Obstacles to Hepatitis C Therapy: Effective Regimens Are Not Enough

Obstacles to Hepatitis C Therapy: Effective Regimens Are Not Enough

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Hepatitis C Virus Epidemiology, Pathogenesis, Diagnosis, and Natural History

Donald P. Kotler, MD - 6/4/2013 

Although the outlook for HCV-infected patients who enter treatment has improved substantially with the introduction of direct-acting agents, various host factors remain as barriers to effective management for some patients. My colleagues and I treat patients in the New York City community of Harlem and its surrounding neighborhoods. As most providers in similar communities are aware, we face challenges including higher rates of comorbidities such as alcoholism, lower response rates to current therapies, and disparities of access to healthcare. Our conclusion is that many patients will not derive the full potential benefit from advances in HCV therapy unless all of these factors are addressed.

Each Patient Brings Their Own Unique Challenges
The patients from our community are affected by a number of important host-related factors that influence their access to and the outcomes of medical care in general and HCV treatment in particular.

Substance abuse, particularly alcoholism, is a significant problem for our patients and is especially concerning since active alcoholism represents a significant challenge to anti-HCV therapy. Surprisingly, alcoholism has received little attention, despite the fact that it accelerates hepatic fibrosis. A prospective, case-controlled study performed at Harlem Hospital Center approximately 20 years ago demonstrated that the combination of HCV infection and heavy alcohol intake, but neither HCV infection nor alcoholism alone, significantly promoted the development of chronic liver disease. Whereas those results suggest the need for greater attention to the management of alcoholism, they also illustrate the presence of a subgroup of patients at serious risk of disease progression who typically are excluded from treatment. Recent studies from the United States and Europe have documented the ability to successfully treat patients with a history of alcoholism, typically by providing some form of integrated care. Maintaining adherence to anti-HCV treatment may be as important or even a more important goal than enforcing abstinence from alcohol intake.

In our community, other patient-related factors may also affect treatment adherence including mistrust of the healthcare system, poor health literacy, inequalities in access to healthcare, as well as outright discrimination. For our patients, these factors might be responsible for poorer adherence as well as poorer outcomes of therapy. This atmosphere of mistrust works in concert with patients’ nihilism and perceived stigma to confound attempts at therapy. Although efforts to improve cultural competence in managing patients and combating host-related obstacles to effective therapy are now routine medical education and core competency initiatives, the reality is that these barriers still exist. The lack of faith may extend beyond the patient and become imbedded in the local healthcare system. A culture of low expectations may influence caregivers so that they do not aggressively promote therapy to their patients. As with all cultures, these biases may be resistant to change.

Stumbling Over Institutional Steps
We have found that it is especially difficult for the medical establishment to engage patients who exist outside the formal healthcare system, especially when the individual harbors a fundamental mistrust in the healthcare system. We have found that some of this mistrust may be mitigated by effective community-based organizations that foster trust by establishing an environment in which people are treated in a nonjudgmental manner.

In addition to efficacious medications, effective HCV therapy also requires appropriate diagnosis and evaluation, recommendation for therapy, access to therapy, acceptance of the diagnosis and its implications by the patient, and adherence to therapy. Medication development is the purview of the pharmaceutical industry, and it has vigorously pursued them, but the diagnosis, treatment recommendations, and treatment access are tasks for the healthcare system and those of us at the front line of care. Our patients bear the responsibility of accepting the diagnosis and adhering to therapy and form the other basis for successful therapeutic outcomes. An increasing amount of attention is being given to screening and linkage to care, but less attention has been placed on assuring treatment access and very little attention has been given to care coordination. To the extent that care coordination and community involvement enhance acceptance and adherence, they will avoid the wasted resources associated with refusal of care and early treatment suspension, as well as liver disease progression.

Your Thoughts?
Do you share our concerns that many patients are effectively excluded from successful treatment by these host-related factors? What is your experience with patients in your communities? Have you tried any interventions to overcome these barriers in your patients? We are keen to hear your experiences.

Topics: HCV - Outcome

HCV treatment improves survival among anemic patients

HCV treatment improves survival among anemic patients

Mohanty A. Clin Gastroenterol Hepatol. 2013;11:741-747.

June 6, 2013
While anemia increased mortality rates among patients with hepatitis C, those who underwent treatment for the infection experienced significantly improved survival in a recent study.

Researchers performed a retrospective analysis of 200,139 veterans with chronic hepatitis C, including 29,510 with anemia, as well as 195,166 controls without HCV. Patients had been enrolled in the Electronically Retrieved Cohort of Hepatitis C-Infected Veterans between 2001 and 2008. HCV treatment was initiated in 1,820 patients with and 17,755 without anemia.

Anemia was more prevalent among patients with HCV than controls (14.7% vs. 12.5%; P<.001). Multivariate analysis indicated significant associations between pretreatment anemia and decompensated liver disease (OR=3.69; 95% CI, 3.53-3.86), chronic kidney disease (OR=3.36; 95% CI, 3.23-3.51) and black race (OR=2.03; 95% CI, 1.95-2.11).

Patients with anemia were significantly less likely to initiate HCV therapy (OR=0.56; 95% CI, 0.56-0.62), with the likelihood of treatment decreasing proportionally with anemia severity (P<.001 for trend).While mortality rates were higher among anemic patients (139.2 per 1,000 person-years vs. 35.9 per 1,000 person-years among those without anemia), treated anemic participants had lower all-cause mortality rates than untreated anemic patients (54.2 per 1,000 person-years vs. 146.8 per 1,000 person-years).

Investigators calculated an adjusted HR of 0.45 (95% CI, 0.39-0.51) for HCV treatment among anemic participants after adjustment for covariates. This risk reduction was similar to that observed among participants without anemia (aHR=0.44; 95% CI, 0.41-0.48), and was not impacted by anemia severity. Sensitivity analysis excluding those with major comorbidities (n=5,925, HCV patients with anemia; n=69,478, without anemia) yielded similar results, including a greater risk reduction among treated participants (HR=0.28; 95% CI, 0.22-0.37).

“Our study shows the importance of identifying and treating individuals with chronic HCV infection who have pretreatment anemia,” the researchers concluded. “Treatment for HCV infection in anemic individuals confers a significant survival advantage after adjusting for numerous comorbidities. A better understanding of pathways that lead to baseline anemia in chronic HCV-infected individuals and targeted therapies to treat this may allow HCV treatment for a higher proportion of individuals.”

Disclosure: The researchers report numerous financial disclosures.

http://www.healio.com/infectious-disease/hepatitis-resource-center-2013/hcv-treatment-improves-survival-among-anemic-patients

Miravirsen-Treating hepatitis C by blocking a cellular microRNA

Podcast: Download TWiV 235

Treating hepatitis C by blocking a cellular microRNA

Miravirsen is a drug that binds to and blocks the function of a cellular microRNA called miR-122 that is required for the replication of hepatitis C virus (HCV). Treatment of chimpanzees chronically infected with HCV with this drug leads to suppression of viral replication. The results of a phase 2b human clinical trial in HCV infected humans indicate that Miravirsen reduces levels of viral RNA without evidence for viral resistance. I asked virologist Stan Lemon (who appeared recently on TWiV 235) his opinion of these findings.

Are you surprised that the antiviral effect of Miravirsen is long lasting?

The Janssen study published in NEJM basically recapitulated what Lanford had observed in HCV-infected chimps treated with the compound, with a very slow onset of antiviral effect, and then a very slow rebound as well. This probably reflects the pharmacokinetics and very high stability of the locked nucleic acid compound, and the time required to sequester endogenous miR-122 – changes in serum cholesterol also move very slowly. I think this is why the antiviral effect (and cholesterol effect) are long-lasting.

Is it surprising that no resistance to Miravirsen was observed?

As for the lack of resistance, it doesn’t surprise me much. This was observed in the chimps as well. The virus is really dependent upon miR-122 for its replication, and can’t readily mutate around it – the requirement for miR-122 reflects more than just the stabilizing effect of miR-122 on the viral genome, as we showed in a recent PNAS paper (Li et al., Proc. Nat’l. Acad. Sci U.S.A., 110:1881-6, 2013) written in follow-up to our earlier demonstration of the stabilizing effect of the miRNA on the HCV genome (Shimakami et al., Proc. Nat’l. Acad. Sci U.S.A. 109: 941-6, 2012, that you reviewed in TWIV 180) – what we know and don’t know about the mechanism of action is summarized in an “opinion” piece now in press in RNA Biology.

Do you think this drug will ultimately get FDA approval?

Given issues of resistance, relapse, and poor pan-genotype coverage with direct-acting antivirals for HCV, all of this should bode well for Miravirsen. However, it has issues like almost all the new therapies under evaluation.

First, the spaghetti plots in the Janssen paper show large variation in the response of individual patients, with some having little effect when receiving Miravirsen. This is unlike studies with enzyme inhibitor antivirals, and I am not aware of any good reason for it other than potential variation in endogenous miR-122 abundance.

A second and greater issue is the cancer concern. Most hepatocellular carcinomas (except those associated with HCV, interestingly enough) demonstrate significant reductions in miR-122 abundance, and miR-122 can reverse some malignancy-associated features of transformed hepatocytes in vitro – thus, miR-122 seems to act much like a tumor suppressor in the liver. miR-122 knockout mice develop normally but have a high incidence of hepatocellular carcinoma. I think this poses real problems for the development of Miravirsen. While one could reasonably argue that short-term exposure to the antagomir is very different than gene knockout, the patients being treated are those at the highest risk for HCC – particularly if there is advanced fibrosis or cirrhosis, which characterizes those most in need of treatment. It is also clear that HCC can manifest itself in patients AFTER therapeutic elimination of the virus. The risk is most certainly greatly reduced, but it is not zero (HCC develops very slowly, and in a multi-centric fashion), and with the evidence that the drug has relatively long-lasting effects on cholesterol (as well as the virus), I think the developers of Miravirsen may find it difficult to defend against future claims that the drug contributed to the development of HCC in some cases. There isn’t a good way to de-risk this, to show that this theoretical concern is not real, and this must be worrying the regulatory authorities – especially since there are now many alternative therapies under evaluation that don’t carry this risk, some of which are looking very good in combination with each other (e.g., advanced NS3 inhibitors, NS5A inhibitors, and nucs).

Source - http://www.virology.ws/
Podcast: Download TWiV 235

Liver-Patient turns to microwave ablation for “inoperable and incurable” tumors

Published on Jun 4, 2013

Gwen McCane was told the tumors in her liver were inoperable and incurable. The tumors were small, but deep inside her liver, the body's largest organ and so rich with blood vessels that any surgery is tricky. At Stanford, Dr. Gloria Hwang gave McCane hope and using microwave ablation, she made a small incision and, guided by imaging, found the tumors and applied microwave heat to destroy them. Gwen McCane was able to go home the next day.

Learn more about Stanford's Cancer Center: http://cancer.stanford.edu/
Or to read the full story: http://stanfordhospital.org/newsEvent...

 

N.Y. AG calls for exemption to insurers' mandatory mail-order policy

N.Y. AG calls for exemption to insurers' mandatory mail-order policy

6/5/2013

By Adam Kerlin

(Reuters) - New York Attorney General Eric Schneiderman has sent letters to 15 state health insurance providers, urging them to modify their policies to allow some members to fill specialty prescriptions at their local drug stores instead of by mail order.

Schneiderman gave them until June 17 to send a copy of their policy exempting members with certain illnesses from buying specialty drugs via mail order or from non-retail pharmacies, or to indicate when they planned to implement a policy. Specialty drugs are high-cost drugs used to treat complex or rare conditions, such as multiple sclerosis, hepatitis C and HIV.

"Every New Yorker deserves easy access to the benefits they pay for," he said in a statement on Monday. "Exempting beneficiaries with qualifying hardships from mandatory mail-order requirements will allow plan members to continue to get drugs they need from their local pharmacies."

In recent years, many health insurers have put in place policies that require members to buy drugs from mail-order or specialty pharmacies, which refill prescriptions by mail and focus on the distribution of expensive drugs for chronic illnesses. Other insurers offer incentives, such as lower co-payments, to members who use mail order.

Schneiderman said the letters were prompted by dozens of complaints his office received from health plan consumers who had concerns about mandatory mail order. These ranged from privacy issues to the spoiling of drugs that required refrigeration.

New York state law permits commercial plan members, or those with insurance not paid for by the government, to obtain any covered prescription at a retail pharmacy, rather than at a mail-order or non-retail pharmacy, as long as the retail pharmacy agrees by contract to accept the same reimbursement terms and conditions as the mail-order or non-retail pharmacy.

MAIL-ORDER LAWSUITS

Mail-order requirements have already spawned litigation in California, where a consumer watchdog group brought a lawsuit against Blue Cross of California in San Diego County Superior Court. The January lawsuit said that requiring people to obtain prescriptions by mail instead of in person violated patients' privacy rights and is discriminatory to HIV/AIDS patients.

That suit settled in May, with Blue Cross agreeing to allow HIV/AIDS patients to opt out of its new mail-order mandate.

Late last year, Empire BlueCross BlueShield, one of New York's largest healthcare providers, notified customers that as of Jan. 1, 2013, drugs on its "Exclusive Specialty Drug List" must be purchased through its specialty mail-order pharmacy.

The policy applied to drugs that were available from a single drug manufacturer and cost more than $1200 per month, including medications for treating serious and debilitating diseases such as Crohn's disease, cancer, hepatitis C and HIV.

After negotiating with Schneiderman's office, Empire agreed to exempt qualifying members from it's mail-order mandate.

Schneiderman referenced the Empire exemption in the letters, saying that such policies "ensure access to critical medicines for consumers."

The attorney general's office did not specify which diseases should qualify for exemptions to mandatory online ordering.

The letters were sent on Monday to Aetna Inc, AXA Equitable Life Insurance Company, CDPHP, CIGNA, EmblemHealth, Inc, Excellus BlueCross BlueShield, Fidelis Care New York, Healthfirst, HealthNow New York Inc, Independent Health, MVP Health Care, Oxford Health Plans, LLC, The Guardian Life Insurance Company of America, UnitedHealth Care and WellPoint, Inc.

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After HCV treatment failure, some success with boceprevir-IFN-ribavirin

After HCV treatment failure, some success with boceprevir-IFN-ribavirin

By: NEIL OSTERWEIL, Internal Medicine News Digital Network

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company.

Three of his coauthors are employees of Merck, and one is a board member.

http://www.internalmedicinenews.com/news/across-specialties/single-article/after-hcv-treatment-failure-some-success-with-boceprevir-ifn-ribavirin/ba9ec84505627d1515ea4ff6229c145f.html

Video-Naim Alkhouri, MD, discusses interferon-free regimens for HCV

Naim Alkhouri, MD, discusses interferon-free regimens for HCV

• June 3, 2013

ORLANDO, Fla. — Naim Alkhouri, MD, of the Digestive Disease Institute at the Cleveland Clinic, provides his perspective on interferon-free therapies for hepatitis C at Digestive Disease Week 2013.
Alkhouri cites encouraging data from trials of sofosbuvir and ribavirin in patients with HCV genotypes 2 and 3, in which high SVR rates were observed after 12 to 16 weeks of treatment. He suggests that interferon-free treatments may become available in the near future, including compounds for use in patients with HCV genotype 1.

http://www.healio.com/infectious-disease/hepatitis-resource-center-2013/naim-alkhouri-md-discusses-interferon-free-regimens-for-hcv

IL-28B Polymorphisms and the Response to Antiviral Therapy in HCV Genotype 2 and 3 Varies by Ethnicity

 

Journal of Viral Hepatitis

IL-28B Polymorphisms and the Response to Antiviral Therapy in HCV Genotype 2 and 3 Varies by Ethnicity

A Meta-Analysis

A. S. Rangnekar, R. J. Fontana

Disclosures

J Viral Hepat. 2013;20(6):377-384.

Abstract
Studies of IL-28B genotype in patients with hepatitis C virus (HCV) genotype 2/3 infection have yielded conflicting results. The aim of this meta-analysis was to obtain a pooled odds ratio (OR) of the impact of IL-28B genotype on achieving sustained virologic response (SVR) in patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin. A meta-analysis with a random effects model was performed, and study heterogeneity and publication bias were assessed. Forty-three percent of the Caucasians (11 studies) and 86% of Asians (five studies) had the favourable IL-28B genotype. In Caucasians, the pooled OR of SVR with the favourable IL-28B genotype was 1.36 (95%CI: 0.98–1.88, P = 0.07) in all patients and 1.55 (95%CI: 1.10–2.18, P = 0.01) in patients treated with pegIFN and ribavirin for ≥24 weeks. In Asians, the pooled OR of SVR in patients with the favourable IL-28B genotype was 1.99 (95%CI: 0.94–4.25, P = 0.07). The favourable IL-28B genotype was also significantly associated with rapid virologic response (RVR) in both groups (Caucasians: OR: 1.82, 95%CI: 1.12–2.96, P = 0.02; Asians: 2.39, 95%CI: 1.39–4.11, P = 0.002), as well as the likelihood of an SVR in a subgroup of 350 Caucasian patients without an RVR (OR: 3.29, 95%CI: 1.67–6.51, P = 0.001). The favourable IL-28B genotype is a statistically significant predictor of SVR and RVR in Caucasian patients treated with pegIFN and ribavirin for 24 weeks. In contrast, the favourable IL-28B genotype is associated with RVR, but not SVR in Asian HCV genotype 2 patients.

Introduction
A single nucleotide polymorphism (SNP) upstream of the interleukin 28B (IL-28B) gene is associated with hepatic responsiveness to interferon therapy in hepatitis C virus (HCV) genotype 1 patients.^[1] The highly variable prevalence of the favourable IL-28B genotype in patients of varying ethnicity, in part, explains differences in the observed sustained virologic response (SVR) rates. Although other host, viral and treatment factors may influence a patient's chance of SVR, the favourable IL-28B genotype is the single most important pretreatment predictor of achieving SVR with peginterferon (pegIFN) and ribavirin therapy in genotype 1 patients.^[2] In contrast, the association of IL-28B and SVR in patients with HCV genotype 2/3 infection remains unclear.^[3–5]
                       
Although patients with HCV genotype 2/3 are more responsive to pegIFN and ribavirin, up to 30% of treated patients will not achieve SVR.^[6] Furthermore, the new direct acting antiviral agents (DAAs), boceprevir and telaprevir, are not approved for the use in patients with HCV genotype 2/3 infection.^[7] As such, pegIFN and ribavirin remain the only currently approved treatment for these patients. This meta-analysis was undertaken to better quantify the effect of the favourable IL-28B genotype on achieving SVR after treatment with pegIFN and ribavirin in patients with chronic HCV genotype 2/3 infection. In addition, the effect of IL-28B on achieving a week 4 rapid virologic response (RVR) as well as the impact of patient ethnicity on SVR was evaluated.

Materials and Methods
Literature Search

A search of the MEDLINE, PUBMED and EMBASE computer databases was performed of manuscripts published between January 2000 and January 2012, using the text words IL-28B, IL28B, IL28 and interleukin 28. Additional electronic and manual searches of abstracts presented at the American Association for the Study of Liver Diseases and American Gastroenterological Association meetings were undertaken from 2007 to 2012. Finally, consultation with expert hepatologists and recursive manual searches of references from published studies were performed.

Study Selection Criteria
Criteria for study inclusion were as follows: (i) published studies of IL-28B genotyping in adults with HCV genotype 2 or 3 infection; (ii) treatment with pegIFN and ribavirin and (iii) a reported outcome of SVR. All published studies were included regardless of sample size, but studies published solely as abstracts were excluded due to a lack of extractable data for SVR stratified by IL-28B genotype. The following exclusion criteria were applied: (i) human immunodeficiency virus (HIV) co-infection, (ii) prior liver transplantation, (iii) use of DAAs and (iv) use of IL-28B SNPs other than rs12979860 or rs8099917. After reviewing all citations identified in the literature search, two investigators (AS, RF) independently applied these selection criteria and extracted data. Any disagreements were resolved by consensus.

Data Extraction
All eligible studies were reviewed in an independent and duplicate manner by both investigators (AS, RF). For each study, the following data were collected: (i) Study: year, location, design, publication status; (ii) Patient factors: number, mean age, baseline serum aspartate aminotransferase (AST), baseline alanine aminotransferase (ALT), body mass index (BMI) and percentage with diabetes mellitus, male gender, treatment naïve and HIV co-infection; (iii) HCV factors: HCV genotype, baseline HCV RNA level, number of patients achieving RVR and SVR; (iv) Treatment factors: duration of pegIFN and ribavirin, type of pegIFN, dose reduction of antiviral medications, use of growth factors; and (v) IL-28B: IL-28B SNP tested and number with each IL-28B genotype who achieved RVR and SVR. Discrepancies in data extraction were resolved by discussion between the investigators.

IL-28B Testing
The two IL-28B SNPs reported in the individual studies were rs12979860 and rs8099917. The favourable genotype for rs12979860 is CC, while the unfavourable genotypes are CT and TT. The favourable genotype for rs8099917 is TT, while the unfavourable genotypes are TG and GG.

Primary Outcome
The primary outcome measure was achievement of SVR after pegIFN and ribavirin treatment, defined as undetectable serum HCV RNA by polymerase chain reaction (PCR) testing 24 weeks after treatment.

Secondary Outcome
A secondary outcome measure was achievement of RVR with pegIFN and ribavirin treatment, defined as an undetectable serum HCV RNA at week 4.

Quality Assessment
Study quality was assessed using an 8-item scoring system based on previously validated tools that focused on study design, population homogeneity and potential study biases.^[8,9] High quality was defined by a score of ≥6 (Table 2).

Statistical Analysis
The estimate of effect was a pooled odds ratio (OR) determined using the DerSimonian and Laird method for a random effects model. Study heterogeneity was assessed by the I ² test, with I ² > 50% suggesting substantial heterogeneity. Publication bias was assessed through the Harbord and Peters tests. Influence analysis was performed to determine whether a single study exerted undue influence. Data from the included studies were analysed separately by patient race. Sensitivity and subgroup analyses were performed based on treatment algorithm, prior treatment and study quality score. All statistics were computed using STATA 11.0 (StataCorp LP, College Station, TX, USA).

Results
An initial search revealed 308 studies of IL-28B among which 88 specifically evaluated virologic outcomes in treated patients An additional 63 studies were excluded due to the inclusion of previously treated patients, acute HCV infection, use of alternative IL-28B SNPs, use of DAAs, inclusion of liver transplant recipients, combined ethnicities or nongenotype 2/3 patients. Of the remaining 25 studies, nine were excluded due to redundant study populations, HIV co-infection or use of alternative treatment regimens, leaving 16 studies in the current analysis (Fig. 1).'

Caucasians With HCV Genotype 2/3

SVR Outcome.There were 11 studies of Caucasians with HCV genotype 2/3.^[3,10–19] Among 1599 patients, 43% had the favourable IL-28B genotype CC at rs12979860 (Table 1). Overall, 83% of patients with the favourable IL-28B genotype achieved SVR as compared to 78% of patients with the unfavourable genotype, with a pooled OR of 1.36 (95%CI: 0.98–1.88, P = 0.07) with low heterogeneity between studies (I ² = 29%). In a subgroup analysis of eight studies that included only treatment naïve patients, the pooled OR of SVR was 1.21 (95%CI: 0.85–1.74, P = 0.29). Among the eight studies with pegIFN and ribavirin treatment for at least 24 weeks, the pooled OR of SVR was 1.55 (95%CI: 1.10–2.18, P = 0.01) as compared to 1.17 (95%CI: 0.53–2.58, P = 0.70) in the studies with variable duration treatment regimens. Among the four studies that used a ribavirin dose ≥800 mg/day for at least 24 weeks, the pooled OR of SVR was 1.02 (95%CI: 0.55–1.92, P = 0.95). The pooled OR was 1.49 (95%CI: 1.02–2.19, P = 0.04) in the six high-quality studies vs 1.33 (95%CI: 0.72–2.43, P = 0.36) in the five low-quality studies (Table 2).

RVR Outcome.
Six studies reported RVR data in 1265 Caucasian patients of which 42% had the favourable IL-28B genotype. Seventy-seven percent of patients with the favourable IL-28B achieved RVR as compared to 65% of patients with the unfavourable genotype, with a pooled OR of 1.82 (95%CI: 1.12–2.96, P = 0.02) and moderate heterogeneity between studies (I ² = 69%).
Among 350 patients who achieved RVR in three studies, 89% of 142 patients with the favourable IL-28B genotype and 85% of 208 patients with the unfavourable IL-28B genotype also achieved SVR (pooled OR: 1.37, 95%CI: 0.71–2.67, P = 0.35). In contrast, among 184 patients who did not achieve RVR, 78% of 68 patients with the favourable IL-28B and 50% of the 116 with the unfavourable IL-28B genotype achieved SVR (pooled OR: 3.29, 95%CI: 1.67–6.51, P = 0.001).

Asians With HCV Genotype 2

SVR Outcome.
There were five studies^[20–24] of 833 Asian patients with HCV genotype 2 infection, in which 86% had the favourable IL-28B genotype. Overall, 86% of patients with the favourable IL-28B genotype achieved SVR, while 75% of patients with the unfavourable IL-28B genotype achieved SVR with a pooled OR of 1.99 (95%CI: 0.94–4.25, P = 0.07). There was low to moderate heterogeneity between studies (I ² = 44%). In a subgroup analysis of the two studies that explicitly included only treatment naïve patients, the pooled OR of SVR was 1.54 (95%CI: 0.81–2.93, P = 0.18). Among the four low-quality studies, the pooled OR was 2.22 (95%CI: 01.14–4.35, P = 0.02).

RVR Outcome. In the two studies reporting RVR data, 88% of the 594 patients had the favourable IL-28B genotype. Eighty-two percent of patients with the favourable IL-28B genotype and 62% of patients with the unfavourable genotype achieved RVR, with a pooled OR of RVR of 2.39 (95%CI: 1.39–4.11, P = 0.002).

Pooled Analysis
After combining the 16 studies with 2432 patients, the pooled OR of SVR in patients with the favourable IL-28B genotype was 1.48 (95%CI: 1.09–2.02, P = 0.01). There was low heterogeneity between studies (I ² = 34%). The pooled OR was 1.27 (95%CI: 0.95–1.69, P = 0.11) in the 10 studies with only treatment naïve patients and 1.44 (95%CI: 0.98–2.11, P = 0.06) among the seven high-quality studies. There was no evidence of publication bias by the Harbord or Peters tests (P = 0.69 and P = 0.33, respectively).

Discussion

While IL-28B genotyping has an important role in HCV genotype 1 patients treated with pegIFN and ribavirin, its value in HCV patients with genotype 2/3 remains less clear.^[2] This meta-analysis demonstrates that the favourable IL-28B genotype is a significant predictor of SVR in Caucasian patients with HCV genotype 2/3 treated with pegIFN and ribavirin for 24 weeks. Additionally, IL-28B genotype may be predictive of SVR in Asian patients with HCV genotype 2, although the pooled OR of SVR did not reach statistical significance perhaps due to inadequate sample size (Fig. 2).

Our results also suggest that the favourable IL-28B genotype increases the odds of achieving RVR in Caucasian and Asian patients with HCV genotype 2/3 infection, a finding similar to that reported in HCV genotype 1 patients.^[2] Furthermore, the results of this study demonstrate that IL-28B genotype may be helpful in stratifying the odds of SVR in patients with HCV genotype 2/3 who do not achieve RVR. Prior data suggest that HCV genotype 2/3 patients with low viral load who achieve RVR may be candidates for a shortened duration of therapy to 12–16 weeks.^[25,26] However, it is unclear whether the favourable IL-28B genotype can be used to further identify patients from this group who are more likely to achieve SVR and/or are at lower risk of relapse. Individual studies have not found an association between IL-28B genotype and SVR rates in patients treated for <24 weeks after achieving RVR, but they may be under-powered.^[13,19] Therefore, IL-28B testing may play an important role in counselling individual patients that are receiving antiviral therapy and particularly in those experiencing side effects who do not achieve RVR.

In the era of DAAs, IL-28B testing in HCV genotype 1 patients may be limited to specific populations in which DAAs are not yet approved, such as in those with HIV co-infection.^[2] In contrast, pegIFN and ribavirin are the only currently approved agents for HCV genotype 2/3 infection. An improved ability to predict SVR may be particularly important for patients intolerant to this regimen, but the absolute difference in response rates in those with and without the favourable IL28-B genotype is small.

In contrast to our results, another recent meta-analysis of IL-28B testing and SVR in patients of combined HCV genotypes reports a statistically significant pooled OR of SVR in Asians with HCV genotype 2 infection,^[5] a finding likely due to the inclusion of only two Asian studies. Our own subgroup analysis of five Asian studies identified a strong trend which does not reach statistical significance. The meta-analysis by Chen et al. also demonstrates a lack of association between the favourable IL-28B genotype and SVR in Caucasian patients with HCV genotype 2/3, although only five studies were included. Assessing the role of IL-28B testing in nonCaucasian patients with HCV genotype 2/3 was limited in our study. Among the five pooled Asian studies, two explicitly included some treatment-experienced patients who may have reduced the impact of IL-28B genotyping in predicting SVR. In addition, there were no studies of HCV genotype 2/3 African American patients, a group with traditionally lower response to interferon. However, a substantially lower proportion of African Americans are infected with HCV genotype 2/3 in the general US population compared to Caucasians (i.e. 5% vs 20–30%).^[27,28] Because of the lack of stratification by HCV genotype in many studies, we were unable to determine whether IL-28B genotype has greater utility in patients with HCV genotype 2 vs 3. However, this issue is worthy of further study because HCV genotype 3 patients with a high baseline HCV RNA level are more prone to relapse after a 24-week course of treatment compared to those with HCV genotype 3 and low viral load or HCV genotype 2 infection.^[29] Finally, how IL-28B testing fits in with other known pretreatment predictors of SVR remains unknown.

In conclusion, this meta-analysis demonstrates that the favourable IL-28B genotype is significantly associated with SVR in Caucasian patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin for 24 weeks. However, the magnitude of the absolute difference in SVR rates (83% vs 78%) is small and may not influence the decision to initiate treatment. In addition, the favourable IL-28B genotype is associated with RVR as well as SVR in patients who do not achieve RVR, and this information may prove useful to clinicians when counselling individual patients during therapy.

Abstract and Introduction

Materials and Methods

Results

Discussion