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In This Issue:
• Prolonged Interferon-based Therapy
• Merimepodib for Prior Nonresponders
• Treating Patients with Cirrhosis
• Acute Hepatitis C
• HCV Sexual Transmission
Prolonged Interferon-based Therapy
Some individuals with hepatitis C may benefit from a longer course of pegylated interferon plus ribavirin, according to a report in the October 2007 Journal of Hepatology. Hepatology experts P. Marcellin, E.J. Heathcote, and A. Craxi discussed the use of early on-treatment response to predict eventual outcomes and to adjust therapy accordingly. “The time at which hepatitis C virus RNA becomes undetectable by a sensitive PCR assay has a huge impact on the probability of achieving a sustained virological response [SVR], particularly in genotype 1 patients, and may be useful in selecting patients for prolonged therapy,” the authors wrote. But they advised against “indiscriminate extension of treatment,” since this can lead to prolonged side effects and higher cost for many patients who will not benefit from longer therapy. However, a subset of “slow responders” with HCV genotype 1 – identifiable based on their responses at weeks 4, 12, and 24 – may benefit from lengthening treatment from the standard 48 weeks to 72 weeks. In one study, for example, prolonging therapy increasing the SVR rate from 32% to 45%. The drawback to this approach is the difficulty of distinguishing at an early stage between “slow responders” and “null responders” who will not respond despite extended treatment.
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Merimepodib for Prior Nonresponders
Researchers are studying several experimental treatments for hepatitis C patients who have not achieved sustained response with standard interferon-based therapy. Results from a Phase 2 clinical trial of one such candidate, merimepodib, were reported in the October 2007 Journal of Hepatology. Merimepodib is a selective inhibitor of the inosine monophosphate dehydrogenase (IMPDH) enzyme that appears to interfere with HCV replication by decreasing levels of guanosine triphosphate, an essential building block of RNA; this may have a synergistic effect with ribavirin, a guanosine nucleoside analog.
P. Marcellin’s research team studied 31 chronic hepatitis C patients who did not achieve SVR with prior interferon plus ribavirin treatment. The participants were randomly assigned to receive 25 mg or 50 mg oral merimepodib every 12 hours or placebo, along with pegylated interferon alfa-2b (PegIntron) plus ribavirin for 24 weeks; at that point, responders had the option to continue therapy for an additional 24 weeks. At week 24, 73% of patients in the 50 mg merimepodib group achieved undetectable HCV RNA, compared with 30% in the placebo group and only 20% in the 25 mg merimepodib group (P = 0.02). Among the 10 people who opted for extended therapy and were followed for six months after completing treatment, one of the five who received 50 mg merimepodib, both of the two who received 25 mg merimepodib, and one of the three who received placebo achieved SVR (due to the small number of subjects, the latter results could be due to chance). Triple-combination therapy was well-tolerated at both merimepodib doses.
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Treating Patients with Cirrhosis
Due to the risk of serious side effects, many experts are hesitant to treat HCV using interferon-based therapy in patients with liver cirrhosis. However, such patients may be in dire need of treatment and can achieve some benefit, according to a study in the October 2007 Journal of Hepatology. V. di Marco and colleagues studied 102 chronic hepatitis C patients (mostly genotype 1) with compensated cirrhosis and portal hypertension who received 1 mcg/kg once-weekly Pegintron for up to 52 weeks; half were randomly assigned to also receive 800 mg/day ribavirin. In an intention-to-treat analysis, 22% of the PegIntron monotherapy patients and 10% of the combination therapy patients achieved SVR (P = 0.06). As is usually the case, people with HCV genotypes 2 or 3 had a higher response rate than those with genotype 1 (67% vs 11%). In addition to genotype, low baseline viral load, undetectable HCV RNA at week 4 of therapy, and good adherence predicted a higher probability of sustained response.
The good news was that patients who achieved SVR had fewer liver disease complications during follow-up compared with nonresponders (6% vs 38%; P = 0.03). “In HCV cirrhosis with portal hypertension, peg-interferon plus ribavirin is a feasible treatment,” the researchers concluded. Although the rate of viral eradication was modest, they added, tailoring therapy by genotype and early virological response allows continuation of treatment for patients who are more likely to achieve SVR. In an accompanying editorial, G.S. Jensen and J.F. Trotter wrote that the reduction in liver complications among responders “justifies an attempt at therapy despite often long odds of cure,” but emphasized the continuing need for more effective therapies for this population.
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Acute Hepatitis C
Because acute HCV infection is often asymptomatic, understanding of its epidemiology, natural history, and outcomes is incomplete, and past studies have yielded conflicting data about spontaneous clearance and treatment response rates. To shed further light on this puzzle, C.C. Wang and colleagues assessed acute infection in a contemporary U.S. cohort of 67 individuals enrolled at multiple clinics between 2003 and 2005; results were reported in the November 15, 2007 Journal of Infectious Diseases. Acute infection was identified based on HCV seroconversion within 1 year of a previous test (45 subjects), new HCV antibody seropositivity plus clinical hepatitis symptoms (21 subjects), or HCV viral sequencing (1 subject). Overall, 64% of the study subjects were asymptomatic. After six months, 18% spontaneously cleared HCV without treatment. The rate of spontaneous clearance differed significantly by sex: 34% for women versus 3% for men (P < 0.001).
With regard to risk factors, two-thirds of the study subjects were injection drug users. Thirteen individuals (19%) had an unknown route of transmission. Of these, all but two (85%) reported high-risk sexual behavior; however, this was defined broadly, and included having sex before age 15, having more than six lifetime sexual partners, exchanging sex for money, sex with a prostitute, and having a same-sex partner, in addition to sex with an injection drug user or a person known to have HCV. Also, 10 people developed acute infection within three months of exposure in a medical setting, three had gotten a tattoo in the past year, and one lived with an HCV positive household member. The study authors concluded that, “High-risk sexual or iatrogenic [medical] exposures may be important contemporary risk factors for HCV infection.”
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HCV Sexual Transmission
Since the early 2000s, there have been several reports of clusters of apparently sexually transmitted acute HCV infection among mostly HIV positive men who have sex with men in large cities in the U.K. and Europe. In the October 1, 2007 issue of AIDS, G.V. Matthews and colleagues described a similar outbreak among gay and bisexual men in Australia.
The Australian Trial of Acute Hepatitis C enrolled 120 participants at 21 sites since August 2004. While 80% of the 94 HIV negative subjects had injection drug use as their most likely risk factor, this fell to 46% for the 26 HIV positive individuals. Conversely, half the HIV positive individuals had male-to-male sexual contact as their primary risk factor, compared with just 1% of the HIV negative group. Heterosexual sex, however, was rarely identified as a risk factor (5% in the HIV negative group, 0% in the HIV positive group). The researchers also found that HIV positive injection drug users started injecting at later age than HIV negative participants (30 vs 23 years), and more often used crystal methamphetamine as opposed to heroin. Further, more HIV negative people had a transmission risk factor besides either sex or injection drug use.
While the Australian report supports several past studies that have found very low rates of sexual transmission of HCV among steady heterosexual partners (mostly in the range of 0% to 5%), the U.S. study described above (Wang et al.) suggests that sexual transmission may be more common than previously recognized in groups other than gay and bisexual men.
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