.

The optimal duration of previous standard therapy with pegIFN-RBV depended on the viral genotype. Patients with genotypes 1, 4, 5, and 6 are generally treated for 48 weeks with pegIFN alfa-2a (180 mcg/weekly) or pegIFN alfa-2b (1–1.5 mcg/kg body weight/weekly) and weight-based daily dose of ribavirin (800–1200 mg). For genotypes 2, and 3 treatment could be completed within 24 weeks.

IFN and RVB still are the standard therapy for non-genotype 1 HCV infection, however recently this standard has changed for genotype 1 infection.

3. Actual Standard Therapy for Genotype 1 HCV Infection

An important step in HCV viral replication involves the nonstructural serine protease NS3-NS4A [17]. This protease induces expression of interferon β and leads to the expression of many interferon stimulated genes, thus producing an antiviral state in infected and surrounding cells [18]. NS3-4A also reduces the intrahepatic production of interferon γ, which might impair the hepatic inflammatory response and contribute to viral persistence [19]. Hence, inhibition of NS3-4A might block viral replication and potentially restore suppressed interferon pathways.

In 2011, the US Food and Drug Administration (FDA) and European Medicines Agency approved the first two linear protease inhibitors, boceprevir and telaprevir. Triple therapy using these drugs in combination with IFN and RBV have become the actual standard of care for GT 1 HCV infection.

Main characteristics of telaprevir and boceprevir are showed in Table 2. A brief summary of the main clinical trials using both drugs is described below.

 

Table 2: FDA approved directly acting antiviral drugs—telaprevir (Incivek) and boceprevir (Victrelis). Modified from Assis and Lin [9].

Telaprevir Boceprevir Formulation 375 mg oral capsule 200 mg oral capsule Dosing 750 mg/7–9 h with a fatty meal* 800 mg every 7–9 h with food* Regimen 12 weeks of triple therapy followed by Peg-IFN/ribavirin alone for 12 or 36 weeks** Start after 4-week lead-in of Peg-IFN and ribavirin for 24 or 44 weeks** Discontinuation If VL >1,000 IU/mL at week 4 or 12, and VL at week 24 If VL >100 IU/mL at week 8, 12, and VL at week 24 Expected SVR Naive: 69–75% Relapser: 84–88% Partial responder: 56–61% Null responder: 31–33% Naive: 63–66% Relapser: 69–75% Partial responder: 40–52% Null responder: not studied RGT If negative VL at weeks 4 and 12, treat with Peg-IFN/ribavirin for 12 more weeks If not, treat for 36 more weeks** Treatment-naive: if negative VL at week 8 and 24, complete treatment at week 28 Previously treated: if negative VL at week 8 and 24, complete treatment at week 36** Barrier to resistance Low (V3M6, R155K) Low (V3M6, R155K) Common adverse effects Anemia (37%) Rash (56%; severe in 4–7%) Anal itching/burning (29%) Anemia (49%) Dysgeusia (43%) Metabolism Hepatic (CYP450)*** Hepatic (CYP450 and aldoketoreductase)*** Interactions Strong inhibitor of CYP3A Strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5 Renal/hepatic adjustment Renal: none Hepatic: do not use if Child-Pugh score >7 Renal: none Hepatic: do not use if Child-Pugh score >7 FDA-labeled indications Chronic HCV genotype 1a or 1b in combination with Peg-IFN and ribavirin, in adults with compensated liver disease (Child-Pugh <7) Chronic HCV genotype 1a or 1b, in combination with Peg-IFN and ribavirin, in adults with compensated liver disease, including cirrhosis, who are previously untreated or who failed previous Peg-IFN/ribavirin treatment Contraindications Pregnancy (due to ribavirin) Coadministration with drugs highly dependent on CYP3A for clearance Pregnancy (due to ribavirin) Coadministration with drugs highly dependent on CYP3A4/5 for clearance Special populations Not approved in decompensated cirrhosis, HIV-HCV or HBV-HCV coinfection, pediatrics, and posttransplant Not approved in decompensated cirrhosis, HIV-HCV or HBV-HCV coinfection, pediatrics, and posttransplant

FDA: US Food and Drug Administration; HBV: hepatitis B virus; HCV: hepatitis C virus; IFN: interferon; R155K: lysine to arginine substitution at position 155; RGT: response guided treatment; SVR: sustained virologic response; VL: viral load; V36M: valine to methionine substitution at position 36. *No dose reduction is allowed because of risk of engender drug resistance. weeks of treatment always for patients with cirrhosis and previous null responders. In telaprevir treatment also for partial responders. In boceprevir also for previously untreated patients who respond poorly to interferon in the lead-in period (<1 log 10 decline in hepatitis C RNA from baseline). ***Special care using first-generation protease inhibitors which are hormonal contraceptives, statins, dihydropyridine calcium channel blockers, and phosphodiesterase-5 inhibitors.

3.1. Telaprevir (TVR)

TVR was firstly described in clinical trials in 2009 [20, 21]. The first phase 3 study was published in 2011 [22]. In this study treatment naive GT 1 infected patients achieved SVR rates of 75% with triple therapy using TVR, as compared with a 44% SVR rate after 48 weeks of standard pegIFN-RBV. As in the ADVANCE trial [22] response guided therapy (RGT) was explored in the ILUMINATE trial [23]. In this study the overall SVR rate for all patients was 72%. For those with undetectable HCV RNA at treatment week 4 and week 12 or extended rapid virological response (eRVR), benefit was not found of extending therapy beyond an additional 4 weeks, as results were comparable (92% for 24 weeks treatment and 88% for 48 weeks treatment). SVR rates in non eRVR patients were only 64%, showing the importance of rapid virological response (RVR). In these studies a low proportions of patient with cirrhosis were included, so there are insufficient data for confident assessments of treatment regimens in advanced fibrosis. In the other hand other special populations showed interesting results in the ADVANCE trial [22]. For example, the SVR rate for patients with GT 1a was consistently lower than for 1b (71 versus 79%). Also black patients had lower SVR rates than non-black patients (62 versus 75%), although much higher than those receiving peg-IFNRBV alone (25%).

Treatment-experienced subjects were included in the phase 3 REALIZE study [24]. It showed that SVR rates were 83–88% for prior relapsers, 54–59% for previous partial responders, and 29–33% for null responders, as compared with 24, 15, and 5% for standard treatment, respectively. Treatment failures were associated with detectable resistant variants in 73% of cases. In contrast to the previous studies, the REALIZE trial included a higher portion of patients with cirrhosis (26%). Although cirrhotic patients had overall worse response, cirrhosis was not always associated with poor response (patients with cirrhosis who had previously relapsed achieved SVR 86% of the time).

3.2. Boceprevir (BOC)

In contrast with TVR trials, all studies of BOC include a 4-week lead-in phase of pegIFN alfa-2b and RBV alone followed by 24–44 weeks of triple therapy, allowing standard therapy to reach steady state in terms of anti-HCV effect before the direct acting antiviral. This lead-in phase was intended to minimise resistance and treatment failure by reducing viral replication before the addition of the third molecule [25].

First clinical trials were published in 2010 [26]. In phase 3 clinical trial SPRINT-2 [27], authors found SVR rates for standard therapy of 44% as compared with 67 and 68% for the arms using BOC. In this study, RGT was assessed and no significant differences were seen in SVR rates between the fixed-duration group (48 weeks of treatment) and the RGT group (28 weeks of treatment). It resulted in RGT recommendations in the product label for BOC.

The RESPOND-2 study [28] evaluated triple therapy with BOC in treatment-experienced patients for patients with some prior response to standard therapy (no previous null responders were enrolled). Overall SVR rates for the treatment arms receiving BOC were 59–66% (69–75% for prior relapsers; 40–52% for previous partial responders) as compared with 21% for standard therapy. Early response to triple therapy (undetectable RNA at week 8) was highly predictive of SVR (100%).

4. Problems in Actual Treatment for Genotype 1 HCV Infection

Main objections with actual triple therapy for GT 1 HCV infection, other than complex regimens and high cost, are summarized below.

4.1. Side Effects and Drug Interactions

Because BOC and TVR must be combined with pegIFN and RBV, toxic effects and drug interactions associated with these protease inhibitors will be in addition to those of the previous standard of care. As a recent meta-analysis showed, TVR or BOC combined with pegIFN and RBV had favorable short-term data on SVR while resulting in more drug-related adverse effects [29]. Anemia is the most frequent side effect with either BOC or TVR [20–28]. How providers should treat anemia is unclear when using these new molecules either to use growth factors (off-label prescribing) or to reduce RBV dose. In addition, BOC and TVR are strong inhibitors of cytochrome P450 3A4 (CYP3A4), so important and commonly prescribed drugs can interact with them, like hormonal contraceptives, statins, dihydropirydine calcium channel blockers, and phosphodiesterase-5 inhibitors [25].

4.1.1. Genotypes and Subgenotypes

Protease inhibitors are highly specific, and since the amino acid sequence of the NS3 protease domain differs significantly between HCV genotypes, their antiviral efficacy differs in different genotypes [30]. Due to the lack of findings from large clinical trials to support the use of TVR or BOC in patients with infections other than GT 1, both molecules should be prescribed only for GT 1 infection. Between subgenotypes, subgenotype 1a has lower rates of response than genotype 1b as showed in previous trials. The most probable reason for this disparity between subtypes is the higher genetic barrier to the development of protease inhibitor resistance that genotype 1b virus has [31].

4.1.2. Drug Resistance

One of the most important lessons from the early studies with TVR and BOC is that used as monotherapy; these agents rapidly select for resistance variants, leading to virological failure. Naturally occurring dominant mutations resistant to the hepatitis C protease inhibitors are present even in previously untreated patients with GT 1 infection [31]. Because similar variants are detected in patients treated with either BOC or TVR, cross-resistance between these drugs is expected; thus, virological failure with triple therapy containing a protease inhibitor is a contraindication for a change from one drug to another.

5. Future Perspectives

5.1. Role of Ribavirin

Some mechanism of action of RBV is well described [32]. It enhances Th1 CD4 responses increasing activity of cytotoxic T lymphocytes and secretion of antiviral cytokines such as interferon-γ and TNF-α. It also stops viral replication by inhibiting the formation of the guanosine nucleoside by inhibiting IMPDH (inosine monophosphatase dehydrogenase), inhibits the NS5B RNA-dependent RNA polymerase, and induces lethal mutagenesis by increasing errors in the translation of E2, NS5A, and NS5B. The role of ribavirin in IFN-based treatment is almost clear as it seems that RBV acts as a potentiator of host interferon-stimulated genes. It suggests that RBV may be uniquely capable of boosting host immune pathways in the cause of viral clearance [33].

Rates of SVR are lower in groups treated with pegIFN and a protease inhibitor than in people given pegIFN and RBV. For example, in the PROVE3 phase 2 trial of TVR for previously treated patients [34], the triple-therapy group had a rate of SVR of 53% compared with 24% in those given pegIFN alfa and TVR, half of those given pegIFN and RBV. In another study [20], viral breakthrough and relapse were also higher in the group of treatment without RBV: 24% and 48% versus 1–6% and 14–30% for the triple-therapy group, respectively.

Although the side effects of ribavirin are attenuated when taken without IFN, they still remain a problem. These include rash, cough, and haemolysis, with only a minor reduction in haemoglobin, unlike that seen in pegIFN-RBV regimens.

With the aim of improving RBV profile security an analogue have been proved in some clinical trials. Taribavirin is an RBV prodrug with a similar spectrum of antiviral activity but with better hepatocyte specificity and less accumulation in erythrocytes. It showed to reduce the anemia that is associated with RBV therapy without decreasing SVR rates [35]. Unfortunately, poorer results were noted in the larger ViSER2 study in which whilst taribavirin did cause less anemia, noninferiority was not achieved [36].

It also appears that RBV will continue to be required to suppress the emergence of viral resistance to DAAs in IFN-free regimens until more potent agents and oral combinations can be found. For example, in a study of Zeuzem et al. [37], the addition of RBV to the direct acting antivirals tegobuvir and GS-9256 substantially reduced the rate of resistance during treatment and also improved the median drop in HCV levels. Results from the 10 patients with HCV genotype 2 or 3 infection who received sofosbuvir alone (with lesser rate of SVR than in the group with RBV) in the study of Gane et al. [38] also suggest a role for ribavirin in the maintenance of an antiviral response.

In the ZENITH study [39], both dual regimens (without RBV) were terminated after the arms met prespecified criteria for discontinuation because of a viral breakthrough rate >25% while no patient in either quad arm (using RBV) experienced viral breakthrough. This observation supports a role for RBV in DAA combinations, especially when low genetic barrier agents are combined. Of note, HCV subtype 1a was present in 11/12 patients who experienced viral breakthroughs.

5.2. Interferon-λ

IFN analogues have been proposed in order to avoid IFN alfa side effects and increase SVR rates. Interferon-λ, the most promising IFN analogue developed, has greater specificity than IFN-2a for the targeting of hepatocellular cells, so there is expectation to significantly reduce unwanted side effects. On the basis of initial clinical trials, interferon-λ appears to be superior to standard interferon with respect to SVR for patients with a much-reduced side effect profile. Zeuzem et al. [40] presented interim results from an ongoing randomized trial in 2011 and demonstrated that for treatment-naive patients with HCV 1–4, there was an increased rate of RVR using (using doses of 180 μg or 240 μg/week) as compared with standard pegIFN alfa-2a. Furthermore, the incidence of flu-like symptoms, musculoskeletal symptoms, and cytopenias was significantly lesser with the use of interferon-λ.

Some recent in vitro data suggest that has pan-genotypic activity against HCV and a nonoverlapping resistance profile to DAAs. It has been also observed that interferon-λ showed an additive to synergistic effect in vitro on HCV replication when combined with various classes of DAAs, including asunaprevir, daclatasvir, and BMS-791325 [41]. Some phase 2 and phase 3 clinical trials using IFN lambda in combination with different DAAs are currently ongoing.

5.3. Interferon-Free Regimens

During viral infection, some of the most prominent cytokines produced are IFNs. The importance of IFNs goes beyond their antiviral activities and includes numerous immunoregulatory functions that affect both innate and adaptive immunities. IFN-induced clearance of HCV is both cytolytic (clearance of HCV-infected hepatocytes) and noncytolytic (intracytoplasmic destruction of HCV without cell injury) [42].

The challenges of IFN-based treatments have remained in place during the first year of the DAA era. These include all of the previously reported contraindications and adverse effects of IFN and RBV therapy. Effective IFN-free regimens would change these problems and are now a priority of investigators.

As noted before, IFN and also RBV are required to block the emergence of DAA resistant viral strains [20, 43] as first generation protease inhibitors are drugs with a low genetic barrier. The main problem with new DAAs development is that new drugs may have cross-resistance with some of the most common mutations seen with TVR and BOC (R155K and D168A) [44]. They have shown cross-resistance to faldaprevir, simeprevir, asunaprevir, and ABT-450. This means that probably second-generation PIs should not be used in patients who have failed current triple therapies. Because R155K mutation requires only one nucleotide exchange for subtype 1a versus two nucleotide exchanges for subtype 1b [45], probably 1a subtype will continue to confer a lower barrier to resistance for second-generation PIs as previously seen for current triple therapy.

5.3.1. First Steps

In October 2010, Gane et al. published results from the INFORM-1 (INterferon-Free regimen fOR the Management of HCV) trial [46]. It was a randomised, double-blind, placebo-controlled, dose-escalation trial. The study included 88 standard of care treatment-naive and treatment-experienced (null and nonnull responder) HCV GT 1 infected patients without cirrhosis, renal impairment, or viral coinfection (HBV or HIV). Patients were assigned to a study drug treatment regimen (<?XML:NAMESPACE PREFIX = "[default] http://www.w3.org/2000/svg" NS = "http://www.w3.org/2000/svg" /> over seven treatment groups; 73 received at least one dose of study drug) or to placebo ( , all of whom received at least one dose). They received up to 13 days oral combination treatment with mericitabine, a nucleoside polymerase inhibitor (500 mg or 1000 mg twice daily), and danoprevir, an NS3-4A protease inhibitor (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily), or placebo. Dose escalation was started in HCV treatment-naive patients; standard-of-care treatment experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of a combination treatment. In the highest-dose cohorts, five of eight treatment-naive patients and two of eight null responders achieved HCV RNA concentrations below the limit of detection (<15 IU/mL) and seven of eight treatment-naive patients and four of eight null responders showed HCV RNA concentrations below the limit of quantification (43 IU/mL). The median change in HCV RNA concentration from baseline to day 14 ranged from −3.7 to −5.2 log 10 IU/mL in the cohorts that received 13 days of combination treatment. The combination of mericitabine and danoprevir was well tolerated with no-treatment-related serious or severe adverse events. This short-term phase 1 study showed for the first time that an interferon-free regimen could suppress viral replication. It was previously observed that the combination of mericitabine with DAAs that have a lower barrier to resistance, such as protease inhibitors, reduces drug resistance in vitro [47]. The INFORM-1 study confirms this benefit in vivo because the combination of mericitabine and danoprevir prevented resistance-associated virological breakthrough that has been reported with monotherapy with a protease inhibitor, including danoprevir.

Later, Zeuzem et al. [48] enrolled thirty-two HCV genotype-1-infected treatment-naive patients with chronic HCV GT 1 infection to be randomly assigned to groups that were given 400 mg or 600 mg BI 207127 (a polymerase inhibitor) 3 times daily plus 120 mg faldaprevir (a protease inhibitor) once daily and 1000 to 1200 mg/day RBV for 4 weeks. Thirty-one patients completed all 4 weeks of assigned combination therapy. In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29, respectively. A higher rate of response was observed in patients with GT 1b compared with GT 1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among GTs. One patient in the group given 400 mg 3 times daily had virologic breakthrough at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely.

The ZENITH study [39] was designed to compare VX-222, a nonnucleotide polymerase inhibitor administered 400 mg twice daily, and TVR alone versus VX-222 and TVR with RBV (triple) or with pegIFN (quadruple) for treatment-naive GT 1 patients. RGT in this study was defined as completion of treatment at week 12 for those with undetectable VL at weeks 2 and 8. At week 24 interim analysis, of those in the quadruple arms who achieved RGT targets, 82–93% of subjects had SVR after 12 week of treatment (SVR12).

5.3.2. Achieving SVR without IFN

Lok et al. published a phase 2 study [49] using an oral-only trial for GT 1 HCV in patients who were prior null responders to standard therapy. This is the first group to demonstrate SVR data with patients receiving a regimen that is completely free of pegIFN. They randomnly assigned 21 patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with pegIFN alfa-2a and RVB (group B, 10 patients) for 24 weeks. They excluded cirrhotic patients. The SVR rate at week 48 after treatment for the group A was low (27%), lower than group B (90%), but it created the expectation which is that new oral regimens will result in improved SVR in subsequent years, allowing even IFN-free regimens. In this study also was important the significance of subgenotypes. Although there were only 2 patients with HCV GT 1b infection in group A, the observation that both of the patients had an SVR after treatment with two direct-acting antiviral agents alone may reflect a higher resistance barrier for this combination of drugs in patients with HCV GT 1b infection than in patients with HCV GT 1a infection. All six patients (GT 1a) who presented viral breakthrough while receiving therapy had resistance mutations to both antiviral agents. The inclusion of pegIFN alfa-2a and RVB with daclatasvir and asunaprevir provided sufficient antiviral activity to suppress the emergence of resistance, an observation that is consistent with in vitro data showing a synergism of IFN and RBV with both direct-acting antiviral agents [50].

A similar finding of a high rate of SVR among patients with HCV GT 1b infection was shown in a pilot study of combination therapy with asunaprevir and daclatasvir in 10 Japanese patients who had HCV GT 1b infection and who had not had a response to previous therapy with pegIFN and RBV (<2 log 10 reduction in HCV RNA level by week 12) [51]. In this phase 2a study, patients were treated with daclatasvir in combination with asunaprevir for 24 weeks. The primary endpoint was the proportion of patients with undetectable HCV RNA at 12 weeks posttreatment. All enrolled patiens were subgenotype 1b. All 9 patients who completed treatment had an SVR. HCV RNA also remained undetectable posttreatment in the patient who discontinued after 2 weeks as he developed hepatotoxicity. There was no viral breakthrough during treatment or relapse of HCV RNA posttreatment.

Another Japanese study using asunaprevir in an IFN-free trial has been recently published [52]. In this trial, 43 chronic HCV GT 1b infected patients, 21 null responders and 22 intolerant to or medically ineligible for pegIFN-RBV therapy, were enrolled. They received dual oral treatment for 24 weeks with daclatasvir and asunaprevir. The primary efficacy end point was SVR12. Overall, 76.7% of patients achieved SVR12 and SVR24, including 90.5% of null responders and 63.6% of ineligible/intolerant patients. There were no virologic failures among null responders. Three (13.6%) ineligible/intolerant patients experienced viral breakthrough and four (18.2%) relapsed posttreatment. Diarrhea, nasopharyngitis, headache, and ALT/AST increases, generally mild, were the most common adverse events; three discontinuations before week 24 were due to adverse events that included hyperbilirubinemia and transaminase elevations (two patients).

The antiviral activity of tegobuvir (a nonnucleoside NS5B polymerase inhibitor) and GS-9256 (an NS3 serine protease inhibitor) as oral combination therapy, or together with RVB or pegIFN alpha-2a and RBV, was assessed in a phase 2, randomized, open-label trial [37]. Treatment-naive patients with GT 1 HCV were assigned 28 days of tegobuvir 40 mg twice daily and GS-9256 75 mg twice daily , tegobuvir and GS-9256 plus RBV 1,000–1,200 mg daily , or tegobuvir and GS-9256 plus pegIFN alpha-2a (180 μg once weekly)/RBV . After 28 days, when RVR was evaluated, all patients received pegIFN-RBV. RVR was observed in 7% (1/15) of patients receiving tegobuvir/GS-9256, 38% (5/13) receiving tegobuvir/GS-9256/RBV, and 100% (14/14) receiving tegobuvir/9256/PEG-IFN/RBV. Authors concluded that in genotype 1 HCV, adding RBV or RBV with pegIFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256.

In 2011, Lawitz et al. showed that monotherapy with sofosbuvir (a polymerase inhibitor) at a dose of 400 mg for 7 days resulted in a profound reduction in the level of HCV RNA in patients with HCV GT 1 infection [53].

Gane et al. published recently the results from the ELECTRON trial [38], a phase 2a study designed to test the safety and efficacy of sofosbuvir and RBV in various IFN-sparing and IFN-free regimens for the treatment of patients with HCV GT 1, 2, or 3 infection. They did not included patients with cirrosis, HBVm or HIV. A total of 40 previously untreated patients with HCV GT 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus RBV for 12 weeks. Three of these groups also received pegIFN alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV GT 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus pegIFN alfa-2a and RBV for 8 weeks. Two groups of patients with HCV GT 1 infection received sofosbuvir and RBV for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. They found that viral kinetics during treatment were nearly identical in all treatment groups and that viral suppression was rapid in all patients, regardless of GT, status with respect to previous treatment, baseline VL, race or ethnic group, IL28B status, and presence or absence of IFN in the regimen. Of the 40 patients, all 10 who received sofosbuvir plus RBV without IFN and all 30 who received sofosbuvir plus RBV for 12 weeks and IFN for 4, 8, or 12 weeks had an SVR at 24 weeks. The presence or absence of pegIFN alfa-2a appeared to have no effect on viral kinetics or rate of SVR. For the other patients with HCV GT 2 or 3 infection, all 10 who received sofosbuvir plus pegIFN alfa-2a and RBV for 8 weeks had an SVR at 24 weeks, as did 6 of 10 who received sofosbuvir monotherapy. Among patients with HCV GT 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had an SVR at 24 weeks. In the last group, most of the patients were GT 1a and had unfavourable IL28B allele types, and all of these patients relapsed when the 12-week oral regimen was completed. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. The IFN-free arm demonstrated the lessening impact on haemoglobin when just RBV plus sofosbuvir was given. Furthermore, there was no effect on absolute neutrophil count when pegIFN alfa-2a was not included in the regimen. No patients discontinued sofosbuvir or RBV in any group.

Preliminary results have also been reported from a phase 2a study evaluating sofosbuvir and daclatasvir for 24 weeks with or without RBV in previously untreated patients with HCV GT 1, 2, or 3 infection [54]. All 44 patients with HCV GT 1 infection had an SVR at 4 weeks after treatment. Among patients with HCV GT 2 or 3 infection, rates of SVR at 4 weeks ranged from 88 to 100%.

Although the high SVR rates were showen using sofosbuvir in the previous studies for GT 1 treatment-naive patients, a press release of the QUANTUM study 24-week data in this population showed an SVR rate of only 59% [55]. So, it is likely that this regimen will not be adequate for genotype 1 patients.

Finally, Poordad et al. published recently a phase 2a study [56] in which the safety and efficacy of the combination of ABT-450/r and ABT-333 with RBV in previously untreated patients with HCV GT 1 infection and in patients with a null or partial response to previous treatment with pegIFN-RBV was assessed. They excluded patients with cirrhosis, renal impairment and coinfection with HBV or HIV. In total, 50 patients were included and all of them received ABT-333 (400 mg twice daily) and RBV (1000 to 1200 mg per day) and one of two daily doses of ABT-450/r. Patients were divided in to 3 groups. Groups 1 and 2 included previously untreated patients; group 1 received 250 mg of ABT-450 and 100 mg of ritonavir and group 2 received 150 mg and 100 mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with pegIFN-RBV, received daily doses of 150 mg of ABT-450 and 100 mg of ritonavir. The primary endpoint was the percentage of patients with eRVR. A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an eRVR; an SVR 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In groups 1, and 2 there were no virologic failures during treatment or during 48 weeks of followup for those who completed treatment. As expected, results were significantly worse in group 3. In this group, 10 of 17 patients (59%) had an eRVR, and 8 (47%) had an SVR 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Resistant variants in NS3 and NS5B were detected in eight patients who had virologic failure; one patient with a relapse had no variants at any signature position. No deaths or serious adverse events occurred during the study. Overall, the most frequent events were fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. In contrast to other trials of IFN-free protease-inhibitor-containing combination therapy in previously untreated patients, where reduced activity against HCV GT 1a as compared with HCV GT 1b was found, no virologic failures occurred among the 31 previously untreated patients who completed treatment, including 26 patients with HCV GT 1a infection in this study. Regarding IL28B genotype in this study, in contrast to previous trials, more than half of the previously untreated patients who completed the study treatment had a CT or TT IL28B genotype, and all had an SVR.

Previous noted results strongly suggest that in the near future IFN-free regimens for HCV infection will become the standard treatment. With that aim there are currently some clinical trials ongoing, investigating new molecules combinations in IFN-free regimens (Table 3).

 

Table 3: Clinical trials ongoing using IFN-free regimens.

Drugs DAA Trial Genotypes Patients Sponsor Faldaprevir + BI207127 + Ribavirin PI NS3/4A + NNPI NS5B Phase 3 1 Treatment-naive Boehringer Ingelheim Simeprevir + TMC647055 + Ritonavir + Ribavirin PI NS3/4A + Ritonavir potentiated NNPI NS5B Phase 2a 1 Treatment-naive and previous relapsers Janssen R & D Simeprevir + Sofosbuvir + Ribavirin PI NS3/4A + NPI NS5B Phase 2a 1 Null responders Janssen R & D Asunaprevir + Daclatasvir PI NS3 + NS5A inhibitor Phase 3 1b Treatment-naive Bristol-Myers Squibb ABT450 + Ritonavir + ABT267 Ritonavir potentiated PI NS3 + NS5A inhibitor Phase 2 1b, 2 Treatment-experienced AbbVie (prior sponsor, Abbott) ABT450 + Ritonavir + ABT267 + ABT333 Ritonavir potentiated PI NS3 + NS5A inhibitor + NNPI NS5B Phase 2 1 Treatment-experienced Abbott Danoprevir + Ritonavir + Mericitabine + Ribavirin Ritonavir potentiated PI NS3/4A + NPI NS5B Phase 2 1 Treatment-experienced Hoffmann-La Roche Sofosbuvir + GS5885 + Ribavirin NPI NS5B + NS5A inhibitor Phase 3 1 Treatment-experienced Gilead Sciences Sofosbuvir + Ribavirin NPI NS5B Phase 3 2, 3 Treatment-naive and Treatment-experienced Gilead Sciences Setrobuvir + Danoprevir + Ritonavir + Mericitabine NNPI NS5B + Ritonavir potentiated PI NS3/4A + NPI NS5B Phase 2 1 Treatment-naive and null responders Hoffmann-La Roche Asunaprevir + Daclatasvir + BMS791325 PI NS3 + NS5A inhibitor + NNPI NS5B Phase 2 1 Treatment-naive Bristol-Myers Squibb Daclatasvir + Sofosbuvir + Ribavirin NS5A inhibitor + NPI NS5B Phase 2 1, 2, 3 Treatment-naive Bristol-Myers Squibb GS5885 + GS9451 + Tegobuvir + Ribavirin NS5A inhibitor + PI NS3/4A + NNPI NS5B Phase 2 1 Interferon ineligible or intolerant subjects Gilead Sciences

DAA: direct acting antiviral; NNPI: nonnucleoside polymerase inhibitor; NPI: nucleoside polymerase inhibitor; PI: protease inhibitor.

5.4. Special Populations

5.4.1. HIV Coinfection

Since the development and widespread application of effective medications for the treatment of HIV disease, coinfection with HCV has become an important cause of morbidity and mortality in HIV infected patients. People with HIV coinfection are more likely to progress to cirrhosis and suffer the complications of end-stage liver disease, hepatocellular carcinoma and death [57].

Eradication of HCV with therapy is associated with a regression of liver fibrosis and improved survival in HIV/HCV coinfected patients [58, 59].

The antiviral effects of IFN vary among coinfected patients, based on effects of HIV infection and/or disease, and many coinfected patients are not eligible for IFN based therapy due to comorbid conditions, particularly psychiatric diseases. The bone-marrow-suppressive effects of IFN are exacerbated in many HIV-infected patients, further complicating the treatment. The development of combination regimens of DAAs that are safe for coinfected patients is therefore of high priority.

Drug interactions between DAA and antiretroviral agents, selection of HCV drug resistance, poor drug adherence, and high cost are among the most important challenges that may arise when using DAA in coinfected patients.

Currently, poor clinical data about the use of DAAs in HIV/HCV-coinfected patients is available.

Promising interim results of triple therapy using TVR are available from a study of coinfected patients with GT 1 [60]. Twelve weeks after treatment was completed, 74% of previously untreated patients with coinfection had undetectable hepatitis C RNA when treated with a TVR-based regimen, compared with 45% of patients treated with pegIFN plus RBV and placebo. Tolerability was comparable to that of TVR treatment in patients with hepatitis C monoinfection. The mean CD4 in this population was above 550 cells/mm³, and there were no drops in the percentage of these cells during therapy nor HIV-RNA rebounds in patients on antiretroviral therapy.

A trial testing BOC in HIV/HCV-coinfected patients included 98 patients that had reached 12 weeks posttreatment [61]. The SVR12 rate was 60.7% in patients treated with BOC plus pegIFN-RBV compared with 26.5% in patients treated with pegIFN-RBV alone. The mean CD4 count was above 600 cells/mm³, as all patients were on antiretroviral therapy (84% on HIV protease inhibitors). There were no drops in the percentage of CD4+ T-cells neither HIV-RNA rebounds. Overall, 14% of patients had to discontinue BOC due to serious adverse events, mainly anemia.

As some experts opine [62], available clinical data may support the use of BOC or TVR in coinfected patients with high CD4 T-cell counts who are not taking ART or those on select ART regimens for which sufficient safety data have been provided. At this moment, the off-label use of TVR may be considered in theory, in patients using atazanavir boosted with ritonavir, raltegravir or efavirenz (using higher TVR dose) based therapies in combination with tenofovir and emtricitabine. On the other hand, it is evident that BOC should not be combined with nonnucleoside reverse transcriptase inhibitors or ritonavir-boosted HIV protease inhibitors.

There are phase 3 clinical trials ongoing using faldaprevir, asunaprevir with daclatasvir, and simeprevir in combination with pegIFN-RBV in coinfected patients. To date there are no clinical trials using IFN sparing regimens in HIV/VHC-coinfected patients.

5.4.2. Nongenotype 1 Patients

Worldwide, 50–70 million subjects are infected with an HCV GT 2, 3, 4, 5, or 6 [63]. In these patients, the combination of pegINF and RBV remains the currently approved standard-of-care treatment and it is results are not optimal especially in GT 4 patients.

In 2011, Foster et al. observed reduced levels of HCV RNA in 9 GT 2 infected patients under treatment with TVR in monotherapy or with pegIFN-RBV [64]. TVR monotherapy or in combination in triple therapy had no activity in 8 genotype 3 patients studied.

In a phase 2a study conducted in 24 genotype 4 patients [65], triple therapy with TVR for 2 weeks induced a greater reduction in the HCV RNA level compared with the standard treatment, however, it did not lead to a greater SVR (62% in both groups).

Preclinical studies with simeprevir showed inhibition of HCV replication across all GT with an IC50 value below 13 nM except for GT-3a protease [66]. However, in a phase 2a trial it showed a weak activity in GT 2 infected patients [67].

Danoprevir has equipotent activity against HCV GT 1, 4, and 6 in vitro [68]. In the DAUPHINE trial [69], all 33 enrolled GT 4 patients achieved SVR12 with different doses of danoprevir boosted with ritonavir (DNVr) for 24 weeks, independently of the DNVr dose and the treatment.

As cited before sofosbuvir showed in the ELECTRON tiral [38] excellent SVR rates for GT 2 and 3, specially in combination with RBV.

In summary early results of clinical trials suggest that oral pegINF free treatments can lead to definitive clearance of the virus in most naive and treatment-experienced GT 2 and 3 HCV infected patients. Also triple therapy with sofosbuvir in combination with pegIFN-RBV have shown promising results for GT 4 HCV infection. Clinical results of the use of DAAs for GT 5 and GT 6 HCV infection are limited.

5.4.3. Other Populations

Limited data is available for some other special populations. For example, triple therapy regimen studies were not performed on subjects with Child-Pugh score >7, and even if there are no data to suggest that TVR or BOC require dose adjustment in advanced cirrhosis, use of this regimen cannot be recommended while pegIFN is a component of the regimen.

As noted previously, although cirrhotic patients had overall worse response in the REALIZE study [24], cirrhosis was not always associated with poor response. No decompensated cirrhotic patients were neither included in IFN free regimen studies. Trials that are large and include adequate numbers of patients with advanced fibrosis will be necessary to prove a drug regimen is competitive. As for cirrhotics, there are insufficient data on new HCV therapy regimens for postliver transplant, renally impaired, black, young (<18), and old (>65) patients.

6. Conclusions

Recent approval of two DAA drug for the treatment of HCV infection has opened a new perspective in HCV therapy. As a result of the side effects of IFN, there is ongoing search for effective IFN-free antiviral regimens. Promising data have been presented in proof-of-concept studies, confirming that SVR without using IFN may be feasible. Ideal drug regimen should work for all GTs and must prevent the emergence of drug resistant viral strains, have a high degree of safety and efficacy, an easy treatment algorithm, and short treatment duration. More studies are needed to support IFN-free regimens, particularly in some difficult-to-treat populations.

Conflict of Interests

The authors declare that they have no conflict of interests.

References

1. D. Lavanchy, “Evolving epidemiology of hepatitis C virus,” Clinical Microbiology and Infection, vol. 17, no. 2, pp. 107–115, 2011. View at Publisher · View at Google Scholar · View at Scopus
2. M. Wise, S. Bialek, L. Finelli, B. P. Bell, and F. Sorvillo, “Changing trends in hepatitis C-related mortality in the United States, 1995–2004,” Hepatology, vol. 47, no. 4, pp. 1128–1135, 2008. View at Publisher · View at Google Scholar · View at Scopus
3. European Paediatric Hepatitis C Virus Network, “Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus,” BJOG: An International Journal of Obstetrics and Gynaecology, vol. 108, no. 4, pp. 371–377, 2001.
4. M. J. Alter, R. J. Gerety, and L. A. Smallwood, “Sporadic non-A, non-B hepatitis: frequency and epidemiology in an urban U.S. population,” Journal of Infectious Diseases, vol. 145, no. 6, pp. 886–893, 1982. View at Scopus
5. L. B. Seeff, “Natural history of hepatitis C,” American Journal of Medicine, vol. 107, no. 6, pp. 10S–15S, 1999.
6. T. J. Liang, B. Rehermann, L. B. Seeff, and J. H. Hoofnagle, “Pathogenesis, natural history, treatment, and prevention of hepatitis C,” Annals of Internal Medicine, vol. 132, no. 4, pp. 296–305, 2000. View at Scopus
7. T. Poynard, P. Bedossa, and P. Opolon, “Natural history of liver fibrosis progression in patients with chronic hepatitis C,” The Lancet, vol. 349, no. 9055, pp. 825–832, 1997. View at Publisher · View at Google Scholar · View at Scopus
8. M. G. Ghany, D. B. Strader, D. L. Thomas, and L. B. Seeff, “Diagnosis, management, and treatment of hepatitis C: an update,” Hepatology, vol. 49, no. 4, pp. 1335–1374, 2009. View at Publisher · View at Google Scholar · View at Scopus
9. D. N. Assis and J. K. Lin, “New phamacotherapy for hepatitis C,” Clinical Pharmacology & Therapeutics, vol. 92, no. 3, pp. 294–305, 2012.
10. H. R. Rosen, “Chronic hepatitis C infection,” The New England Journal of Medicine, vol. 364, no. 25, pp. 2429–2438, 2011. View at Publisher · View at Google Scholar
11. L. Chemello, L. Cavalletto, E. Bernardinello, M. Guido, P. Pontisso, and A. Alberti, “The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C,” Journal of Hepatology, Supplement, vol. 23, supplement 2, pp. 8–12, 1995. View at Scopus
12. M. W. Fried, M. L. Shiffman, K. R. Reddy et al., “Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection,” The New England Journal of Medicine, vol. 347, no. 13, pp. 975–982, 2002. View at Publisher · View at Google Scholar · View at Scopus
13. L. D. Pedicone, C. A. Brass, J. K. Albrecht et al., “Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection,” The New England Journal of Medicine, vol. 361, no. 6, pp. 580–593, 2009. View at Publisher · View at Google Scholar · View at Scopus
14. M. Laguno, C. Cifuentes, J. Murillas et al., “Randomized trial comparing pegylated interferon -2b versus pegylated interferon -2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients,” Hepatology, vol. 49, no. 1, pp. 22–31, 2009. View at Publisher · View at Google Scholar · View at Scopus
15. D. Ge, J. Fellay, A. J. Thompson et al., “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance,” Nature, vol. 461, no. 7262, pp. 399–401, 2009. View at Publisher · View at Google Scholar · View at Scopus
16. V. di Martino, C. Richou, J. P. Cervoni, 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, vol. 54, no. 3, pp. 789–800, 2011. View at Publisher · View at Google Scholar
17. B. D. Lindenbach and C. M. Rice, “Unravelling hepatitis C virus replication from genome to function,” Nature, vol. 436, no. 7053, pp. 933–938, 2005. View at Publisher · View at Google Scholar · View at Scopus
18. E. Foy, K. Li, C. Wang et al., “Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease,” Science, vol. 300, no. 5622, pp. 1145–1148, 2003. View at Publisher · View at Google Scholar · View at Scopus
19. E. D. Brenndorfer, A. Brass, J. Soderholm, et al., “Hepatitis C virus non-structural 3/4A protein interferes with intrahepatic interferon-γ production,” Gut, vol. 61, no. 4, pp. 589–596, 2012. View at Publisher · View at Google Scholar
20. C. Hézode, N. Forestier, G. Dusheiko, et al., “Telaprevir and peginterferon with or without ribavirin for chronic HCV infection,” The New England Journal of Medicine, vol. 360, no. 18, pp. 1839–1850, 2009. View at Publisher · View at Google Scholar
21. J. G. McHutchison, G. T. Everson, S. C. Gordon et al., “Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection,” The New England Journal of Medicine, vol. 360, no. 18, pp. 1827–1838, 2009. View at Publisher · View at Google Scholar · View at Scopus
22. I. M. Jacobson, J. G. McHutchison, G. Dusheiko et al., “Telaprevir for previously untreated chronic hepatitis C virus infection,” The New England Journal of Medicine, vol. 364, no. 25, pp. 2405–2416, 2011. View at Publisher · View at Google Scholar · View at Scopus
23. K. E. Sherman, S. L. Flamm, N. H. Afdhal, et al., “Response-guided telaprevir combination treatment for hepatitis C virus infection,” The New England Journal of Medicine, vol. 365, no. 11, pp. 1014–1024, 2011. View at Publisher · View at Google Scholar
24. S. Zeuzem, P. Andreone, S. Pol et al., “Telaprevir for retreatment of HCV infection,” The New England Journal of Medicine, vol. 364, no. 25, pp. 2417–2428, 2011. View at Publisher · View at Google Scholar · View at Scopus
25. B. L. Pearlman, “Protease inhibitors for the treatment of chronic hepatitis C genotype-1 infection: the new standard of care,” The Lancet Infectious Diseases, vol. 12, no. 9, pp. 717–728, 2012. View at Publisher · View at Google Scholar
26. P. Y. Kwo, E. J. Lawitz, J. McCone, et al., “Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial,” The Lancet, vol. 376, no. 9742, pp. 705–716, 2010. View at Publisher · View at Google Scholar
27. F. Poordad, J. McCone Jr., B. R. Bacon et al., “Boceprevir for untreated chronic HCV genotype 1 infection,” The New England Journal of Medicine, vol. 364, no. 13, pp. 1195–1206, 2011. View at Publisher · View at Google Scholar · View at Scopus
28. B. R. Bacon, S. C. Gordon, E. Lawitz et al., “Boceprevir for previously treated chronic HCV genotype 1 infection,” The New England Journal of Medicine, vol. 364, no. 13, pp. 1207–1217, 2011. View at Publisher · View at Google Scholar · View at Scopus
29. M. Sitole, M. Silva, L. Spooner, M. K. Comee, and M. Malloy, “Telaprevir versus boceprevir in chronic hepatitis C: a meta-analysis of data from phase II and III trials,” Clinical Therapeutics, vol. 35, no. 2, pp. 190–197, 2013. View at Publisher · View at Google Scholar
30. T. Asselah and P. Marcellin, “Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow,” Liver International, vol. 32, supplement 1, pp. 88–102, 2012. View at Publisher · View at Google Scholar
31. T. Kuntzen, J. Timm, A. Berical et al., “Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients,” Hepatology, vol. 48, no. 6, pp. 1769–1778, 2008. View at Publisher · View at Google Scholar · View at Scopus
32. W. P. Hofmann, E. Herrmann, C. Sarrazin, and S. Zeuzem, “Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms,” Liver International, vol. 28, no. 10, pp. 1332–1343, 2008. View at Publisher · View at Google Scholar · View at Scopus
33. E. Thomas, J. J. Feld, Q. Li, Z. Hu, M. W. Fried, and T. J. Liang, “Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models,” Hepatology, vol. 53, no. 1, pp. 32–41, 2011. View at Publisher · View at Google Scholar · View at Scopus
34. J. G. McHutchison, M. P. Manns, A. J. Muir et al., “Telaprevir for previously treated chronic HCV infection,” The New England Journal of Medicine, vol. 362, no. 14, pp. 1292–1303, 2010. View at Publisher · View at Google Scholar · View at Scopus
35. F. Poordad, E. Lawitz, M. L. Shiffman et al., “Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C,” Hepatology, vol. 52, no. 4, pp. 1208–1215, 2010. View at Publisher · View at Google Scholar · View at Scopus
36. P. Marcellin, R. G. Gish, N. Gitlin et al., “Safety and efficacy of viramidine versus ribavirin in ViSER2: randomized, double-blind study in therapy-naive hepatitis C patients,” Journal of Hepatology, vol. 52, no. 1, pp. 32–38, 2010. View at Publisher · View at Google Scholar · View at Scopus
37. S. Zeuzem, P. Buggisch, K. Agarwal, et al., “The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C,” Hepatology, vol. 55, no. 3, pp. 749–758, 2012. View at Publisher · View at Google Scholar
38. E. J. Gane, C. A. Stedman, R. H. Hyland, et al., “Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C,” The New England Journal of Medicine, vol. 368, no. 1, pp. 34–44, 2013. View at Publisher · View at Google Scholar
39. D. R. Nelson, E. J. Gane, I. M. Jacobson, A. M. di Bisceglie, K. Alves, and M. J. Koziel, “VX-222/telaprevir in combination with peginterferon-alpha-2a and ribavirin in treatment-naïve genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis,” Hepatology, vol. 54, p. 1435, 2011, abstract LB-14.
40. S. Zeuzem, S. Arora, B. Bacon, et al., “Pegylated interferon-lambda (PegIFN-λ) shows superior viral response with improved safety and tolerability versus pegIFN-a-2a in HCV patients, (G1/2/3/4): EMERGE phase IIb through week 12,” in Proceedings of the 46th Annual Meeting of the European Association for the Study of the Liver (EASL '11), Berlin, Germany, April 2011, http://www.natap.org/2011/EASL/EASL_29.htm.
41. J. Friborg, S. Levine, C. Chen, A. K. Sheaffer, S. Chaniewski, and F. McPhee, “Combination of interferon lambda with direct-acting antiviral agents are highly efficient in suppressing hepatitis C virus replication,” Antimicrob Agents Chemother, vol. 57, no. 3, pp. 1312–1322, 2013. View at Publisher · View at Google Scholar
42. L. Malmgaard, “Induction and regulation of IFNs during viral infections,” Journal of Interferon and Cytokine Research, vol. 24, no. 8, pp. 439–454, 2004. View at Publisher · View at Google Scholar · View at Scopus
43. T. L. Kieffer, C. Sarrazin, J. S. Miller et al., “Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients,” Hepatology, vol. 46, no. 3, pp. 631–639, 2007. View at Publisher · View at Google Scholar · View at Scopus
44. C. Sarrazin, C. Hézode, S. Zeuzem, and J. M. Pawlotsky, “Antiviral strategies in hepatitis C virus infection,” Journal of Hepatology, vol. 56, supplement 1, pp. S88–S100, 2012.
45. C. Sarrazin and S. Zeuzem, “Resistance to direct antiviral agents in patients with hepatitis C virus infection,” Gastroenterology, vol. 138, no. 2, pp. 447–462, 2010. View at Publisher · View at Google Scholar · View at Scopus
46. E. J. Gane, S. K. Roberts, C. A. M. Stedman et al., “Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial,” The Lancet, vol. 376, no. 9751, pp. 1467–1475, 2010. View at Publisher · View at Google Scholar · View at Scopus
47. M. McCown, S. Rajyaguru, S. Kular, N. Cammack, and I. Najera, “Suppression of in vitro resistance development after treatment of the HCV replicon with NS3/4a inhibitor ITMN-191 (R7227) in combination with nucleoside inhibitor R7128 or R1626,” Journal of Hepatology, vol. 50, p. S349, 2009.
48. S. Zeuzem, T. Asselah, P. Angus, et al., “Efficacy of the protease inhibitor BI, 201335, polymerase inhibitor BI, 207127, and ribavirin in patients with chronic HCV infection,” Gastroenterology, vol. 141, no. 6, pp. 2047–2055, 2011. View at Publisher · View at Google Scholar
49. A. S. Lok, D. F. Gardiner, E. Lawitz, et al., “Preliminary study of two antiviral agents for hepatitis C genotype 1,” The New England Journal of Medicine, vol. 366, no. 3, pp. 216–224, 2012. View at Publisher · View at Google Scholar
50. F. McPhee, A. K. Sheaffer, J. Friborg, et al., “Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032),” Antimicrobial Agents and Chemotherapy, vol. 56, no. 10, pp. 5387–5396, 2012. View at Publisher · View at Google Scholar
51. K. Chayama, S. Takahashi, J. Toyota, et al., “Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null-responders.,” Hepatology, vol. 55, no. 3, pp. 742–748, 2012. View at Publisher · View at Google Scholar
52. Y. Suzuki, K. Ikeda, F. Suzuki, et al., “Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options,” Journal of Hepatology, 2012. View at Publisher · View at Google Scholar
53. E. Lawitz, M. Rodriguez-Torres, J. Denning, et al., “Once daily dual-nucleotide combination of PSI-938 and PSI-7977 provides 94% HCV RNA<?XML:NAMESPACE PREFIX = "[default] http://www.w3.org/1998/Math/MathML" NS = "http://www.w3.org/1998/Math/MathML" />< LOD at Day 14: first purine/pyrimidine clinical combination data (the NUCLEAR study),” Journal of Hepatology, vol. 54, supplement 1, p. S543, 2011, abstract 1370.
54. M. Sulkowski, D. Gardiner, E. Lawitz, et al., “Potent viral suppression with the alloralcombination of daclatasvir (NS5A inhibitor) and GS-7977 (nucleotide NS5B inhibitor), +/−, ribavirin, in treatment-naive patients with chronic HCV GT1, 2, or 3,” in Proceedings of the 47th Annual Meeting of the European Association for the Study of the Liver, Barcelona, Spain, April 2012.
55. Gilead Sciences, “Gilead announces early sustained virologic response rates for GS-7977 plus ribavirin in genotype 1 treatment-naive hepatitis C patients: interim results reported from ELECTRON and QUANTUM studies,” 2012, http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle&ID=1684792&highlight.
56. F. Poordad, E. Lawitz, K. V. Kowdley, et al., “Exploratory study of oral combination antiviral therapy for hepatitis C,” The New England Journal of Medicine, vol. 368, no. 1, pp. 45–53, 2013. View at Publisher · View at Google Scholar
57. M. S. Sulkowski, R. D. Moore, S. H. Mehta, R. E. Chaisson, and D. L. Thomas, “Hepatitis C and progression of HIV disease,” Journal of the American Medical Association, vol. 288, no. 2, pp. 199–206, 2002. View at Scopus
58. V. Soriano, P. Labarga, A. Ruiz-Sancho, J. Garcia-Samaniego, and P. Barreiro, “Regression of liver fibrosis in hepatitis C virus/HIV-co-infected patients after treatment with pegylated interferon plus ribavirin,” AIDS, vol. 20, no. 17, pp. 2225–2227, 2006. View at Publisher · View at Google Scholar · View at Scopus
59. J. Berenguer, E. Rodríguez, P. Miralles, et al., “Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus,” Clinical Infectious Diseases, vol. 55, no. 5, pp. 728–736, 2012. View at Publisher · View at Google Scholar
60. D. Dieterich, V. Soriano, K. Shermann, et al., “Telaprevir in combination with peginterferon alfa-2a/ribavirin in HCV/HIV co-infected patients: 24-week treatment interim analysis,” Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections (CROI '12), Seattle, March 2012, abstract 46.
61. J. Mallolas, S. Pol, A. Rivero, et al., “Boceprevir plus peginterferon/ribavirin for the treatment of HIV-HCVcoinfected patients: end of treatment week 48 interim results,” in Proceedings of the 47th Annual Meeting of the European Association for the Study of the Liver (EASL '12), Barcelona, Spain, April 2012, abstract 366.
62. M. Rodríguez-Torres, “Focus on drug interactions: the challenge of treating hepatitis C virus infection with directacting antiviral drugs in the HIV-positive patient,” Current Opinion in Infectious Diseases, vol. 26, no. 1, pp. 50–57, 2013.
63. C. Wartelle-Bladou, G. le Folgoc, M. Bourlière, and L. Lecomte, “Hepatitis C therapy in non-genotype 1 patients: the near future,” Journal of Viral Hepatitis, vol. 19, no. 8, pp. 525–536, 2012.
64. G. R. Foster, C. Hézode, J. P. Bronowicki, et al., “Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections,” Gastroenterology, vol. 141, no. 3, pp. 881–889, 2011. View at Publisher · View at Google Scholar
65. Y. Benhamou, J. Moussalli, V. Ratziu, 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, vol. 52, pp. 719A–720A, 2010.
66. T. I. Lin, O. Lenz, G. Fanning et al., “In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitory,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 4, pp. 1377–1385, 2009. View at Publisher · View at Google Scholar · View at Scopus
67. C. Moreno, T. Berg, T. Tanwandee, et al., “Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study,” Journal of Hepatology, vol. 56, no. 6, pp. 1247–1253, 2012. View at Publisher · View at Google Scholar
68. J. M. Gottwein, T. K. Scheel, T. B. Jensen, L. Ghanem, and J. Bukh, “Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses,” Gastroenterology, vol. 141, no. 3, pp. 1067–1079, 2011. View at Publisher · View at Google Scholar
69. G. Everson, C. Cooper, C. Hezode, 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,” Journal of Hepatology, vol. 56, p. S466, 2012.

Source

Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial

The Lancet Infectious Diseases, Early Online Publication, 12 June 2013

doi:10.1016/S1473-3099(13)70149-X

Prof Mark Sulkowski MD a, Prof Stanislas Pol MD b, Josep Mallolas MD c, Hugo Fainboim MD d, Curtis Cooper MD e, Jihad Slim MD f, Antonio Rivero MD g, Carmen Mak PhD h, Seth Thompson PhD h, Anita YM Howe PhD h, Larissa Wenning PhD h, Peter Sklar MD h, Janice Wahl MD h, Dr Wayne Greaves MD h , for the P05411 study investigators†

Summary

Background

Rates of sustained virological response (SVR) to peginterferon—ribavirin are low in patients with hepatitis C virus (HCV) genotype 1 and HIV. We aimed to assess efficacy and safety of triple therapy with boceprevir plus pegylated interferon alfa-2b (peginterferon) and ribavirin, which increases rates of SVR in patients with HCV alone.

Methods

In our double-blind, randomised controlled phase 2 trial, we enrolled adults (18—65 years) with untreated HCV genotype 1 infection and controlled HIV (HIV RNA <50 copies per mL) at 30 academic and non-academic study sites. We randomly allocated patients (1:2) according to a computer generated sequence, stratified by Metavir score and baseline HCV RNA level, to receive peginterferon 1·5 μg/kg per week with weight-based ribavirin (600—1400 mg per day) for 4 weeks, followed by peginterferon—ribavirin plus either placebo (control group) or 800 mg boceprevir three times per day (boceprevir group) for 44 weeks. Non-nucleoside reverse-transcriptase inhibitors, zidovudine, and didanosine were not permitted. The primary efficacy endpoint was SVR (defined as undetectable plasma HCV RNA) at follow-up week 24 after end of treatment. We assessed efficacy and safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00959699.

Findings

From Jan 15, 2010, to Dec 29, 2010, we enrolled 99 patients, 98 of whom received at least one treatment dose. 40 (63%) of 64 patients in the boceprevir group had an SVR at follow-up week 24, compared with ten (29%) of 34 control patients (difference 33·1%, 95% CI 13·7—52·5; p=0·0008). Adverse events were more common in patients who received boceprevir than in control patients: 26 (41%) versus nine (26%) had anaemia, 23 (36%) versus seven (21%) pyrexia, 22 (34%) versus six (18%) decreased appetite, 18 (28%) versus five (15%) dysgeusia, 18 (28%) versus five (15%) vomiting, and 12 (19%) versus two (6%) neutropenia. Three patients who received boceprevir plus peginterferon—ribavirin and four controls had HIV virological breakthrough.

Interpretation

Boceprevir in combination with peginterferon—ribavirin could be an important therapeutic option for patients with HCV and HIV.

Funding Merck.

Source

Am I Number 12 ?

Electron micrographs of hepatitis C virus purified from cell culture. Scale bar is 50 nanometers.
Courtesy of the Center for the Study of Hepatitis C, The Rockefeller University.
Pix - wikipedia

Sunday, Jun 23, 2013

Dr Th Dhabali Singh

When the fact that Hepatitis C deaths are more than HIV/AIDS related deaths in Manipur was revealed by the Opposition leader in Manipur Assembly a few days ago and the same was published in different morning dailies the next day, many people must have been caught unawares. The severity of the prevalence of Hepatitis C in Manipur was also previously made known through the 11th February 2013's edition of The Telegraph in its front-page news with the headline "Manipur worst hit by Hepatitis C".

In this news, besides highlighting Hepatitis C prevalence in Manipur, the Centre was urged to provide a separate budget for tackling Hepatitis C and also the inclusion of drugs used for the treatment on the list of National Essential Medicines. Because of the high number of intravenous drug users, Manipur has been the worst hit amongthe North-Eastern states. Second comes Nagaland and the third is Mizoram. Manipur's case is unique because of the high HIV/Hepatitis C co-infection rate and according to a recent survey conducted by the Indian Council of Medical Research, 98 percent of HIV-infected people in Churachandpur district were co-infected with Hepatitis C.

AM I NUMBER 12?

One in 12 people worldwide is living with either chronic Hepatitis B or C. The numbers are absolutely staggering and the prevalence is far higher than HIV or any cancer. While the public awareness about HIV is high mainly due to relentless campaigns and the media, the awareness of Hepatitis B or C is abysmally low and the majority of those infected are unaware. In 2008, the World Hepatitis Alliance launched the global awareness programme under the banner, 'Am I Number 12?' to communicate the fact that one in 12 people worldwide is living with either chronic Hepatitis B or C. The campaign encourages people to question themselves rather than stigmatise others and to GET TESTED if they think they could be at risk.

HEPATITIS B AND HEPATITIS C

Hepatitis B and Hepatitis C represent two of the major threats to global health. Because many people feel no symptoms, both Hepatitis B and C are 'silent' viruses, and one could be infected for years without knowing it. Both Hepatitis B and C can lead to liver cirrhosis where one is exposed to life-threatening complications such as bleeding, ascites, liver cancer and liver failure.

Hepatitis B virus is highly infectious and about 50-100 times more infectious than HIV. The virus is transmitted through blood and other body fluids like saliva, semen and vaginal fluid of an infected person. According to the World Health Organisation (WHO) estimates, two billion people have been infected with the Hepatitis B virus worldwide and approximately 350 million people are living with chronic infections. Unlike Hepatitis C, there is a vaccine that can prevent the infection.

Four out of five people infected with Hepatitis C develop chronic infection, which may cause cirrhosis and liver cancer after 15-30 years. Hepatitis C is spread mainly through blood-to-blood contact, and like Hepatitis B, usually, there are no obvious symptoms. WHO estimates that about three to four million people are newly infected with Hepatitis C every year.

DIAGNOSIS AND TESTS

For Hepatitis B: To diagnose the infection of Hepatitis B, the blood needs to be checked for the Hepatitis B surface antigen (HBsAg). The HBs is a part of the virus that mostly appear six to twelve weeks after infection. If the test is positive, it is very likely that one has Hepatitis B and further tests are required for confirmation, to check if the infection is new or old and, to see if one needs treatment or not.WHO recommends that all blood donations are tested for this marker to avoid transmission to recipients.Other tests include:

* Testing for antibodies to Hepatitis B surface antigen – A positive test indicates that one has naturally cleared the virus or has been vaccinated against it. Having antibodies to Hepatitis B (anti-HBs) is actually good because it means one is protected against future infection by the virus and is no longer contagious.

* Testing for antibodies to Hepatitis B core antigen –A positive test means one has had a recent infection or an infection in the past. A positive test for antibodies to Hepatitis B core antigen combined with a positive HBsAg indicates one has chronic infection.

* Hepatitis B virus DNA polymerase chain reaction (PCR) test – HBV DNA PCR is used for both Qualitative as well as Quantitative (viral load) testing.

For Hepatitis C: The blood is checked for HCV antibodies (anti-HCV). If the test is positive, it means either one is infected with it or was infected with it but has already cleared the virus. The test is mandatory for blood donations in almost all countries. Hepatitis C antibodies usually take seven to nine weeks to appear in the bloodstream after infection. Hepatitis C virus RNA testing is used to confirm the diagnosis. PCR detection of Hepatitis C virus-RNA in serum is mostly used to confirm acute Hepatitis C infection and also to identify viraemia in the chronic disease, particularly in anti-Hepatitis C virus antibody-negative individuals.

AWARENESS CAN CHECK THE SPREAD OF HEPATITIS B AND C

World Hepatitis Day is observed every year on July 28 and on this day, health authorities and NGOs across the world hold special programmes to make people aware of these viral infections. Hepatitis C has claimed more lives than HIV because the cost of medicines is very high, and presently, in India there is no government policy to help patients as in the case of HIV/AIDS. A patient has to spend six to eight lakh rupees annually for treatment. Unlike HIV/AIDS, there is no official data as there is no survey conducted to know the exact status of Hepatitis C or B in Manipur.

Spreading awareness remains the key to fighting against Hepatitis B and C. Like in one of the poster campaigns for World Hepatitis Day says, "The clock is ticking. Act now to protect a new generation."

---

* Dr Th Dhabali Singh wrote this article for The Sangai Express
The writer is Senior Consultant Pathologist and Managing Director, BABINA Diagnostics, Imphal
This article was posted on June 22, 2013.

Which Drugs Are Safe in Patients with Cirrhosis?

Published in Journal Watch Gastroenterology June 21, 2013

A new review contains practical guidance to answer this oft-asked, important question.

Prescribing providers routinely raise the concern of medication safety for their patients with cirrhosis because of fear of precipitating hepatic decompensation from acute, drug-induced liver injury. To synthesize current information on this topic, investigators systematically reviewed relevant articles indexed in MEDLINE and unpublished information from the U.S. Food and Drug Administration.

Highlights include the following:

• Because of pharmacokinetic changes that occur in patients with cirrhosis and may necessitate dose adjustments, lower doses are generally recommended, especially in patients with significant liver dysfunction.
• Opioid analgesics, anxiolytics, and sedatives should be used with caution because they can precipitate hepatic encephalopathy.
• Nonsteroidal anti-inflammatory drugs should be avoided, as they are a common cause of adverse drug reactions (renal failure and gastrointestinal bleeding) in this population.
• Paracetamol (acetaminophen) can be used safely at low doses (2–3 g daily) for short durations and should be considered first-line treatment for pain.
• Statins can be used safely; they are considered by the FDA to carry a very low risk for serious liver injury, and recent studies support their safety in liver disease and suggest a possible beneficial effect in fatty liver disease.
• Proton-pump inhibitors and, to a lesser degree, histamine-2 blockers have recently been associated with serious infections in patients with cirrhosis, so clinicians should limit their use to valid indications.

Comment: Although most medications have not been sufficiently studied in patients with cirrhosis, most can be safely prescribed in this setting. Even certain potentially hepatotoxic drugs can be used safely if given at a lower dose and monitored carefully. Importantly, clinicians need to be more concerned about drugs that precipitate or worsen renal failure or provoke either gastrointestinal bleeding or encephalopathy, all of which are more common in this patient population.

— Atif Zaman, MD, MPH

Citation(s):

Lewis JH and Stine JG. Review article: Prescribing medications in patients with cirrhosis — a practical guide. Aliment Pharmacol Ther 2013 Jun; 37:1132. (http://dx.doi.org/10.1111/apt.12324)

Medline abstract (Free)

Source

AIDS 10 years later: Global HIV infections decreasing

Provided by Healio

June 20, 2013

Ten years after the implementation of the US President’s Plan for Emergency AIDS Relief, or PEPFAR, 1 million babies have been born HIV-free as of June, according to a press release from the US Department of State.

“Preventing mother-to-child transmission has been a central pillar of our fight against the disease, and just this month we reached the truly landmark moment on the HIV/AIDS timeline,” US Secretary of State John Kerry said at the PEPFAR 10th Anniversary Celebration.

In the past decade, global HIV infections have decreased nearly 20%, and in sub-Saharan Africa, the number of new infections and AIDS-related deaths decreased by nearly one-third.

“Last year alone, PEPFAR supported HIV testing and counseling for nearly 50 million people, and while just 300,000 people in low and middle income countries were receiving antiretroviral treatment 10 years ago, today PEPFAR is directly supporting more than 5 million people on treatment,” Kerry said.

Today, the United States supports three times more people on ART than it did in 2008.

In July 2012, the United States announced a $20 million fund to support country-led plans to expand high-impact comprehensive package of HIV prevention, treatment and care services for key populations, including men who have sex with men, injection drugs users and sex workers.

Kerry said the funding will be awarded to Cambodia, Ghana, Nepal, Senegal, Swaziland, Zimbabwe and two regional programs.

“This has been a decade of remarkable progress,” Kerry said. “But obviously, our work is not done. Millions still become infected every year and millions are still dying. But we can now say with confidence something we could perhaps only dream of before … and that is we can achieve an AIDS-free generation, and that is within our grasp now.”

Source

Meds to Treat Addiction Often Hard to Get

By David Pittman, Washington Correspondent, MedPage Today

Published: June 20, 2013

WASHINGTON -- Medicaid programs and health insurance companies are hindering access to FDA-approved drugs that treat opioid addiction, according to a report released Thursday by the American Society of Addiction Medicine (ASAM).

The 216-page report -- called the "most comprehensive" on addiction medications to date -- showed wide variation in state coverage of opioid addiction medications, with many Medicaid programs requiring other treatments to fail before covering addiction drugs.

Furthermore, private insurance companies use techniques like prior authorization to restrict access to drugs like buprenorphine (Probuphine), methadone, and naltrexone (Vivitrol), the Chevy Chase, Md. group said.

The restrictions come at a time when the CDC has declared prescription opioid abuse and addiction an epidemic, with nearly 4 million Americans addicted to prescription opioids.

"We have effective ways of treating these devastating illnesses," Tom McLellan, PhD, chief executive and founder of the Treatment Research Institute -- the organization that conducted the study -- said at a press conference here. "Let's start using them."

A little more than half of state Medicaid programs (28) cover all three drugs, the report found. "However, it is important to note that the extent of coverage varies greatly among the states, and access requirements attached to any or all of these medications differ from one state to another," the authors wrote.

For example, prior authorization is required by Medicaid in 42 states for buprenorphine. Coverage limits for lifetime benefits and daily doses are also common.

The study of private insurance carriers found similar barriers in their health plans, with spotty coverage of products such as buprenorphine/naloxone (Suboxone) and injectable naltrexone.

The report shows that "we could be saving lives and effectively treating the disease of addiction if state governments and insurance companies remove roadblocks to the use of these medications," ASAM president Stuart Gitlow said at the press conference.

Removing those roadblocks, however, may be difficult for states and health plans.

Congressional limits exist on the number of patients physicians can prescribe to at once. "I have 100, and I have a waiting list of 270," Gitlow said. "I'm not coming anywhere near meeting the need, and those patients have nowhere else to go because the only other docs prescribing are full."

Also, prescribers also need a special Drug Enforcement Administration waiver created by the Drug Addiction Treatment Act of 2000 to prescribe certain opioid addiction drugs.

The FDA subjects buprenorphine-containing products to a rigorous risk evaluation and mitigation strategy (REMS) with several elements to assure safe use, including patient monitoring and prescriber certification programs. The agency has deemed the risk-benefit profile of such products unfavorable enough to try to restrict their access.

The report also examined studies that evaluated buprenorphine, methadone, injectable naltrexone, and oral naltrexone and concluded a benefit in patient outcomes as well as costs.

"I can say with no hint of opinion here, it's simple fact, they are all effective," McLellan said. "They're effective not just in reducing opioid use, they're effective in so many other ways that are important to societies and families."

He called these medications "underutilized," saying about 30% of treatment programs use such drugs and about half of the patients in those programs receive such medication.

Gitlow and McLellan called on growing a coalition of interested parties, including the various addiction medicine groups, to raise awareness on the issue and educate the public and policymakers about their needs.

Source

Better Testing Catches Early HIV Infection

By Michael Smith, North American Correspondent, MedPage Today

Published: June 21, 2013

Action Points

• New approaches to HIV testing can detect acute infections that would have gone undetected with older methods.
• Note that new 4th-generation tests detect both immunoglobulin M-class and G-class antibodies as well as the p24 antigen whereas early immunoassays detected only immunoglobulin G-class antibodies to HIV.

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

New approaches to HIV testing can detect acute infections that would have gone undetected with older methods, according to a CDC report.

A 4th-generation immunoassay, coupled with an HIV-1/HIV-2 antibody differentiation test, picked up acute infections where traditional methods did not, according to two studies reported by CDC in the June 20 issue of Morbidity and Mortality Weekly Report.

The acute phase of infection -- which plays a "disproportionate" role in transmission -- is the period between the appearance of HIV RNA in plasma and the detection of HIV antibodies, the agency noted.

Testing for HIV has usually begun with an immunoassay, followed by a Western blot or indirect immunofluorescence assay if the initial test is positive.

Early immunoassays detected only immunoglobulin G-class antibodies to HIV. That was improved so that 4th-generation tests detect both immunoglobulin M-class and G-class antibodies as well as the p24 antigen, an important HIV protein.

Because the p24 antigen can be detected before antibodies appear, the 4th-generation tests can pick up some acute HIV infections, the agency report noted.

But a negative supplemental test with a Western blot or indirect immunofluorescence assay has often resulted in erroneously classifying people as HIV-negative, the report added.

Two evaluations of the new test algorithm suggest it is likely to do better:

• HIV screening at a Phoenix emergency department identified 37 undiagnosed HIV infections from July 2011 through February 2013, including 12 (or 32.4%) in the acute phase that would not have been found using earlier methods.
• A three-site screening program found 99 cases with a positive first test and a negative supplemental test; 55 (or 55.6%) were shown to be acute HIV infections but a large proportion of those would not have been found by traditional methods.

The new algorithm begins with a 4th-generation immunoassay, followed by the HIV-1/HIV-2 antibody test. If that second assay is negative or indeterminate, the definitive step is testing for the presence of HIV RNA.

In the Phoenix emergency room, the agency reported, the first test found 37 cases of infection, including 25 in which the supplemental test was positive and 12 in which it was negative or indeterminate.

RNA testing confirmed acute HIV infection in those 12, the CDC report said.

The median HIV viral load among those 12 was 3,636,176 copies of HIV RNA per milliliter, compared with 27,125 copies per milliliter among the 25 with established infection, the report said.

In the Screening Targeted Populations to Interrupt On-going Chains of HIV Transmission with Enhanced Partner Notification (STOP) study, initial testing of 37,876 patients, screened from September 2011 through September 2012, found HIV in 654, or 1.7%.

Of those, 99 had a negative or indeterminate result on the HIV-1/HIV-2 antibody differentiation test, but HIV RNA was present in 55, indicating an acute infection. The traditional supplemental tests -- Western blot or indirect immunofluorescence assay -- were negative in 37 cases and indeterminate in seven, the agency reported.

Taken together, the agency report said, the findings show that acute HIV infection detected with newer immunoassays is often misclassified as HIV-negative by traditional supplemental tests, "potentially leading to adverse clinical outcomes for patients and further HIV transmission within the community."

The researchers cautioned that the findings might not apply to all screening programs. The Phoenix program aimed to screen as many people as possible, but some tests might have been ordered because of an increased index of suspicion.

And the STOP study looked at people at high risk for HIV, so that the proportion of infections that were acute might be higher than in other populations, the agency report noted.

The analysis was supported by the CDC. Peters is an employee of the agency.

Primary source: Morbidity and Mortality Weekly Report
Source reference:
Centers for Disease Control and Prevention "Detection of acute HIV infection in two evaluations of a new HIV diagnostic testing algorithm -- United States, 2011–2013" MMWR 2013; 62: 489-494.

Source

Breast cancer, hep C, MS drugs may come with higher copays in California

June 21, 2013 12:30 pm by Wolfson, Bernard J.

The Affordable Care Act might not make care much more affordable for some Californians who need expensive prescription drugs to treat chronic illnesses or just to stay alive.

The health plans to be marketed in the California insurance exchange, established under President Barack Obama's health reform law, will follow the lead of Medicare and a growing number of commercial insurers by charging co-insurance payments ranging from 10 to 30 percent on a number of high-cost "specialty" drugs. These include medications for treating rheumatoid arthritis, multiple sclerosis, hepatitis C, breast cancer, leukemia and other conditions.

Advocates for the sick are unhappy that Covered California has decided to adopt this model, which imposes much higher costs on many patients than more traditional policies that offer the drugs for a flat co-payment.

"It's disappointing that the state is in a way institutionalizing what we believe is a practice that harms those who are in the greatest medical need," says Lisa Nelson, director of state government affairs for the Leukemia and Lymphoma Society.

Whether sick patients would be financially worse off in the exchange depends on their current insurance coverage -- and on which of the four basic exchange plans they choose, since each has different premiums, co-insurance levels and annual caps on patient out-of-pocket spending.

Covered California's spokesman, Dana Howard, said the exchange officials had to balance several important factors, and in the end they believed the decisions they made were "the most feasible way to provide health plans that are affordable both in terms of premiums and cost sharing." He noted that lower-income people, who would be most affected by the high drug costs, are also the ones who will benefit the most from subsidies intended to reduce their premiums and out-of-pocket costs.

Sonja Radovic, a 45-year-old working mother of two who was diagnosed with breast cancer five years ago, would not qualify for any of those subsidies. She said her expense for Feraston, a hormonal drug, could skyrocket by as much as 10 times should she ever need to buy coverage through the exchange -- from the current $860 a year to $8,600 under the plan with the lowest premium.

She is confident that her employer, a small business with 11 employees, will keep its current coverage, though that could conceivably change should the economy sour again. "What part of 'Affordable' are they not understanding?" Radovic asks. "And that's just on one drug. What about other even more expensive specialty drugs?"

Feraston is far from the most expensive medication. The average cost of treating a variety of cancers with one of five specialty drugs is $3,682 per month, or $44,184 a year, according to Express Scripts, the giant St. Louis-based pharmacy benefit-management company. For multiple sclerosis, the average cost is $3,584 per month, and for hepatitis C the monthly price tag is $3,284.

Kalydeco, the only effective therapy for cystic fibrosis, can carry a price tag of up to $180,000 per year, says Suzanne J. Tschida, a vice president at Optum RX, a Minnesota-based pharmacy benefit-management company whose main operations are in Irvine.

In 2012, specialty drugs accounted for 24.5 percent of all U.S. prescription drug spending, even though less than 2 percent of the population is affected by the related illnesses, according to Express Scripts.

Still, if you are one of the unlucky 2 percent and you're paying 20 or 30 percent of even the somewhat-less-stratospherically-priced drugs, it could quickly overwhelm your household budget. For plans in Covered California, the amount patients must pay out of their own pockets each year before their insurers will cover 100 percent of their medical expenses is as high as $6,350 for individual plans and $12,700 for family plans.

"I think it shows that these benefits designs essentially discriminate against people who have these serious illnesses," says Dan Mendelson, CEO of Avalere Health Inc., a Washington, D.C.-based medical data company.

An Avalere study showed that when monthly out-of-pocket payments hit $100, 10 percent of patients stopped filling their prescriptions. At $500 a month, 25 percent stopped. That can lead to sicker patients and an even greater financial burden on the health care system down the line, many observers argue.

Not everybody buying coverage in the exchange will be affected equally. In Covered California's second least-expensive plan, individuals with incomes between $15,856 and $22,980 will face much lower co-insurance payments, reduced or no deductibles and an out-of-pocket maximum of just $2,250. Howard acknowledges that it might still be "a strain" for those people to cope with their medical expenses, but "we think this $2,250 annual limit on their payments will help many avoid bankruptcy."

Mendelson notes that Covered California did not invent this type of health-plan design. It is merely following a trend that started with Medicare's Part D drug benefit and has been adopted in recent years by many commercial insurers. The proportion of private commercial plans that make enrollees pay a percentage of specialty drug costs rather than a flat dollar co-payment rose from 14 percent in 2008 to 34 percent last year, according to Avalere.

"In some ways, the implementation (of such plans) by the exchange makes the affordability of specialty drugs a more visible problem, but it's not introducing a new problem for the people who need these drugs," says Ha Tu, a senior researcher at the Center for Studying Health System Change, a Washington, D.C.-based think tank.

Joan W. Clements, a 70-year-old Costa Mesa resident who was diagnosed with chronic myeloid leukemia nearly 12 years ago, knows that as well as anybody. She has been kept alive for more than a decade by Gleevec, a revolutionary drug that has turned her disease from fatal to manageable. Over the past decade, Clements has seen the total cost of her Gleevec nearly double, from $6,000 to $11,000 a month.

With a 30 percent co-insurance payment under her Medicare drug plan, and a gap in coverage known as the "donut hole," Clements' out-of-pocket payments for the drug would be unaffordable on the modest Social Security income that she and her husband, Jerry, receive each month. Luckily for her, Novartis, which manufactures Gleevec, provides a subsidy to cover the amount that Medicare doesn't. Otherwise, says Clements, "I would be dead."

Nelson, of the Leukemia and Lymphoma Society, says California could have chosen differently. She notes that the insurance exchange in New York limits patient liability on specialty drugs to a flat dollar co-payment that tops out at $70 per prescription.

Tu argues that such a generous benefit will lead to a spike in premiums that will deter the young and the healthy from buying insurance and create an ever-sicker pool of insured people whose medical needs will only reinforce the escalating cost of insurance. In California, that is unlikely to happen, she says, though the high co-insurance payments are "a horrible thing for people who are sick."

Why some drugs cost so much

By 2019 or 2020, specialty medications are expected to account for half of all drug spending. Managing their fast-rising costs is key to keeping health insurance premiums affordable for all. Here are some of the factors driving the escalation in prices and spending on specialty drugs:

Sources: Express Scripts; Ha Tu, Center for Studying Health System Change; Avalere Health Inc.

Contact the writer: 714-796-2440 or bwolfson@ocregister.com ___

(c)2013 The Orange County Register (Santa Ana, Calif.)

Visit The Orange County Register (Santa Ana, Calif.) at www.ocregister.com

Distributed by MCT Information Services

Source

UAB Hospital Emergency Department to screen patients for hepatitis C

Friday, June 21, 2013

By Bob Shepard

The Emergency Department at the University of Alabama at Birmingham (UAB) Hospital will begin testing baby boomers for the hepatitis C virus (HCV) in August 2013. All patients born between 1945 and 1965 who present at the ED for any cause will be offered a blood test for HCV as part of their routine examination.

The testing is part of a Centers for Disease Control and Prevention (CDC) initiative designed to identify patients with HVC and get them into appropriate treatment. The CDC estimates that one-time testing of all Baby Boomers could detect 800,000 additional people with hepatitis C and save more than 120,000 lives because 75 percent of these infections are curable with new treatments.

“We anticipate screening between 8,000 and 12,000 Baby Boomers for HCV in 2013 and expect to identify between 260 to 400 new cases of HCV infection at UAB,” said James Galbraith, M.D., associate professor of emergency medicine and head of the UAB HIV and HCV screening programs. “The overall target is the approximate 3.2 million people in the United States who the CDC estimates have chronic hepatitis C virus infection — many of whom are unaware they are infected because they don’t look or feel sick.”

Hepatitis C is a contagious liver disease that ranges from a mild illness lasting a few weeks to a serious, lifelong illness that attacks the liver. It is spread primarily through contact with the blood of an infected person. Today, most people become infected with the virus by sharing needles or other equipment to inject drugs. Before 1992, when widespread screening of the blood supply began in the United States, hepatitis C also was commonly spread through blood transfusions and organ transplants.

The HCV screening program mirrors a similar ED-based program at UAB Hospital to screen for HIV, the virus responsible for AIDS. That program, which began in August 2011, screens for the presence of HIV in all willing adult patients ages 18-65 seeking treatment at the UAB Emergency Department. Of the more than 30,000 screened, Galbraith says the program has identified and referred to treatment more than 150 people who were HIV positive.

The CDC estimates that one-time testing of all Baby Boomers could detect 800,000 additional people with hepatitis C and save more than 120,000 lives because 75 percent of these infections are curable with new treatments.

Patients testing positive for HCV will be linked to appropriate antiviral treatment services through the UAB Liver Center, Liver Transplant Clinic and 1917 Liver Clinic. A linkage coordinator will also help positive HCV cases establish a primary care physician to maintain consistent health care throughout the progression of their disease. UAB Charity Care services will help patients with limited resources obtain appropriate medical care.

UAB ED nurse manager India Alford, RN, says the program will not disrupt patient care in the Emergency Department.

“Patients in the Baby Boom generation will be electronically identified at registration and the patient’s nursing provider will conduct a required HCV assessment,” Alford says. “During the brief three-item assessment, nursing providers will notify the individuals about the CDC’s recommendation and the screening will be available at no cost.”

Unless they refuse, an automated HCV antibody assay will be ordered for eligible patients unaware of their HCV status. Results of the HCV assay will be available within 30 minutes and delivered to patients prior to discharge.

“These day-to-day screening operations would not be possible without the dedicated support of the ED nursing and laboratory staff,” Galbraith says.

A contract from the CDC Foundation’s Viral Hepatitis Action Coalition is providing start-up funding for the UAB project.

Source