March 28, 2012

ICVH 2012: Next-Generation HCV Protease Inhibitor Shows Promise

From Medscape Medical News

Megan Brooks

March 28, 2012 (New York, New York) — In vitro data on a next-generation hepatitis C virus (HCV) NS3/4A protease inhibitor garnered considerable interest here at the International Conference on Viral Hepatitis 2012.

MK-5172, being developed by Merck & Co, demonstrated "potent activity" against the majority of primary first-generation protease inhibitor resistance-associated variants (RAVs) in biochemical and cell-based phenotype assays, reported Richard J. Barnard, PhD, from Merck & Co.

MK-5172 also inhibited patient-derived NS3 proteases across HCV genotypes and retained activity against HCV proteases isolated from 5 patients with vaniprevir RAVs.

In his presentation, Dr. Barnard noted that virologic failure with first-generation protease inhibitors is often associated with the emergence of RAVs; it is important that next-generation molecules are pangenotypic and active against first-generation protease inhibitor RAVs. "MK-5172 fulfills the profile expected of a next-generation" HCV protease inhibitor, he said.

Douglas T. Dieterich, MD, professor of medicine from the division of liver diseases at Mount Sinai School of Medicine in New York City, who was not involved in the study, told Medscape Medical News that "MK-5172 represents a promising potential best-in-class second-generation protease inhibitor."

"MK-5172 is a truly second-generation protease inhibitor," he explained. "This is really good news for the people who have already failed treatment with a first-generation protease inhibitor."

MK-5172, Dr. Dieterich said, "has activity against the most common resistance mutations caused by telaprevir and boceprevir. Even more encouraging for global use, it is active against genotypes 1, 2, 4, 5, and 6."

Dr. Barnard reports being an employee of Merck & Co and owning stock in the company. Dr. Dieterich reports financial relationships with Bristol-Myers Squibb, Gilead Sciences, Roche Laboratories, and Boehringer Ingelheim.

International Conference on Viral Hepatitis (ICVH) 2012: Oral Abstract: 79340. Presented March 26, 2012.

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March 28, 2012 4:37 pm

Tumor response assessment to sorafenib in patients with advanced hepatocellular carcinoma: do we need new criteria?

By Dr Mohmed Bouattour

Sorafenib, an oral multi-tyrosine kinase inhibitor, is the first and so far the only drug that has shown overall survival benefit in patients with advanced hepatocellular carcinoma (HCC) in two large multicenter, double-blind, placebo-controlled randomized phase III trials [1-2]. Despite the survival benefit in this population, sorafenib has been infrequently associated with changes in tumors dimensions, challenging standard RECIST criteria [3]. Tumor shrinkage and dimensional change, usually assessed to define tumor response of cytotoxic drugs based on the morphological RECIST criteria, was observed in less than 5% of patients. Furthermore, changes in tumor angiogenesis are observed such as decrease in the number of vessels in tumor masses and the appearance of large areas of intratumor necrosis (Figure 2). This feature is acknowledged to reflect the antitumor activity of antiangiogenic drugs that does not always translate into changes in the diameter of the tumor, making the radiological evaluation of efficacy using standard RECIST criteria often inappropriate [4].

In the phase II study evaluating sorafenib [5], among 11 patients strictly evaluated for intratumor necrosis appearance in addition to RECIST criteria, several tumors had size increasing and as well as increasing tumor necrosis. Before treatment, the mean diameter of these tumors was 6.4 cm (interval 2.5 to 14.2 cm) and the mean proportion of tumor necrosis was 9.8% (interval 0.4% to 33.5%). After treatment, the mean diameter of these tumors was 7.2 cm (interval 1.7 to 16.0 cm) and the mean proportion of tumor necrosis was 27% (interval 0.7 to 75%) [5]. Similar observations were shown with sunitinib [6] and bevacizumab [7].

Given this context, experts have suggested new response criteria based on changes in tumor vascularization and density. The modified RECIST criteria (mRECIST) were an amendment of the RECIST criteria; they take into account dimension changes in the tumor arterial enhancement [8]. Choi criteria [9] where composite criteria, covering tumor size and tumor density in CT scan, have been proposed to evaluate response to sunitinib, another potent antiangiogenic agent, in HCC patients [10].

We recently showed in the American Association for the Study of Liver Disease meeting (AASLD) 2011 at San Francisco, interesting results about the relevance of theses criteria in patients with advanced HCC and treated with sorafenib [11]. In our study, 60 patients were evaluated according to those criteria by CT-scan performed within 3 months of treatment. At the first tumor evaluation,we observed that only 2 patients (3.3%) experienced a decrease ≥ 30% of the largest diameter. The majority of patients (51.6%) had no significant changes in tumor size. This confirms the low response rates by RECIST criteria observed with sorafenib. According to mRECIST, 12 patients (21.4%) were categorized as early responder with 2 complete response (3.3%) and 10 partial response (16.7%). When we apply the Choi criteria, we noticed that 27 patients (45%) were considered as partial responders and 14 patients (23.3%) had tumor stabilization. Interestingly, these new criteria were able to identify responders with better overall survival. In fact, responder patients according to mRECIST had better OS than progressive patients (> 14.4 months vs. 5.8 months, respectively, p = 0.0008). Moreover, Choi criteria can predict overall survival in patients with HCC treated by sorafenib since the median OS in the group of responder patients was > 14.4 months compared to the median OS of 6 months in the group of progressive patients (p= 0.0012) [11]. Our results were comparable to another published study [12] in which the best tumor response rates of 53 patients were assessed by RECIST and mRECIST. In this cohort, the rates of objective response, stable disease were 2% and 79% respectively according to RECIST and 23% and 57% respectively by mRECIST. Similar to our results, response according mRECIST criteria can predict survival, since the median OS in the group of responder patients was 18 months compared to the median OS of 8 months in the group non-responder patients (p= 0.013) [12].

Taken together, those results stress the need to evaluate behind tumor size changes, vascular modification and disturbance observed with sorafenib and other antiangiogenic agents in patients with HCC. Further robust studies should take into account those criteria to validate them clinical practice.

References

1. Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-90.
2. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34.
3. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, el al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-16.
4. Bouattour M, Dreyer C, Faivre S, Raymond E. Evaluation of antiangiogenic effects: biomarkers and functional imaging. International Oncology Updates: Present and future for antiangiogenic therapies in cancer. Permalyer Barcelona, 2010: 63-84.
5. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293-300.
6. Faivre S, Bouattour M, Dreyer C, Raymond E. Sunitinib in hepatocellular carcinoma: redefining appropriate dosing, schedule, and activity endpoints. J Clin Oncol 2009; 27: 248-50.
7. Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992-98.
8. Lencioni, R. & Llovet, J. M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).
9. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007 ;25:1753-9.
10. Faivre S, Zappa M, Vilgrain V, Boucher E, Douillard JY, Lim HY, et al. Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. Clin. Cancer Res. 2011; 17, 4504–12.
11. Bouattour M, Wassermann J, Bruno O, et al. Blinded independent centralresponse assessment using RECIST, modified RECIST, and Choi criteria in patients treated with sorafenib for advanced advanced hepatocellular carcinoma. Oral communication presented at ILCA 2011 in Hong Kong and at AASLD 2011 in San Francisco. Hepatology; 2011 54(S1) (A 270).
12. Edeline J, Boucher E, Rolland Y, Vauléon E, Pracht M, Perrin C,et al. Comparison of tumor response by Response Evaluation Criteria in Solid Tumors(RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer. 2012;118(1):147-56.

About the Author

Dr-Mohamed-Bouattour-150x150

Dr Mohamed Bouattour

Mohmed Bouattour is a Clinical physician in the department of Oncology and Hepatology at Beuajon Hospital in France. Dr. Mohamed Bouattour received his Gastroenterology Hepatology training at the Faculty of medicine of Sfax and Tunis in Tunisia. He completed and achieved his fellow at the department of Hepatology and Oncology in Beaujon Hospital in Paris France. He is currently a practitioner in Beaujon Hospital at these departments.

His interests go toward the field of Hepatology to study liver disease, hepatic malignancies and clinical trials to evaluate new agents in hepatocellular carcinoma.

Dr. Mohamed Bouattour is a peer reviewer for several scientific journals and has authored and co-authored more than 20 publications as well as book chapters. He is an active member of the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver (AASLD) and The American Society of Clinical Oncology (ASCO).

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The Journal of Sexual Medicine

Early View (Online Version of Record published before inclusion in an issue)

Shiu-Dong Chung MD1,2,3, Joseph J. Keller MPH4, Yu-Chih Liang PhD4, Herng-Ching Lin PhD3,*

Article first published online: 29 FEB 2012

DOI: 10.1111/j.1743-6109.2012.02663.x

© 2012 International Society for Sexual Medicine

Keywords:
  • Chronic Liver Diseases;
  • Erectile Dysfunction;
  • Hepatitis
ABSTRACT

Introduction. Chronic liver diseases are often accompanied by hypogonadism, testicular atrophy, and a reduction in libido, all of which are factors that may contribute to the development of erectile dysfunction (ED). However, large-scaled studies investigating the association between ED and viral hepatitis are still sparse.

Aim. This study aimed to estimate the association between ED and a prior diagnosis of viral hepatitis using a population-based dataset with a case-control design in Taiwan.

Methods. We identified 6,429 patients with ED as cases and randomly selected 32,145 subjects as controls. We used conditional logistic regression to compute the odds ratio (OR) for having previously received a diagnosis of viral hepatitis between cases and controls.

Main Outcome Measure. The prevalence and odds of having been previously diagnosed with hepatitis B, hepatitis C, a coinfection with hepatitis B and C, and viral hepatitis of other etiology were calculated between cases and controls.

Results. Of the 38,574 sampled subjects, 3,930 (10.2%) had viral hepatitis before the index date; viral hepatitis was found in 900 (14.0%) cases and in 3,030 (9.4%) controls. After adjusting for monthly income, geographic location, hypertension, diabetes, hyperlipidemia, hepatic steatosis, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome, cases were found to be more likely to have prior viral hepatitis than controls (OR = 1.51, 95% confidence interval [CI] = 1.39–1.64, P < 0.001). A much higher proportion of coinfection with viral hepatitis B and C was additionally found among cases (OR = 1.84, 95% CI = 1.72–1.97) than controls.

Conclusions. We conclude that ED was associated with prior viral hepatitis, especially with a coinfection of hepatitis B and C, after adjusting for potential confounders. Chung S-D, Keller JJ, Liang YC, and Lin HC. Association between viral hepatitis and erectile dysfunction: A population-based case-control analysis. J Sex Med **;**:**–**.

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Screening for HCV Infection in Jails - Viewpoint

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JAMA. 2012 March 26

Anne C. Spaulding, MD, MPH
David L. Thomas, MD, MPH

Jails are an ideal setting for routine hepatitis C virus (HCV) screening. At the turn of this century, the Centers for Disease Control and Prevention estimated that 16% to 41% of US inmates had serological evidence of prior HCV exposure and 12% to 35% had chronic infection.1 This high prevalence of hepatitis C, coupled with the fact that more than 7 million individuals passed through jails and prisons each year in the late 1990s, suggested that persons released from the criminal justice system may account for up to 29% to 43% of the 2.7 million to 3.9 million persons infected with hepatitis C in the United States.1,2

Most inmates with chronic hepatitis C are not aware of their infection. Although exact data on recognition of infection are not available, even in the US general population, only 25% to 35% of persons infected with HCV are aware of their condition.2 In recent years, 9 million unique individuals enter and leave jails yearly and an additional 1.5 million persons spent an entire year in prison.3 If, conservatively, 12% are infected with HCV, and because in marginalized populations those who are unaware of infection would likely be closer to 75% rather than 65%, then it is possible that as many as 1.0 million persons with undiagnosed HCV infection might come in contact with the correctional system each year.

According to US Supreme Court case law in Estelle v Gamble (429 US 97 [1976]), correctional facilities cannot display deliberate indifference to the health care needs of their residents. Thus, some HCV care has been provided in the correctional systems. However, because HCV therapy may last for up to 48 weeks, the infection could realistically only be treated in approximately 1% of incarcerated persons, according to modeling using parameters derived from a combined jail-prison correctional system.4 Finding hepatitis C among convicted persons with long sentences carries ethical obligations to treat appropriate candidates once the diagnosis is confirmed. The difference between those who could be potentially treated compared with those infected occurs because in short-term correctional facilities the median length of stay is 48 hours and jail detainees account for 95% of the persons incarcerated in and released from correctional facilities.3 The majority of persons entering a correctional facility during a given year stay for less than 12 months. Because treatment could not realistically be provided for short-term inmates, HCV screening has not been routinely conducted in jails, an omission that may represent a missed opportunity to identify persons with undiagnosed HCV infection.

Recognition of HCV infection matters. In May 2011, the US Food and Drug Administration approved 2 new, direct acting agents for treatment of genotype 1 chronic HCV infection. When used with the former standard of care (peginterferon and ribavirin), boceprevir or telaprevir increases cure rates by 20% to 30%. In addition, 40% to 60% of individuals will be able to abbreviate treatment substantially with the new drugs.5 A recent study suggested that HCV treatment can be effectively provided in community settings. Project ECHO (Extension for Community Health Care Outcomes) offers a model to increase availability of hepatitis treatment not just in prisons but also in publicly funded community health centers so that the incarcerated setting is not the only place in which an indigent person can access care.6 With the advent of "all oral" HCV treatments in the future, treatment feasibility and effectiveness will increase further, thus amplifying the public health importance of expanded HCV detection in jails.7

Recognition of HCV infection in a rapidly changing environment is possible. In February 2011, the US Food and Drug Administration approved a rapid fingerstick HCV test; a waiver that would allow its use in jails and other facilities without laboratory licensure was granted in November 2011. Thus, the HCV assay can be performed in 20 minutes on jail entrants, using point of care, opt-out testing strategies, that have been proven successful for HIV testing among inmates.8 Following opt-out hepatitis C screening in jails, downstream health care can be coordinated between jails, prisons, and the community. In a demonstration project designed to integrate opt-out HIV screening with other medical services, including hepatitis C testing, at the Fulton County, Georgia, jail, persons with positive test results were referred to a public hepatitis clinic integrated into the primary care services of Atlanta's Grady Memorial Hospital. This project is consistent with the Department of Health and Human Services Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis,9 which calls for improved access to hepatitis treatment in primary care settings. In addition, the Affordable Care Act will eventually provide a mechanism for funding the care of persons whose HCV infection is identified in jails and who are released subsequently.

There are challenges to widespread implementation of HCV screening in short-term and long-term correctional facilities. Provision of medical screening and treatment is not the primary mission of correctional facilities. Jails are challenged with high throughput and entrants may have insufficient time for the counseling and confirmatory testing that are optimal in HCV screening programs. HCV screening and the coordination of care with existing health care facilities will require funding, although the economic benefits of HCV screening are long-term and may be realized by different state or federal agencies than those asked to fund the programs.

These challenges can be overcome and HCV screening could be implemented routinely in jails. Focusing efforts on detainees with a high pretest probability of having hepatitis C can decrease the number of tests that would need to be performed to find these infected persons.1 Directing HCV testing to persons born between 1945 and 1965, the birth cohort that includes an estimated two-thirds of those individuals currently infected with HCV in the United States, and following diagnosis with treatment using direct acting agents, has been shown to be cost-effective in community clinical settings.10 Concentrating on the 1945-1965 birth cohort in the correctional setting should likewise optimize the yield of HCV screening programs.

Thus, implementation of opt-out HCV screening should be considered for persons incarcerated in jails. If 70% of the approximately 1 million persons with hepatitis C who are in correctional facilities are offered the opportunity to have HCV testing, and if 70% accept such an offer, HCV screening in detainees may lead to the identification of as many as a half million new cases of hepatitis C in the first year of the program. Coupled with counseling and referral for treatment if released, such programs could have enormous effects on the HCV epidemic in the United States. With new treatments and new diagnostics, local public health agencies should invite jails to partner in hepatitis C screening.

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HCV CO-infection Guidelines Updated- New HCV Treatment

Considerations for Antiretroviral Use in Patients with Coinfections

Hepatitis C (HCV)/HIV Coinfection

(Last updated:3/27/2012; last reviewed:3/27/2012)

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HIV/Hepatitis C Coinfection

Updates to this section focus on the newly approved HCV NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, the known interactions between these drugs and ART, and interim results from current ongoing research in HIV/HCV coinfected patients. The updated section includes preliminary recommendations on coadministration of the HCV NS3/4A drugs and ART.

A combination regimen of peginterferon and ribavirin (PegIFN/RBV) has been the mainstay of treatment for HCV infection. In HCV genotype 1-infected patients without HIV, addition of a HCV NS3/4A protease inhibitor (PI) boceprevir or telaprevir to PegIFN/RBV significantly improves the rate of sustained virologic response (SVR) [14, 15]. Clinical trials of these HCV PIs in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection in HIV-infected patients are currently under way. Both boceprevir and telaprevir are substrates and inhibitors of CYP3A4/5 and p-glycoprotein (p-gp); boceprevir is also metabolized by aldo-ketoreductase. These drugs have significant interactions with certain ARV drugs that are metabolized by the same pathways. As such, the presence of HCV infection and the treatment of HCV may influence HIV treatment as discussed below.

Concurrent treatment of HIV and HCV is feasible but may be complicated by high pill burden, drug interactions, and overlapping drug toxicities. In this context, the decision to treat chronic HCV should also include consideration of the medical need for such treatment on the basis of an assessment of HCV disease stage. Some clinicians may choose to defer HCV therapy in HIV/HCV-coinfected patients with no or minimal liver fibrosis. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (boceprevir or telaprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment.

Considerations for the use of HCV NS3/4A protease inhibitors (boceptrevir and telapracir) and antiretroviral therapy:

The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly.

Boceprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. After 4 weeks of PegIFN/RBV therapy, boceprevir is added to the regimen for 24, 32, or 44 additional weeks of HCV therapy. Data on the use of an HCV regimen containing boceprevir together with ART in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with boceprevir plus PegIFN/RBV (64 patients) than with PegIFN/RBV alone (34 patients). In this study, patients received ART that included HIV-1 ritonavir-boosted atazanavir (ATV/r), darunavir (DRV/r), or lopinavir (LPV/r) or raltegravir (RAL) plus dual NRTIs [40].

Boceprevir is primarily metabolized by aldo-keto reductase, but because the drug is also a substrate and inhibitor of CYP3A4/5 and p-gp enzymes, it may interact with ARVs metabolized by these pathways. Based on drug interaction studies in healthy volunteers, boceprevir can be coadministered with RAL [41]. However, coadministration of boceprevir with ATV/r, DRV/r, LPV/r, or efavirenz (EFV) is not recommended because of bidirectional drug interactions [42, 43] (see Table 15a and 15b). Importantly, the pharmacokinetic (PK) interactions of HIV PIs with boceprevir were not identified before the approval of boceprevir and before participant enrollment in the HIV/HCV-coinfection trial; consequently, some coinfected patients have received HIV PIs and boceprevir during HCV treatment. Patients who are currently receiving these drug combinations should be advised not to stop any medication until contacting their health care providers. If therapy with HIV PIs and boceprevir is continued, patients should be closely monitored for HIV and HCV responses and consideration should be given to switching the HIV PI or EFV to RAL during boceprevir therapy. Additional clinical trial data are needed to determine if other ARVs may be coadministered with boceprevir.

Telaprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. Telaprevir is administered in combination with PegIFN/RBV for the initial 12 weeks of HCV therapy followed by 12 or 36 weeks of additional treatment with PegIFN/RBV. Data on the use of this regimen in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with telaprevir plus PegIFN/RBV (38 patients) than with PegIFN/RBV alone (22 patients). In this study, patients received ART containing EFV or ATV/r plus tenofovir/emtricitabine (TDF/FTC) or no ART during the HCV therapy [44].

Because telaprevir is a substrate and an inhibitor of CYP3A4 and p-gp enzymes, the drug may interact with ARVs metabolized by these pathways. On the basis of drug interaction studies in healthy volunteers and data on responses in coinfected patients enrolled in the small clinical trial noted above, telaprevir can be coadministered with ATV/r [45] and RAL [46] at the standard recommended dose of telaprevir (750 mg every 7Ð9 hours) and with EFV at an increased dose of telaprevir (1125 mg every 7Ð9 hours) (see Table 15b); however, coadministration of telaprevir with DRV/r, fosamprenavir/ritonavir (FPV/r), or LPV/r is not recommended because of bidirectional drug interactions [45]. Data on PK interactions of telaprevir with other ARVs including non-nucleoside reverse transcriptase inhibitors (NNRTIs) other than EFV and with maraviroc (MVC) are not available; therefore, coadministration of telaprevir with other ARVs cannot be recommended.

Following are preliminary recommendations for the use of boceprevir or telaprevir in HIV patients coinfected with HCV genotype 1 based on current ART use. These recommendations may be modified as new drug interaction and clinical trial information become available.

Capture

Patients receiving other ARV regimens:

· If HCV disease is minimal (no or mild portal fibrosis), consider deferring HCV treatment given rapidly evolving HCV drug development.

· If good prognostic factors for HCV treatment response are presentÑIL28B CC genotype or low HCV RNA level (<400,000 International Unit [IU]/mL)Ñconsider use of PegIFN/RBV without HCV NS3/4A PI.

· On the basis of ART history and HIV genotype testing results, if possible, consider switching to the ART regimens listed above to permit the use of boceprevir or telaprevir.

· For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed. In such patients, telaprevir may be the preferred HCV NS3/4A PI because its duration of use (12 weeks) is shorter than that of boceprevir (24 to 44 weeks).

In summary, HCV coinfection and use of PegIFN/RBV with or without HCV NS3/4A PIs (telaprevir or boceprevir) to treat HCV may impact the treatment of HIV because of increased pill burden, toxicities, and drug-drug interactions. Because ART may slow the progression of HCV-related liver disease, ART should be considered for most HIV/HCV-coinfected patients, regardless of CD4 count. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (telaprevir or boceprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug-drug interactions and/or drug toxicities that may develop during the period of concurrent HIV and HCV treatment. The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly.

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PR-Logo-Newswire

PRESS RELEASE

March 28, 2012, 2:29 p.m. EDT

KING OF PRUSSIA, Pa., March 28, 2012 /PRNewswire via COMTEX/ -- Administration of albumin reduces morbidity and mortality in cirrhotic patients undergoing large-volume paracentesis due to severe ascites, according to a new meta-analysis published online today in Hepatology, the official journal of the American Association for the Study of Liver Diseases. Compared with alternative treatments, albumin, a natural plasma-derived protein that expands blood plasma volume, significantly reduced the circulatory dysfunction that often occurs after large-volume paracentesis and also significantly reduced the occurrence of hyponatremia (low blood sodium levels). In addition, risk of death was 36 percent lower in patients receiving albumin than in those receiving other treatments.

"Albumin is the gold standard for preventing circulatory dysfunction following paracentesis greater than five liters. However, other volume expanders as well as vasoconstrictors have been considered as potential alternatives," said Mauro Bernardi, M.D., Professor of Internal Medicine at Bologna University, Bologna, Italy and lead author of the meta-analysis. "Our findings, which combine all the available evidence from randomized clinical trials, confirm that albumin is the best choice for prevention of circulatory dysfunction, and for the first time show decreased incidence of hyponatremia and improved survival with albumin use."

Within 10 years of receiving a diagnosis, the majority of patients with liver cirrhosis develop ascites, or fluid accumulation in the abdominal cavity. Symptoms include abdominal swelling, major discomfort and impaired breathing often necessitating hospitalization. Patients with ascites have a poor prognosis, with a 50 percent mortality rate over two years. To relieve the pressure caused by the excessive abdominal fluid, a procedure called paracentesis uses a needle to drain the fluid from the abdominal cavity. However, the abrupt removal of large amounts of fluid can worsen existing circulatory dysfunction, leading to a reduction in effective volemia that adversely affect the kidney and other organs.

The meta-analysis, which included results from 17 randomized clinical trials with 1,225 total patients, found that albumin reduced the risk of post-paracentesis circulatory dysfunction by 61 percent compared with alternative treatments. The analysis also found that the risk of hyponatremia, a condition associated with worsening brain function and death, was decreased 42 percent with albumin administration compared to other treatments, further supporting the well-accepted clinical practice of infusing albumin as the first choice in adjunctive treatment for patients requiring large-volume paracentesis.

About CSL Behring

CSL Behring is a global leader in the plasma protein biotherapeutics industry. Passionate about improving the quality of patients' lives, CSL Behring manufactures and markets a range of safe and effective plasma-derived and recombinant products and related services. The company's therapies are used in the treatment of immune deficiency disorders, hereditary angioedema, haemophilia, von Willebrand disease, other bleeding disorders and inherited emphysema. Other products are used for the prevention of hemolytic diseases in the newborn, in cardiac surgery, organ transplantation and in the treatment of burns. The company also operates one of the world's largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical company with headquarters in Melbourne, Australia. For more information, visit www.cslbehring.com .

Contact:Sheila A. Burke, Director, Communications & Public RelationsWorldwide Commercial OperationsCSL Behring 610-878-4209 (o)484-919-2618 (c)Sheila.Burke@cslbehring.com 

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HIV and hepatitis C survival in used syringes




Uploaded by on May 8, 2009

An description of the experiments done at Yale university to find out how long HIV and hepatitis C can survive in used syringes.


doi: 10.3949/ccjm.79a.11082

Cleveland Clinic Journal of Medicine March 2012 vol. 79 3 213-222

  1. NAIM ALKHOURI, MD
  1. Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
  1. NIZAR N. ZEIN, MD*

+ Author Affiliations

  1. Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
  1. ADDRESS: Nizar N. Zein, MD, Department of Gastroenterology and Hepatology, A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail zeinn@ccf.org.

Abstract

Recent trials evaluated the safety and efficacy of two protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), added to standard care with pegylated interferon and ribavirin, in patients with chronic hepatitis C virus (HCV) infection. These drugs open the door for triple therapy and other new therapies involving combinations of other direct-acting antiviral agents to become the new standard of care for this population.

Key points

Standard care with the combination of pegylated interferon and ribavirin produces a sustained virologic response in about 40% of patients infected with HCV genotype 1, the most prevalent genotype in North America.

New phase 3 trials showed that the addition of an oral protease inhibitor (boceprevir or telaprevir) increased the sustained virologic response rates to 70% in patients infected with HCV genotype 1.

Boceprevir and telaprevir must be used in combination with pegylated interferon and ribavirin; they should not be used as monotherapy because of concern about the development of drug-resistant mutations.

The main side effects of boceprevir were anemia and dysgeusia. Adverse events associated with telaprevir included rash, pruritus, anemia, and diarrhea.

The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).

Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.

This review summarizes the results of recent phase 3 clinical trials that evaluated the safety and efficacy of these new agents (TABLE 1).15

A MAJOR PUBLIC HEALTH PROBLEM

HCV infection is a major public health problem. Nearly 4 million people in the United States are infected.6,7 Most patients with acute HCV infection become chronically infected, and up to 25% eventually develop cirrhosis and its complications, making HCV infection the leading indication for liver transplantation.810

Chronic HCV infection has a large global impact, with 180 million people affected across all economic and social groups.11 The highest prevalence of HCV has been reported in Egypt (14%), in part due to the use of inadequately sterilized needles in mass programs to treat endemic schistosomiasis. In developed countries, hepatocellular carcinoma associated with HCV has the fastest growing cancer-related death rate.12

T1_medium

TABLE 1 Phase III clinical trials of boceprevir and telaprevir

 

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

The goal of HCV treatment is to eradicate the virus. However, most infected patients (especially in the United States and Europe) are infected with HCV genotype 1, which is the most difficult genotype to treat.

Successful treatment of HCV is defined as achieving a sustained virologic response—ie, the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy. Once a sustained virologic response is achieved, lifetime “cure” of HCV infection is expected in more than 99% of patients.13

The current standard therapy for HCV, pegylated interferon plus ribavirin for 48 weeks, is effective in only 40% to 50% of patients with genotype 1 infection.14 Therefore, assessing predictors of response before starting treatment can help select patients who are most likely to benefit from therapy.

Viral factors associated with a sustained virologic response include HCV genotypes other than genotype 1 and a low baseline viral load.

Beneficial patient-related factors include younger age, nonblack ethnicity, low body weight (≤ 75 kg), low body mass index, absence of insulin resistance, and absence of advanced fibrosis or cirrhosis.

More recently, a single-nucleotide polymorphism near the interleukin 28B (IL28B) gene, coding for interferon lambda 3, was found to be associated with a twofold difference in the rates of sustained virologic response: patients with the favorable genotype CC were two times more likely to achieve a sustained virologic response than patients with the CT or TT genotypes.1517

PROTEASE INHIBITORS: MECHANISM OF ACTION

HCV is a single-stranded RNA virus, and its genome encodes a single polyprotein of about 3,000 amino acids. This polyprotein is cleaved by proteases during and after translation into four structural and six nonstructural proteins. The NS3/4A protease plays an important role in viral replication by cleaving the HCV polyprotein and releasing most of the nonstructural proteins (FIGURE 1).18,19

(Click on picture to enlarge)

F1_medium

FIGURE 1.

T2_medium

TABLE 2 Adverse events reported in clinical trials of boceprevir and telaprevir

NS3/4A protease inhibitors rely on the principle of end-product inhibition, in which the cleavage product of the protease (a peptide) acts to inhibit the enzyme activity; this is why they are called peptidomimetics. The active site of the NS3/4A protease is a shallow groove composed of three highly conserved amino acid residues, which may explain why protease inhibitors display high antiviral efficacy but pose a low barrier to the development of resistance.20

Protease inhibitors are prone to resistance

The development of viral resistance to protease inhibitors has been a major drawback to their use in patients with chronic HCV infection.21

HCV is a highly variable virus with many genetically distinct but closely related quasispecies circulating in the blood at any given time. Drug-resistant, mutated variants preexist within the patient’s quasispecies, but only in small quantities because of their lesser replication fitness compared with the wild-type virus.22 When direct-acting antiviral therapy is started, the quantity of the wild-type virus decreases and the mutated virus gains replication fitness. Using protease inhibitors as monotherapy selects resistant viral populations rapidly within a few days or weeks.

HCV subtypes 1a and 1b may have different resistance profiles. With genotype 1a, some resistance-associated amino acid substitutions require only one nucleotide change, but with genotype 1b, two nucleotide changes are needed, making resistance less frequent in patients with HCV genotype 1b.23

BOCEPREVIR

Boceprevir is a specific inhibitor of the HCV viral protease NS3/4A.

In phase 3 clinical trials, boceprevir 800 mg three times a day was used with pegylated interferon alfa-2b (PegIntron) 1.5 μg/kg/week and ribavirin (Rebetol) 600 to 1,400 mg daily according to body weight.

Before patients started taking boceprevir, they went through a 4-week lead-in phase, during which they received pegylated interferon and ribavirin. This schedule appeared to reduce the incidence of viral breakthrough in phase 2 trials, and it produced higher rates of sustained virologic response and lower relapse rates compared with triple therapy without a lead-in phase.

Rapid virologic response was defined as undetectable HCV RNA at week 4 of boceprevir therapy (week 8 of the whole regimen).

Boceprevir in previously untreated patients with HCV genotype 1: The SPRINT-2 trial

The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial1 included more than 1,000 previously untreated adults with HCV genotype 1 infection (938 nonblack patients and 159 black patients; two other nonblack patients did not receive any study drug and were not included in the analysis). In this double-blind trial, patients were randomized into three groups:

  • The control group received the standard of care with pegylated interferon and ribavirin for 48 weeks

  • The response-guided therapy group received boceprevir plus pegylated interferon and ribavirin for 24 weeks after the 4-week lead-in phase; if HCV RNA was undetectable from week 8 to week 24, treatment was considered complete, but if HCV RNA was detectable at any point from week 8 to week 24, pegylated interferon and ribavirin were continued for a total of 48 weeks.

  • The fixed-duration therapy group received boceprevir, pegylated interferon, and ribavirin for 44 weeks after the lead-in period.

In the overall cohort, the rates of sustained virologic response were 63% in the response-guided therapy group and 66% in the fixed-duration therapy group compared with 38% in the control group (P < .001 for both) (TABLE 2). In the subgroup of patients who were black, the rates were 42%, 53%, and 23%, respectively. Overall, 44% of patients in the response-guided therapy group were able to stop all treatment at 28 weeks.

The rate of relapse was 8% and 9% in the boceprevir groups vs 23% in the control group. Patients in the boceprevir groups who had a decrease in HCV RNA of less than 1 log10 during the lead-in phase were found to have a significantly higher rate of boceprevirresistant variants than those who achieved a decrease of HCV RNA of 1 log10 or more.

Boceprevir in previously treated patients with HCV genotype 1: The RESPOND-2 trial

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) (RESPOND-2) trial2 was designed to assess the efficacy of combined boceprevir, pegylated interferon, and ribavirin for repeat treatment of patients with HCV genotype 1. These patients had previously undergone standard treatment and had a reduction of 2 log10 or more in HCV RNA after 12 weeks of therapy but with detectable HCV RNA during the therapy period or had had a relapse (defined as undetectable HCV RNA at the end of a previous course of therapy with HCV RNA positivity thereafter). Importantly, null-responders (those who had a reduction of less than 2 log10 in HCV RNA after 12 weeks of therapy) were excluded from this trial.

After a lead-in period of interferon-ribavirin treatment for 4 weeks, 403 patients were assigned to one of three treatment groups:

  • Pegylated interferon and ribavirin for 44 weeks (the control group)

  • Boceprevir, pegylated interferon, and ribavirin in a response-guided regimen

  • Boceprevir, pegylated interferon, and ribavirin for 44 weeks (the fixed-duration group).

Sustained virologic response was achieved in only 21% of patients in the control group. Adding boceprevir increased the rate to 59% in the response-guided therapy group and to 67% in the fixed-duration group. Previous relapsers had better rates than partial responders (69%–75% vs 40%–52%).

Importantly, patients who had a poor response to pegylated interferon and ribavirin during the lead-in phase (defined as having less than a 1-log decrease in the virus before starting boceprevir) had significantly lower rates of sustained virologic response and higher rates of resistance-associated virus variants.

Side effects of boceprevir

Overall, boceprevir is well tolerated. The most common side effects of triple therapy are those usually seen with pegylated interferon and ribavirin, such as flulike symptoms and fatigue (TABLE 2). However, anemia was more frequent in the boceprevir groups in both SPRINT-2 and RESPOND-2 (45%–50% compared with 20%–29% in the control groups). Erythropoietin was allowed in these studies and was used in about 40% of patients.

The other common side effect associated with boceprevir was dysgeusia (alteration of taste). Dysgeusia was reported by approximately 40% of patients; however, most dysgeusia events were mild to moderate in intensity and did not lead to treatment cessation.

In the SPRINT-2 trial,1 the study drugs had to be discontinued in 12% to 16% of patients in the boceprevir groups because of adverse events, which was similar to the rate (16%) in the control group. Erythropoietin was allowed in this trial, and it was used in 43% of patients in the boceprevir groups compared with 24% in the control group, with discontinuation owing to anemia occurring in 2% and 1% of cases, respectively.

TELAPREVIR

Telaprevir, the other protease NS3/4A inhibitor, has also shown efficacy over current standard therapy in phase 3 clinical trials. It was used in a dose of 750 mg three times a day with pegylated interferon alfa-2a (Pegasys) 180 μg per week and ribavirin (Copegus) 1,000 to 1,200 mg daily according to body weight. A lead-in phase with pegylated interferon and ribavirin was not applied with telaprevir, as it was in the boceprevir trials. Extended rapid virologic response was defined as an undetectable HCV RNA at weeks 4 and 12 of therapy.

Telaprevir in previously untreated patients with HCV genotype 1

The ADVANCE study3 was a double-blind randomized trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon and ribavirin in more than 1,000 previously untreated patients. The three treatment groups received:

  • Telaprevir, pegylated interferon, and ribavirin for 8 weeks, followed by pegylated interferon and ribavirin alone for 16 weeks in patients who achieved an extended rapid virologic response (total duration of 24 weeks) or 40 weeks in patients who did not (total duration of 48 weeks)

  • Telaprevir, pegylated interferon, and ribavirin for 12 weeks, followed by pegylated interferon-ribavirin alone for 12 (total of 24 weeks) or 36 weeks (total of 48 weeks) according to extended rapid virologic response

  • Standard care with pegylated interferon and ribavirin for 48 weeks.

The rate of sustained virologic response was 69% in the group that received telaprevir for 8 weeks and 75% in the group that received it for 12 weeks compared with 44% in the control group (P < .0001 for both) (TABLE 2). Patients infected with HCV genotype 1b had a higher sustained virologic response rate (79%) than those infected with HCV genotype 1a (71%).

Sustained virologic response rates were lower in black patients and patients with bridging fibrosis or cirrhosis, but were still significantly higher in the telaprevir groups than in the control group. The results of this subset analysis were limited by small numbers of patients in each category.

In total, 57% of those who received telaprevir for 8 weeks and 58% of those who received it for 12 weeks achieved an extended rapid virologic response and were able to cut the duration of their therapy in half (from 48 weeks to 24 weeks).

The relapse rates were 9% in the telaprevir groups and 28% in the control group.

The rate of virologic failure was lower in patients who received triple therapy than in those who received interferon-ribavirin alone (8% in the group that got telaprevir for 12 weeks and 13% in the group that got it for 8 weeks, vs 32% in the control group). The failure rate was also lower in patients with HCV genotype 1b infection than in those with genotype 1a.

The ILLUMINATE study4 (Illustrating the Effects of Combination Therapy With Telaprevir) investigated whether longer duration of treatment than that given in the ADVANCE trial increased the rate of sustained virologic response. Previously untreated patients received telaprevir, interferon, and ribavirin for 12 weeks, and those who achieved an extended rapid virologic response were randomized at week 20 to continue interferonribavirin treatment for 24 or 48 weeks of total treatment.

The sustained virologic response rates in patients who achieved an extended rapid virologic response were 92% in the group that received pegylated interferon and ribavirin for 12 weeks, and 88% in those who received it for 48 weeks. Thus, the results of this study support the use of response-guided therapy for telaprevir-based regimens.

Telaprevir in previously treated patients with HCV genotype 1: The REALIZE trial

In this phase 3 placebo-controlled trial,5 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:

  • Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks

  • Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin

  • Pegylated interferon and ribavirin for 48 weeks (the control group).

The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.

This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects

As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (TABLE 2).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,3 and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.

In the ADVANCE trial,3 study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,4 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

For treatment algorithms, see the eFIGURES that accompany this article online.

Boceprevir in previously untreated patients
  • Week 0—Start pegylated interferon and ribavirin

  • Week 4—Add boceprevir

  • Week 8—Measure HCV RNA

  • Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL

  • Week 24—Measure HCV RNA; stop treatment if it is detectable

  • Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24

  • Week 36—Measure HCV RNA; stop boceprevir

  • Week 48—Stop all treatment (eFIGURE 1).

Boceprevir in previously treated patients
  • Week 0—Start pegylated interferon and ribavirin

  • Week 4—Add boceprevir

  • Week 8—Measure HCV RNA

  • Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL

  • Week 24—Measure HCV RNA; stop treatment if it is detectable

  • Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin

  • Week 48—Stop all treatment (eFIGURE 2).

Telaprevir in previously untreated patients and prior relapsers
  • Week 0—start telaprevir, pegylated interferon, and ribavirin

  • Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL

  • Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL

  • Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin

  • Week 48—Stop all treatment (eFIGURE 3).

Telaprevir in patients who previously achieved a partial or null response
  • Week 0—Start telaprevir, pegylated interferon, and ribavirin

  • Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL

  • Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin

  • Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable

  • Week 48—Stop all treatment (eFIGURE 4).

Drug interactions with boceprevir and telaprevir

Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV

Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.24

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.25 Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.26 The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.27 Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.28 Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al29 demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.29

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.

FUTURE PERSPECTIVES

With the introduction of the first direct-acting antiviral medications for HCV (boceprevir and telaprevir), 2011 will be marked as the year that changed hepatitis C treatment for the better. Triple therapy with pegylated interferon, ribavirin, and either boceprevir or telaprevir has the potential for increasing the rate of sustained virologic response to around 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. The IL28B polymorphisms appear to play a role in the rate of sustained virologic response achieved with triple therapy, with preliminary data showing a better response rate in patients who have the CC genotype.17

These drugs will add up to $50,000 to the cost of treating hepatitis C virus infection, depending on the drug used and the length of treatment. However, they may be well worth it if they prevent liver failure and the need for transplantation.

Many questions remain, such as how to use these new regimens to treat special patient populations—for example, those with a recurrence of HCV infection after liver transplantation, those co-infected with HCV and human immunodeficiency virus, and those infected with HCV genotypes other than genotype 1.

Other direct-acting antiviral agents that specifically target the replication cycle of HCV are currently in clinical development. In fact, the future has already started with the release of the Interferon-Free Regimen for the Management of HCV (INFORM-1) study results.30 This was the first trial to evaluate an interferon-free regimen for patients with chronic HCV infection using two direct-acting antiviral drugs (the protease inhibitor danoprevir and the polymerase inhibitor RG7128), with promising results.

Footnotes

  • * Dr. Zein has disclosed consulting, teaching, speaking, and receiving research funding from Merck (makers of boceprevir) and Vertex (makers of telaprevir).

  • Copyright© 2012 The Cleveland Clinic Foundation

References

Source

From Journal of Viral Hepatitis

H.-Y. Rao; D.-G. Sun; D. Jiang; R.-F. Yang; F. Guo; J.-H. Wang; F. Liu; H.-Y. Zhang; H.-H. Zhang; S.-C. Du; Q. Jin; H. Qin; A.-S.-F. Lok; L. Wei

Posted: 03/28/2012; J Viral Hepat. 2012;19(3):173-181. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Single nucleotide polymorphisms (SNPs) near the IL28B gene have been shown to be associated with response to treatment for chronic hepatitis C and also with spontaneous clearance of hepatitis C virus (HCV) infection. We analysed the association between IL28B genetic variants and spontaneous clearance of HCV infection in 376 HCV-infected Chinese paid plasma donors. Genotyping of eight SNPs near the IL28B region was performed by the iPLEX system (MassARRAY® SNP Genotyping; Sequenom) in all donors, and sequencing was performed on all 80 donors who cleared HCV and on 160 of 296 donors who did not clear HCV to validate the genotypes. Eighty (21.3%) donors spontaneously cleared HCV. Four SNPs were significantly associated with spontaneous HCV clearance: rs8099917 TT (vs GT), rs8105790 TT (vs CT), rs12980275 AA (vs AG) and rs10853728 CC (vs CG or GG) with OR (95% CI) 15.27 (2.07–112.50), 14.88 (2.02–109.72), 7.92 (1.88–33.32) and 2.32 (1.22–4.42) respectively. No association between the other four IL28B SNPs including rs12979860 and spontaneous HCV clearance was found. Women had a higher rate of spontaneous HCV clearance than men [56/213 (26.3%) vs 24/163 (14.6%), P = 0.007], and this was true even after stratification for IL28B genotypes with OR of 1.9–2.2 among those with favourable genotypes. Our results confirmed that IL28B polymorphism is associated with spontaneous clearance of HCV in Chinese subjects, but the SNPs that predict HCV clearance in Chinese subjects were different from those reported in Caucasians. Women were more likely to clear HCV infection regardless of IL28B genotypes.

Introduction

Hepatitis C virus (HCV) infection is rated by the World Health Organization as a global health problem, based on its prevalence, the high rate (50–85%) of chronicity, the rate of severe complications such as cirrhosis and hepatocellular carcinoma, as well as the high costs of antiviral therapy and liver transplantation.[1–3]

There is a significant difference in response to treatment with pegylated interferon plus ribavirin in patients of different race or ethnicity, with sustained virological response rates of 28%, 34%, 52% and 76% in African American, Hispanic, Caucasian American and Asian patients respectively with genotype 1 HCV infection.[4–7] Likewise, racial differences in the rate of spontaneous viral clearance have been reported.[8,9] These racial differences suggest a genetic influence on HCV outcome.

Ge et al.[10] identified a key role for variation in a region close to the interleukin-28B (IL28B) gene on chromosome 19, which codes for interferon-lambda-3, in predicting response to pegylated interferon plus ribavirin therapy in patients with genotype 1 chronic HCV infection. This finding has been confirmed in other independent cohorts.[11–13] In addition, the IL28B single nucleotide polymorphism (SNP) most strongly associated with treatment response, rs12979860, has also been shown to be significantly associated with spontaneous hepatitis C clearance.[14–16] Tanaka et al.[17] found other SNPs in close proximity to IL28B that were associated with treatment response in Japanese patients, with rs8099917 and rs12980275 having the strongest association. Rauch et al.[12] also reported that rs8099917 was significantly associated with treatment response as well as with spontaneous clearance of HCV infection in Swiss and German patients. An association between rs8099917 and spontaneous HCV clearance was also shown in a study of Spanish patients.[18]

Data on the association between IL28B genetic variants and treatment response or spontaneous viral clearance in Chinese patients with HCV infection are limited. In a study of 2371 persons from different continents, Thomas et al.[14] found that the frequency of the C allele at rs12979860 was roughly 95% among Chinese, 70% among Caucasians and 25–40% among Africans. Ge et al.[10] noted that the linkage between rs12979860 and rs8099917 is high among Caucasians but low among African Americans. These data suggest that the IL28B variants that have the strongest association with spontaneous HCV clearance and response to HCV treatment in different racial/ethnic groups may be different.

Between 1972 and 1990, several outbreaks of non-A, non-B hepatitis linked to plasma donation occurred at plasmapheresis centres in Hebei Province Guan County, China. These donors have been followed for 12–19 years after initial documentation of HCV infection and roughly 20% have cleared HCV infection spontaneously. This cohort provided a unique opportunity to evaluate the role of host genetics in the outcome of HCV infection in a population with fairly homogenous ethnic background. Here, we present data on the association between IL28B genetic variation and spontaneous HCV clearance in these HCV-infected plasma donors.

Patients and Methods
Patient Population

Commercial plasma donation was introduced in China in the 1970s. Prior to each donation, the donors were required to have normal alanine aminotransferase (ALT) and no evidence of hepatitis B virus (HBV) infection based on negative test result for hepatitis B surface antigen (HBsAg). Nevertheless, incidences of non-A and non-B hepatitis continued to occur, and multiple outbreaks among six villages and one town occurred in Hebei Province Guan County between 1972 and 1990. The cause of these outbreaks was believed to be related to the return of red cells to donors through contaminated transfusion lines. Post-transfusion non-A, non-B hepatitis outbreaks also occurred among the plasma recipients; however, this study was focused on the donors.

After hepatitis C testing became available, donors from five villages and one town were tested for hepatitis C antibody (anti-HCV) in 1991, and donors from the sixth village were tested for anti-HCV in 1998. Of the 864 registered paid donors, 792 (91.7%) came back for anti-HCV testing and 450 (56.8%) of these 792 tested positive. Donors who tested positive for anti-HCV were invited to return for follow-up assessment every 5–6 years between 1991 and 2008 and once a year thereafter. At each visit, the donors were evaluated and blood was tested for anti-HCV and ALT. HCV RNA was tested during follow-up visits in 2002, 2009 and 2010. All donors who previously tested positive for anti-HCV were invited to participate in a study of IL28B genetic variation during their follow-up visit in 2010. Blood was drawn for biochemical tests, HCV RNA, HCV genotype and IL28B SNPs during the 2010 visit. HCV clearance was defined as undetectable HCV RNA on at least two follow-up evaluations including the visit in 2010 in subjects who were anti-HCV positive during initial screening in 1991 or 1998. All donors in our study were of Han ancestry.

The Ethical Committee of Human Experimentation in Peking University People's Hospital approved the study, and the study was performed in accordance with the Helsinki Declaration of 1975. The plasma donors were enrolled after providing written informed consent for the follow-up study, and additional consent for genetic testing was provided during the 2010 visit.

Biochemical Tests

Fasting blood samples collected at each follow-up visit were tested for ALT, aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase, total bilirubin (TBil), direct bilirubin, total protein and albumin by an automated biochemical analyser 7600 (Hitachi, Tokyo, Japan).

Virology Tests

Tests for anti-HCV were carried out using enzyme immunoassay (Chiron, Emeryville, CA, USA) between 1991 and 2005 and chemiluminescent microparticle immunoassay (Architect; Abbott, Chicago, IL, USA) after 2005. HCV RNA was quantified with real-time fluorescence quantitative assay (PG Biotech Company, Shenzhen, China) that has a lower limit of detection of 500 IU/mL between 2002 and 2008 and with Cobas Ampliprep/Cobas Taqman HCV assay (Roche Molecular Diagnostics, Branchburg, NJ, USA) that has a lower limit of detection of 15 IU/mL after 2008. HCV genotype was determined with restriction fragment length polymorphism.[19] HBsAg (Abbott) and anti-HIV were detected by enzyme immunoassay (BioMérieux, Boxtel, the Netherlands).

IL28B SNPs Genotyping

The genomic region associated with response to hepatitis C treatment identified by Ge et al.[10] and Tanaka et al.[17] contains several highly linked SNPs around the IL28B gene. In our cohort, we selected the following SNPs for genotyping: rs12979860, rs10853728, rs11881222, rs12980275, rs4803219, rs4803223, rs8099917 and rs8105790. DNA from the subjects was extracted from peripheral blood using standard methods. Genotyping was performed by the iPLEX system (MassARRAY® SNP Genotyping; Sequenom, San Diego, CA, USA) for all 376 donors. DNA from the donors was blind coded and tested using a 384 format SpectroCHIP™ microarray (Sequenom). A matrix-assisted laser desorption/ionization time-of-flight mass spectrometer was used for data acquisitions from the SpectroCHIP™. Results were analysed using Sequenoms MassARRAY RT™ software (Sequenom). To validate the results of the iPLEX system, we sequenced the region surrounding the IL28B gene that covered the eight SNPs for all donors who cleared HCV and a random selection of approximately 50% of the donors who did not clear HCV. Samples were amplified, and the amplicons were subjected to direct sequencing using the Big Dyes Termination version 1.1 kit (ABI) and the ABI Prism 3730 genetic analyser (Applied Biosystems, Foster City, CA, USA). Sequence results were analysed using Polyphred software (Applied Biosystems). Results of the iPLEX system and direct sequencing were compared.

Statistical Analysis

Genotype frequencies were obtained by direct counting, and statistical analysis was performed by the chi-square test. Qualitative data were also analysed by the chi-square test and odds ratio (OR) with 95% confidence intervals (95% CI). Median values of quantitative variables were compared using a nonparametric test (Mann–Whitney two-tailed test). P-values <0.05 were considered statistically significant. The statistical software package used was SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results
Rate of Spontaneous HCV Clearance

Of the 450 donors who tested positive for anti-HCV in 1991 or 1998, 36 had died (18 because of liver diseases), and 33 were lost to follow-up by May 2010 (Fig. 1). Five donors with HBV co-infection were excluded. The remaining 376 HCV-infected plasma donors were tested for IL28B SNPs, 163 were men and 213 women, with a mean age of 53.2 ± 8.0 years and a mean BMI of 24.5 ± 3.2 (kg/m2) at the time of the study. None of the donors had received hepatitis C treatment because all of them were farmers and their medical insurance did not cover hepatitis C treatment. All the donors were serum anti-HIV negative. Eighty (21.3%) donors had spontaneous clearance of HCV infection (95% CI: 17.1–25.4). All 80 remained anti-HCV positive in 2010; of these, 70 had sample/cutoff (S/CO) ratio ≥5 and 10 had S/CO ratio <5 on the anti-HCV test in 2010.

(Click on picture to enlarge)

759019-fig1

Figure 1. Flow diagram showing the disposition of 864 registered plasma donors.

Spontaneous viral clearance was more likely to occur in women than in men, 26.3% (56/213) vs 14.7% (24/163) (P = 0.007). As the donors were not regularly followed up before 1991 or 1998 and most had no symptoms of acute hepatitis during the outbreaks, the onset of infection and the severity of the acute infection could not be ascertained. There was no correlation between age at the time of study and spontaneous HCV clearance. All the donors had ALT tested at least once during the outbreaks, and 153 (40.7%) had elevated ALT on more than one occasion during the outbreaks. The rate of spontaneous HCV clearance was similar in donors with and without elevated ALT during the outbreaks [39/153 (25.5%) vs 41/223 (18.4%) P = 0.10].

During the 2010 visit, donors who had persistent HCV infection had significantly higher mean ALT, AST and γ-GT and lower platelet count than those who cleared HCV. Of the 296 donors who were still HCV RNA positive, 83.8%, 12.8% and 3.4% had HCV genotype 1b, 2a and 1b/2a infection, respectively.

Frequency of IL28B SNPs

Analysis of the IL28B genotype results of 240 donors (80 with spontaneous HCV clearance and 160 with persistent HCV infection) who were tested by both the iPLEX system and by sequencing showed a concordance rate of 97.8–100% for the eight SNPs studied; therefore, the results of the iPLEX system will be presented in this study.

Of the 376 donors, 180 (48.5%, 95% CI: 43.4–53.6) were homozygous for CC, 189 (50.9%, 95% CI: 45.9–56.0) were heterozygous (CT) and only 2 (0.5%, 95% CI: −0.2–1.3) were homozygous for TT at rs12979860, reflecting a C allele frequency of 74.0% (95% CI: 70.8–77.2). Frequency of the other IL28B SNPs is shown inTable 1. No significant deviations in standard genotype quality control according to the Hardy–Weinberg Equilibrium for six SNPs were noted (rs12979860, rs10853728, rs12980275, rs4803223, rs8099917 and rs8105790), while there were significant deviations for two SNPs (rs11881222 and rs4803219).

Association Between IL28B SNPs and Spontaneous Clearance of HCV Infection

Spontaneous HCV clearance was associated with four of the eight IL28B SNPs tested. The IL28B genetic variants rs8099917 [TT vs GT, OR 15.3 (95% CI: 2.1–112.5), P = 0.002], rs8105790 [TT vs CT, OR 14.9 (95% CI: 2.0–109.8), P = 0.0024], rs12980275 [AA vs AG, OR 7.9 (95% CI: 1.9–33.3), P = 0.0043] and rs10853728 [CC vs CG or GG, OR 2.3 (95% CI: 1.2–4.4), P = 0.0206] were associated with a significantly higher rate of spontaneous clearance of HCV (Table 2). Thus, for rs8099917, the SNP with the strongest association with spontaneous HCV clearance, 24.1% of TT homozygous subjects (77/319; 95% CI: 19.4–28.8) and only 2.0% (1/49, 95% CI: 1.9–6.0) of GT heterozygous subjects had spontaneous clearance of HCV.

The other four IL28B SNPs including rs12979860 were not associated with the spontaneous clearance of HCV infection. For rs12979860, spontaneous HCV clearance was observed in 24% (43/180, 95% CI: 17.7–30.1), 19.1% (36/189, 95% CI: 13.5–24.7) and 50% (1/2, 95% CI: 19.3–119.3) subjects with CC, CT and TT genotypes respectively (P = 0.33).

As women had a higher rate of spontaneous HCV clearance than men, the prevalence of favourable genotypes between men and women was compared, and the results showed no significant difference between men and women for all eight SNPs studied (Table 1). Women were significantly more likely to have spontaneous HCV clearance than men even after stratification for IL28B genotype with odds ratio of 1.9–2.2 among those with favourable genotypes (Table 3). As an example, among those with rs8099917 TT genotype, 29.5% women but only 16.9% men had spontaneous HCV clearance, OR 2.1 (95% CI: 1.2–3.6), P = 0.0093.

Haplotype Analysis

Pair-wise linkage disequilibrium between the SNPs is shown in Fig. 2. Four SNPs (rs12980275, rs8105790, rs12979860 and rs8099917) were in strong linkage disequilibrium. The haplotype ATCT with favourable alleles in these four SNPs was not associated with spontaneous HCV clearance. However, donors with the haplotype ATTC, favourable alleles in the four SNPs that were independently shown to be associated with spontaneous HCV clearance (rs12980275, rs8105790, rs8099917 and rs10853728) were significantly more likely to have spontaneous HCV clearance than those who did not have this haplotype, 24.8% (64/258) vs 13.5% (14/104), OR 2.1 (95% CI: 1.1–4.0), P = 0.018.

759019-fig2

Figure 2. Pair-wise linkage disequilibrium pattern of the IL28 region. The degree of linkage disequilibrium between any two SNPs is described by r2 values (among 0.97–1.00). Rs12980275, rs8105790, rs12979860 and rs8099917 are within a genomic block that encompasses the IL28B gene.

Multivariate Analysis of Factors Associated With Spontaneous HCV Clearance

Multivariate analysis including the following variables – gender, the four IL28B SNPs that were significant on univariate analysis and the haplotype ATTC comprising rs12980275, rs8105790, rs8099917 and rs10853728 – showed that IL28B SNP rs8099917 (OR = 14.88, 95% CI: 2.02–109.7, P = 0.008) was the most significant factor associated with spontaneous HCV clearance. Addition of the other three IL28B SNPs or the haplotype ATTC to the SNP rs8099917 did not improve the association with spontaneous HCV clearance.

Gender had an independent effect on spontaneous HCV clearance, the odds ratio for women to clear HCV infection in the multivariate model for all donors was 1.95 (95% CI: 1.14–3.32), for donors with rs8099917 TT was 2.05 (95% CI: 1.18–3.53) and for donors with the haplotype ATTC was 1.97 (95% CI: 1.09–3.55) when compared with men.

Association Between IL28B Genotype and HCV RNA Level and HCV Genotype

Analysis of the HCV RNA levels of the 276 subjects who had detectable HCV RNA at the 2010 visit showed that there was no difference in HCV RNA levels between the subjects with favourable and those with unfavourable genotypes at the four IL28B SNPs shown to be associated with spontaneous HCV clearance. There was also no difference in the distribution of HCV genotypes between the subjects with favourable and those with unfavourable IL28B genotypes.

Discussion

In this study of 376 HCV-infected Chinese paid plasma donors, we found that IL28B gene variants were significantly associated with the spontaneous clearance of HCV infection. The SNP that had the strongest association with spontaneous clearance of HCV infection was rs8099917, and persons with the TT genotype were 15 times more likely to clear HCV than those with the GT genotype. However, the SNP rs12979860 that has been shown to be most strongly associated with response to pegylated interferon and ribavirin and to spontaneous HCV clearance in Caucasians and African Americans was not associated with spontaneous HCV clearance in our study.[10–14]

Thomas et al.[14] studied 1008 subjects in six independent cohorts and found that rs12979860 CC genotype was predictive of spontaneous HCV clearance among individuals of both European and African ancestry. An association between rs12979860 CC genotype and spontaneous HCV clearance was also shown by Tillmann et al.[16] who studied 190 German women and by Montes-Cano et al.[18] in a study of 353 Spanish subjects. In all three studies, only one SNP (rs12979860) was tested. An association between rs8099917 TT genotype and response to pegylated interferon and ribavirin treatment had been reported in the studies of Caucasian patients and Japanese patients with chronic HCV infection.[11,12,17] An association between rs8099917 TT genotype and spontaneous clearance of HCV infection was also demonstrated in a study of 132 predominantly Caucasian patients in Australia and a study of 1362 Swiss and German patients.[12,15] Only two SNPs (rs8099917 and rs12980275) were tested in the study in Australia. The study in Switzerland tested more than 500 000 SNPs. Analysis of data from 1213 individuals with available data at both rs12979860 and rs8099917 found that rs12979860 genotype was highly associated with chronic HCV infection and was in strong linkage disequilibrium with rs8099917.[12]

In this study, we tested eight SNPs and found an association between spontaneous HCV clearance and four SNPs including rs8099917, rs8105790, rs12980275 and rs10853728 but not rs12979860. Ge et al.[10] had noted that the linkage between rs8099917 and rs12979860 is high among Caucasians, but low among African Americans. We found that rs8099917 was strongly linked to rs12979860 (r2 = 1.00), rs12980275 (r2 = 0.97) and rs8105790 (r2 = 1.00) in our study. In our study, all donors with rs12979860 CC had rs8099917 TT genotype, but donors with rs12979860 CT could be rs8099917 TT or TG.

The rs12979860 C allele frequency in the Chinese Han population (83 subjects from Beijing, China) was reported to be 93.4% in HapMap and 94–98% in Thomas' study of 47 Chinese in Taiwan and 59 Chinese in San Francisco, but it was only 74% in our study. The rs8099917 T allele frequency in the Chinese Han population was reported to be 93.5% in HapMap and 93.3% in our study. The subjects in our study all came from one county, Hebei, in the northern part of China. So, the SNP allele frequencies in our study might be only representative of the northern local region. While most Chinese in the major cities of China are of Han ancestry, other ancestries predominate in some parts of China. Studies involving larger numbers of Chinese in different regions of China are necessary to determine the precise frequency of the favourable alleles at rs12979860 and rs8099917 among Chinese of various ancestries.

In this study, the SNP rs8099917 had the strongest association with spontaneous HCV clearance. Although three other SNPs (rs10853728, rs 12980275 and rs8105790) in the IL28B region were independently associated with spontaneous HCV clearance, inclusion of these three SNPs or the haplotype ATTC with favourable alleles at these three SNPs plus rs8099917 did not improve the prediction of spontaneous HCV clearance in the multivariate model compared with rs8099917 alone. Several studies showed that women were more likely to undergo spontaneous HCV clearance than men. One study of 67 persons with acute HCV infection, 66% of whom were injection drug users, found that HCV clearance occurred in 34% of women compared with 3% of men (P < 0.001).[20] Another study followed 135 injection drug users with incident HCV infection and found that the age-adjusted hazard ratio of spontaneous HCV clearance for women was 2.91 (95% CI: 1.68–5.03).[21] A systematic review of 31 longitudinal studies that included 314 subjects showed that the relative risk of spontaneous HCV clearance for men was 0.43 (95% CI: 0.36–0.53) (P = 0.00001).[22]

Two recent studies examined gender, IL28B genetic variants and spontaneous HCV clearance. In Grebely et al.'s[15] study of 132 Australians, rs8099917 TT genotype (adjusted hazard ratio 3.78, 95% CI: 1.04–13.76) was the only factor predicting spontaneous HCV clearance on multivariate analysis, but female gender and jaundice during the acute illness were not. In Montes-Cano et al.'s[18] study of 352 Spanish subjects, rs12979860 CC genotype was associated with a higher rate of spontaneous HCV clearance in both men (72.4%vs 27.6%) and women (72.5%vs 27.5%) compared with those with CT or TT genotype. In this study, we found that women had a higher rate of spontaneous HCV clearance than men, 26.3%vs 14.6%, and this difference persisted even after stratification for IL28B genotypes. Among those with rs8099917 TT genotype, women were twice as likely to have spontaneous HCV clearance as men. Female gender remained an independent predictor of spontaneous HCV clearance in the multivariate model, with OR of 1.95.

Some studies found that the presence of jaundice or symptoms during acute HCV infection was associated with a higher rate of spontaneous HCV clearance.[15,16,22] Tillmann et al.[16] found that jaundice during acute infection was associated with an increased chance of spontaneous HCV clearance (42.9%vs 13.7%) in persons with non-CC genotype at rs12979860, but not in those with CC genotype (56.3%vs 60.6%). In this study, spontaneous HCV clearance rate was similar in donors with and without documented ALT elevation during the outbreaks, but the donors were not regularly monitored, and it is possible that ALT was not tested at the time of acute infection. We were also not able to determine whether any of the donors had symptomatic illness or were jaundiced during the acute infection.

In summary, in this study of a large homogenous cohort of HCV-infected plasma donors, we found that 21.3% had spontaneous HCV clearance. We confirmed that IL28B genotype is associated with spontaneous HCV clearance with rs8099917 TT genotype showing the strongest association, while rs12979860 CC genotype had no association. Women had a higher rate of spontaneous HCV clearance regardless of IL28B genotype. Our results suggest that while IL28B genotype is associated with spontaneous HCV clearance in patients of diverse racial/ethnic background, the SNP with the strongest association may vary. Further studies are needed to confirm this observation and to clarify whether other factors such as gender and severity of the acute illness are independent predictors of spontaneous HCV clearance after correction for IL28B genotype. These results will help in determining which patients with acute HCV infection should start on antiviral therapy and which ones to be monitored.

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