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In This Issue:
Higher-Dose Pegylated Interferon + Ribavirin
In an effort to improve response to interferon-based therapy, researchers have explored various alternative regimens, including higher drug doses. In the October 2008 issue of Hepatology, M. Fried and colleagues described a study comparing the efficacy of standard-dose versus high-dose pegylated interferon alfa-2a (Pegasys) plus ribavirin in treatment-naive patients with HCV genotype 1, high viral load (> 800,000 IU/mL), and heavy body weight (> 85 kg, or about 190 lb) – three factors associated with poor response.
Participants were randomly assigned to receive either 180 or 270 mcg/week Pegasys plus either 1200 or 1600 mg/day ribavirin for 48 weeks, in four different combinations. Patients who received the higher Pegasys dose experienced significantly greater declines in HCV RNA than those who received the standard 180 mcg/week dose when combined with either 1600 or 1200 mg/day ribavirin (P = 0.04 and 0.06, respectively). Indeed, patients who got the higher doses of both drugs were most likely to achieve sustained virological response (SVR; 47%) and least likely to experience relapse (19%). This regimen, however, was less well-tolerated than those containing lower doses.
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Impact of Body Weight
Given the increased emphasis on tailored therapy, researchers have explored individual factors that predict good or poor response. As described in the September 2008 Journal of Medical Virology, M. Rodriguez-Torres and colleagues retrospectively assessed factors associated with treatment response in Latino patients with HCV genotype 2 or 3. All 35 participants (26 with genotype 2 and 9 with genotype 3) received standard therapy using 180 mcg/week Pegasys plus 800 mg/day ribavirin for 24 weeks. Ribavirin – which helps prevent post-treatment relapse – is usually dose-adjusted by weight for patients with hard-to-treat HCV genotype 1, but is typically given at a lower fixed dose for genotypes 2 or 3.
Six months after completion of treatment, 69% of genotype 2 patients and 89% with genotype 3 achieved SVR (for an overall rate of 74%). Relapse rates were 28% for genotype 2 patients and 11% for genotype 3 patients (overall 24%). Individuals who weighed more than 75 kg (or about 165 lb) were twice as likely to experience relapse than lighter patients (29% vs. 14%, respectively). In a multivariate analysis, higher weight was the only significant risk factor for post-treatment relapse (P = 0.043), suggesting that heavier patients might not be reaching an adequate concentration of ribavirin using the fixed 800 mg/day dose.
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Uncommon Routes of HCV Transmission
HCV is most commonly transmitted through direct inoculation of blood, for example via an accidental needle-stick or shared drug injection equipment. But approximately 20% of people with HCV have no known risk factors, leading researchers to study less well established potential transmission routes.
Intranasal Drug Use
A study in the October 1, 2008 Clinical Infectious Diseases adds to the evidence that HCV may be transmitted via shared straws or bills used to snort drugs, since intranasal drug use can damage the mucous membranes of the nose and cause bleeding. A. Sagiv and colleagues measured blood and HCV RNA in nasal secretions and on drug-snorting equipment collected from 38 patients with active chronic hepatitis C at a community health clinic in East Harlem, New York. Participants provided nasal swab samples and plastic soda straws used to “snort air.”
Trace amounts of blood were detected in 28 of 38 nasal secretion samples (74%), though only three of 38 straws (8%) contained obvious blood. HCV RNA was detected in five nasal secretion samples (13%) and on two straws (5%). Two of the nasal swabs without evident blood nevertheless harbored HCV, while three samples with blood traces had no detectable HCV. Furthermore, 71% of participants reported nasal inflammation, 11% had a perforated nasal septum, 8% had lesions of the nasal membranes, and 8% reported having nose bleeds at least once weekly. “We demonstrate the virological plausibility of intranasal transmission by confirming that blood and HCV RNA are present in the nasal secretions and drug-sniffing implements of HCV-infected intranasal drug users,” the investigators concluded.
In another study, reported in the September 1, 2008 Clinical Infectious Diseases, E. Girou and colleagues looked at so-called “nosocomial” HCV transmission in a healthcare setting. Screening at a French university hospital revealed two new cases of HCV seroconversion among patients undergoing long-term kidney dialysis, which led to an investigation of whether they were infected in the dialysis unit. Genetic analysis showed that one of these individuals was infected with the same HCV strain as a patient with chronic infection treated in the unit. More than 700 environmental surface samples were collected, of which 11% contained hemoglobin (a component of blood) and 7% contained HCV RNA; prior research has shown that HCV can remain viable on surfaces for up to 16 hours. Only about one-third of providers practiced appropriate hand washing and removed gloves immediately after patient care. Poor hand hygiene and a low ratio of nurses to patients were found to be independent predictors of blood on environmental surfaces. “Blood-contaminated surfaces may be a source of HCV cross-transmission in a hemodialysis unit,” the researchers concluded. “Strict compliance with hand hygiene and glove use and strict organization of care procedures are needed to reduce the risk of HCV cross-transmission among patients undergoing hemodialysis.”
Transmission within Families
Unsafe medical procedures are responsible for many cases of HCV transmission in developing countries, but a significant proportion remain unaccounted for, leading some experts to suggest that family or household transmission may play a role in endemic regions. In the September 2008 issue of Gut, S. Plancoulaine and colleagues described an investigation of family clustering of HCV infections in a highly endemic area in rural Egypt. The seroepidemiological survey included 3994 individuals, ranging in age from 2 to 88 years, in 475 family clusters. The overall HCV seroprevalence rate was 12%, and the rate increased with age. After adjusting for potential confounding factors, highly significant intrafamilial similarity in HCV seroprevalence was observed between fathers and their children, between mothers and their children, and between siblings, with a weaker correlation between spouses. Genetic analysis revealed greater similarity of HCV strains between family members than between unrelated individuals. The researchers concluded that these findings could be explained in part by intrafamilial viral transmission, but also noted that “genetic factors may make some individuals or family groups more susceptible to HCV infection.”
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Coinfection and Fibrosis Progression
Several studies have indicated that liver disease due to hepatitis C may progress more rapidly in HIV positive individuals, but data have been inconsistent. H.H. Thein and colleagues conducted two systematic literature reviews and meta-analyses to estimate annual liver disease progression rates according to current fibrosis stage. Results from the analysis of HCV monoinfected individuals were published in the August 2008 Hepatology and described in the September Journal Review. A similar analysis of HIV/HCV coinfected patients appeared in the October 1, 2008 issue of AIDS.
The coinfection analysis included data from 3567 participants in 17 natural history studies. The overall prevalence of liver cirrhosis was 21% (range 16%-28%) after 20 years and 49% (range 40%-59%) after 30 years. The rate of fibrosis progression appeared to be relatively constant over time. Comparing results from the two analyses, the researchers found that, overall, HIV/HCV coinfected patients were about twice as likely as HCV monoinfected individuals to develop cirrhosis, but this varied according to use of highly active combination antiretroviral therapy (HAART) to treat HIV. While coinfected patients not receiving HAART were 2.5 times more likely to develop cirrhosis, this fell to 1.7 times more likely for those on HAART. “Our results confirm that chronic hepatitis C outcomes are worse among coinfected individuals,” the investigators concluded. “Over the period studied, HAART did not appear to fully correct the adverse effect of HIV infection on HCV prognosis.” These findings suggest that HIV positive people may benefit from earlier hepatitis C treatment to slow or prevent liver disease progression.
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