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Hepatitis C

DDW 2008: Significance of Transient HCV Viral Load

Response to treatment for chronic hepatitis C virus (HCV) infection is measured in terms of reduction in HCV RNA level, or viral load. End-of-treatment response (ETR) is defined as undetectable HCV RNA at the completion of therapy (24 or 48 weeks, depending on HCV genotype). Sustained virological response (SVR) - typically considered a "cure" - is continued undetectable viral load 24 weeks after completion of treatment.

EASL 2008: Boceprevir Added to Pegylated Interferon/Ribavirin Increases Sustained Response in Treatment-naive Patients and Some Prior Non-responders

About half of all people with chronic hepatitis C virus (HCV) infection achieve a cure, or sustained virological response (SVR), with the standard treatment of pegylated interferon plus ribavirin; rates are even lower for patients with difficult-to-treat HCV genotype 1. Thus, researchers have studies various antiviral agents that directly target various stages of the HCV lifecycle.

At the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan, researchers presented data on Schering-Plough's investigational oral HCV NS3 serine protease inhibitor boceprevir (formerly known as SCH503034).

Triple Combination Therapy

In a late-breaker session, Paul Kwo of Indiana University School of Medicine and colleagues presented interim results from HCV SPRINT-1, a Phase 2 study assessing the safety and efficacy of boceprevir in combination with pegylated interferon and ribavirin in 595 treatment-naive patients with genotype 1 chronic hepatitis C treated in the U.S. (77%), Canada, and Europe; 16% were black (a group that responds less well to interferon-based therapy) and 7% had liver cirrhosis at baseline.

Participants were randomly allocated to various regimens containing 800 mg twice-daily boceprevir, 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron), and weight-based ribavirin (Rebetol):

• Boceprevir plus pegylated interferon plus 800-1400 mg/day ribavirin for 28 or 48 weeks (no lead-in arm);

• Pegylated interferon plus ribavirin for 48 weeks (standard therapy control arm).

The rationale for this novel approach, according to Schering-Plough, is that both pegylated interferon and ribavirin reach steady-state concentrations by week 4; therefore, patients in the lead-in arm would have boceprevir added after the other drugs have already reached optimal levels. Further, pegylated interferon will have activated the immune system by the time boceprevir is added. Researchers hope this strategy might minimize "functional monotherapy" with the protease inhibitor before high enough levels of pegylated interferon and ribavirin are achieved, which may reduce the risk of drug resistance.

The primary study endpoint of the study will be SVR, or undetectable HCV RNA (below 15 IU/mL) 24 weeks after completion of treatment. For the interim analysis, researchers presented response rates 12 weeks after completion of therapy -- or "SVR12" -- in the 28-week arms. This data was not yet available for participants treated for 48 weeks.

Results

• In an intent-to-treat analysis, the SVR rate in the lead-in, 28-week, full-dose ribavirin arm was 57%, compared with 55% in the arm that received triple therapy from the outset.

• Similar results were seen at week 12 (79%, 69%, and 34%, respectively).

• RVR, or undetectable HCV RNA after 4 weeks of boceprevir, was a good predictor of sustained response.

• 11%-15% of patients discontinued treatment in the boceprevir arms, compared with 8% in the control arm.

• The incidence of rash-related adverse events was similar in the boceprevir-containing arms and the pegylated interferon/ribavirin control arm.

Based on these findings, the investigators concluded, "Four weeks of treatment with [pegylated interferon/ribavirin] prior to boceprevir administration markedly increased RVR and EVR and reduced viral breakthrough by 50%."

"This new treatment paradigm has the potential to maximize efficacy of multi-drug combinations and minimize the risk of resistance by identifying responders to [pegylated interferon/ribavirin]," they continued. "Interim results also demonstrate that full dose ribavirin is optimal."

"These interim results are very encouraging, especially given the response seen with a shorter course of therapy in a difficult-to-treat patient population," said Dr. Kwo in a press release issued by Shering-Plough. "Boceprevir has been well tolerated by patients in this study, including in the longer duration treatment arms, and we look forward to further results from this ongoing study."

Final results from SPRINT-1 are expected to be available in early 2009.

Indiana University School Of Medicine, Indianapolis, IN; Alamo Medical Research, San Antonio, TX; Mount Vernon Endoscopy Center, Alexandria, VA; University of Miami Center for Liver Diseases, Miami, FL; Baylor College of Medicine, Houston, TX; Indianapolis Gastroenterology Research Foundation, Indianapolis, IN; South Florida Center of Gastroenterology, Wellington, FL; Liver Specialists of Texas, Houston, TX; Henry Ford Hospital, Detroit, MI; Digestive Disease Associates, Baltimore, MD; Univ Of California-Davis, Sacramento, CA; Liver and Intestinal Research Center, Vancouver, Canada; Weill Medical College Of Cornell Univ, New York NY; Digestive Healthcare Of Georgia, Atlanta, GA; Schering-Plough Research.

Null Responders

In a related study, researchers looked at response to boceprevir combination therapy in 357 "null responders" with genotype 1 HCV who had less than a 2 log10 drop in HCV RNA after 12 weeks of prior treatment with pegylated interferon/ribavirin, or failure to achieve undetectable viral load if treated longer than 12 weeks.

Participants received 1.5 mcg/kg/week pegylated interferon (PegIntron) plus boceprevir at doses of 100, 200, 400, or 800 mg, some with ribavirin. The control arm received standard therapy, adding boceprevir if HCV remained detectable. Early data showed that the lower doses of boceprevir were less effective, so all patients who demonstrated virological response to boceprevir switched to triple combination therapy using 800 mg boceprevir for an additional 24 weeks.

SVR rates ranged from 2% in the control group to 14% using the boceprevir regimens studied, though no patients received triple therapy with the highest dose of boceprevir for the full treatment period. Individuals who experienced a viral load decrease greater than 2 log10 at week 12 were most likely to achieve undetectable HCV RNA on triple therapy. Boceprevir resistance mutations were detected in a majority of subjects who did not achieve SVR.

The investigators concluded that, "Some 'null' responders to [pegylated interferon/ribavirin] can achieve an SVR with [pegylated interferon/ribavirin/800 mg boceprevir], but response is dependent on residual interferon responsiveness." They added that, "Treatment failures to [pegylated interferon/ribavirin] with > 2 log10 viral drop at [week 12] may be good candidates" for triple therapy.

University of Miami School of Medicine, Miami, FL; Cedars-Sinai Medical Center, Los Angeles, CA; Weill Medical College of Cornell University, New York, NY; Northwestern University, Chicago, IL; St. Louis University, St. Louis, MO; Alamo Medical Research, San Antonio, TX; Henry Ford Hospital, Detroit, MI; Duke University Medical Center, Durham, NC; Liver Institute at Methodist Dallas, Dallas, TX; A.P.H. Paris, Hopital Pitie-Salpetriere, Paris, France; Johns Hopkins Univ, Baltimore MD; Hospices Civils De Lyon Hotel Dieu, Lyon, France; Opedale Molinette, Torino, Italy; Univsitaetsklinikum Des Saarlandes, Homburg/Saar, Germany.

Boceprevir Resistance Mutations

Finally, researchers presented results from a clonal analysis of mutations in the HCV NS3 protease domain in non-responders treated with boceprevir.

HCV RNA was assessed at baseline, day 14 (end-of-treatment), and day 28 (end-of-follow-up) in samples collected from 22 patients treated with 400 mg boceprevir 2 or 3 times daily.

Mutations were detected at 51 different amino acid positions within the NS3 protease, with a frequency greater than 5% by the end of treatment. Mutations at 5 amino acid positions (V36, T54, R155, A156, V170) previously shown to confer resistance to boceprevir in vitro were detected in 14 patients. However, no mutations at position A156 were detected at the end-of-follow-up.

J W Goethe University Hospital, Medizinische Klinik I, 60590 Frankfurt am Main, Germany; Saarland University Hospital, Klinik für Innere Medizin II, Homburg, Germany; Schering Plough, Kenilworth, NJ.

4/29/08

References

P Kwo, E Lawitz, J McCone, and others. Interim Results from HCV SPRINT-1: RVR/EVR from Phase 2 Study of Boceprevir Plus PegINTRON (Peginterferon Alfa-2b)/Ribavirin in Treatment-Naïve Subjects with Genotype-1 CHC. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

E Schiff, F Poordad, I Jacobson, and others. Boceprevir (B) Combination Therapy in Null Responders (NR): Response Dependent on Interferon Responsiveness. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

S Susser, MW Welker, M Zettler, and others. Clonal Analysis of Mutations Selected in the HCV NS3 Protease Domain of Genotype 1 Non-Responders Treated with Boceprevir (SCH503034). 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional Source

Schering-Plough Corporation. Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL. Press release. April 26, 2008.

Accelerated Liver Disease Progression in HIV-HCV Coinfected Patients May Be Due to Increased Liver Inflammation

Although results have not been not entirely consistent, several studies have shown that HIV-HCV coinfected patients tend to experience more rapid liver disease progression than HIV negative people with hepatitis C alone. A study reported in the January 11, 2008 issue of AIDS suggests a possible mechanism underlying accelerated liver disease progression in coinfected individuals.

 

Acute HIV-HCV Coinfection Increasingly Common in U.K.; HCV Superinfection Reported in France

Several outbreaks of apparently sexually transmitted acute hepatitis C virus (HCV) infection have been reported in recent years in large cities in the U.K. and Europe, primarily among HIV positive men who have sex with men (MSM)Two new reports on sexually transmitted HCV in HIV positive men were published in the March 12, 2008 issue of AIDS.

Eltrombopag Raises Platelet Counts, Enabling Initiation of Interferon-based Therapy for Hepatitis C

Thrombocytopenia, or low platelet count, can lead to easy bruising and prolonged bleeding. People with advanced liver fibrosis or cirrhosis often develop thrombocytopenia, and it can also be a side effect of interferon alfa therapy. For this reason, patients with pre-existing thrombocytopenia are typically advised not to use interferon-based therapy for hepatitis C, even though they may be the ones who need treatment most urgently.

Methamphetamine Promotes Hepatitis C Virus Replication in Human Liver Cells

While there have been numerous studies of hepatitis C in individuals who inject drugs (primarily heroin), less is known about the effects of non-injection drugs on hepatitis C virus (HCV) infection. Methamphetamine is a stimulant that may be taken as a pill, injected, snorted, smoked, or administered anally. In the April 2008 Journal of Viral Hepatitis, L. Ye of the University of Pennsylvania School of Medicine and colleagues reported on a laboratory study looking at whether methamphetamine inhibits innate immunity in host cells, thereby facilitating HCV replication in human hepatocytes (liver cells). 

Acute Hepatitis C Infection and Spontaneous Viral Clearance in Adults and Children

Studies of acute hepatitis C virus (HCV) infection can be challenging, since a majority of infected people do not experience symptoms, and thus do not present for care and HCV testing.

CROI 2008: Rapid Liver Fibrosis Progression in HIV Positive Men with Acute HCV Infection

In recent years there have been reports of several outbreaks of apparently sexually transmitted acute hepatitis C among mostly HIV positive men who have sex with men (MSM) in European cities and Australia. These cases are notable because the patients were known to already be infected with HIV when they acquired HCV (typically HCV is acquired first).

Several studies have shown that HIV-HCV coinfected individuals with chronic hepatitis C tend to experience more rapid liver fibrosis progression. But little is known about the effect of HIV on liver disease in people with acute HCV infection.

At the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) last February, Daniel Fierer and colleagues from Mt. Sinai School of Medicine in New York City presented early data from a prospective study of HIV positive MSM with acute HCV infection, defined as the first 6 months after HCV infection. The researchers considered a combination of 3 criteria as indicators of acute hepatitis C: recent seroconversion to HCV antibody positive status, marked elevations in serum alanine aminotransferase (ALT) level, and wide fluctuations in HCV viral load.

Study participants underwent liver biopsy within 4 months of the first-noted ALT elevation. Fibrosis was staged using the Scheuer system, on a scale of 0 to 4. Fibrosis progression rate (FPR) was calculated by dividing the fibrosis stage by the interval between the dates of the recent ALT elevation and the biopsy.

As previously reported, among the first 5 enrolled patients, 4 already had moderate portal fibrosis during acute hepatitis C. At this year’s CROI, taking place this week in Boston, the researchers presented a poster describing further data from more study participants.

Results

  • Of the 11 patients who underwent liver biopsy, 9 did so within 4.5 months of detection of ALT elevation, and 2 within 16 months.
  • Despite the short duration of HCV infection, 9 of the 11 (82%) had stage 2 fibrosis and 1 had stage 1 fibrosis.
  • The mean FPR in these 11 patients was 4.5 (± 3.3) units per year.
  • No causes of liver damage other than acute HCV infection were identified.
  • In the analysis of risk factors for HCV acquisition, only 4 patients reported even a single episode of intravenous drug use.
  • However, non-injection drug use and high-risk sexual behavior were common.
  • 7 reported club drug (including methamphetamine) use and 10 reported unprotected anal intercourse with multiple partners.

Based on these findings, the researchers concluded, “Acute HCV infection of MSM with underlying HIV infection resulted in early and rapid progression of liver fibrosis, with FPR rates far in excess of other settings of HCV infection.”

“Many of these HIV-infected men with acute HCV used non-injection drugs and had unprotected sex with multiple partners,” they continued. “Some appear to have become HCV-infected via sexual activity.”

The investigators recommended that, “More intensive prevention and screening strategies for acute HCV in MSM are needed,” and “further research is needed to identify the disease processes leading to this highly accelerated liver injury.”

Mt Sinai School of Medicine, New York, NY.

2/5/08

Reference

D Fierer, A Uriel, D Carriero, and others. An Emerging Syndrome of Rapid Liver Fibrosis in HIV-infected Men with Acute HCV Infection. 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA. February 3-6, 2008. Abstract 1050.

Adherence to Hepatitis C Treatment among Recovering Heroin Users on Methadone Maintenance

As reported in the September 2007 issue of the European Journal of Gastroenterology and Hepatology, Diana Sylvestre, MD, from the University of California at San Francisco and colleagues evaluated the impact of mental health issues, active drug use, and other potential adherence barriers in a real-world sample of recovering drug users on methadone maintenance therapy.