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In This Issue:
• HCV Genotype and Disease Progression
• HCV Genotype Recombination
• 16-Week Treatment for Genotype 2
• Atorvastatin Does Not Inhibit HCV Replication at Normal Doses
• Insulin Resistance
• HIV and Perinatal HCV Transmission
• Mitochondrial Toxicity Due to Ribavirin Plus NRTIs
HCV Genotype and Disease Progression
It is well known that individuals with genotype 1 HCV do not respond as well to interferon-based therapy as those with genotypes 2 or 3, but less is known about the effect of genotype on the natural history of hepatitis C. As reported in the March 2007 Journal of Viral Hepatitis, H.E. Harris and colleagues analyzed serum samples from 749 individuals enrolled in the UK Hepatitis C National Register and extracted information on clinical outcomes from the database. They found that 69% of patients who spontaneously cleared HCV had genotype 1, compared with 51% of those who developed chronic infection. However, among individuals with continued detectable HCV viral load, those with genotype 1 were more likely to have higher-than-average histological scores than those with genotypes 2 or 3. These data suggest that while spontaneous clearance may occur more often with genotype 1, this genotype may cause more aggressive liver disease.
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HCV Genotype Recombination
In the April 2007 Journal of Virology, F. LeGrand-Abravanel and colleagues described a strain of HCV that appeared to combine two previously recognized genotypes. The researchers compared the genetic sequence of an HCV strain found in southwest France with reference strains in HCV sequence databases. They discovered an apparent recombinant virus with genotype 2 at the 5' end and genotype 5 at the 3' end, with the crossover point located between the NS2 and NS3 genes. “Recombination between HCV genotypes must now be considered in studies on HCV virus epidemiology and evolution, and predictions of the virus response to antiviral therapy,” the authors concluded.
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16-Week Treatment for Genotype 2
Current hepatitis C treatment guidelines call for 24 weeks of therapy with pegylated interferon plus ribavirin for patients with genotype 2 or 3 HCV. But a shorter course may be sufficient for certain genotype 2 patients, according to a report in the April 2007 issue of Gut. M.L. Yu and colleagues from Taiwan studied 150 genotype 2 patients who were randomly assigned to receive either 16 weeks (n = 50) or 24 weeks (n = 100) of pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day ribavirin. In the 16-week arm, 86% of subjects experienced rapid virological response (RVR), or undetectable HCV RNA after four weeks of treatment, compared with 87% in the 24-week arm. Six months after completion of therapy, 94% of patients in the 16-week arm and 95% in the 24-week arm achieved sustained virological response (SVR). Comparing sustained outcomes in patients who did and not achieve RVR, the difference was more dramatic in the 16-week arm (100% with SVR in the RVR group vs 57% in the non-RVR group) compared with the 24-week arm (SVR rates of 98% and 77%, respectively). Treatment was equally well tolerated in both arms. The researchers concluded that 16-week and 24-week treatment “provided equal efficacy” in genotype 2 patients with rapid response.
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Atorvastatin Does Not Inhibit HCV Replication at Normal Doses
In July 2006, researchers reported that certain HMG-CoA reductase inhibitors, or statins, suppressed HCV replication in vitro. But a small pilot study reported in the April 2007 issue of Hepatology suggests that in patients, statins may not be active against HCV at normal doses. J.G. O’Leary evaluated the effect of atorvastatin (Lipitor) on HCV RNA levels in 10 hepatitis C patients who were taking 20 mg daily to manage high cholesterol. In the earlier laboratory study, atorvastatin was one of two statins that demonstrated moderate HCV inhibitory activity; fluvastatin (Lescol) exhibited the strongest anti-HCV activity, while pravastatin (Pravachol) did not inhibit HCV. In patients, while serum cholesterol levels decreased as expected, there was no statistically significant change in HCV RNA levels after 4 or 12 weeks compared with baseline. The authors concluded that, “atorvastatin, and likely all HMG-CoA reductase inhibitors, does not inhibit HCV RNA replication in vivo at conventional doses,” but they added that it remains to be seen whether statins might inhibit HCV if used with interferon, as was done in the in vitro study.
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In the March 12, 2007 issue of AIDS, A. Howard and colleagues reported data from a cross-sectional study of 267 HIV positive and 179 “at-risk” HIV negative adults without a history of diabetes. More than half (59%) had HCV infection, and three-quarters of this group had detectable HCV RNA. Overall, 98 participants (22%) had abnormal glucose tolerance, of whom 29 had frank diabetes. Among HIV positive individuals, neither use of antiretroviral therapy in general, nor protease inhibitors specifically (used by 52%), were associated with insulin resistance or abnormal glucose tolerance. Among obese patients, abnormal glucose tolerance was more common among HCV positive compared with HCV negative individuals, but this association was not observed among non-obese participants. The researchers concluded that, “The potential impact of HCV coinfection and obesity on glucose metabolism should be recognized in clinical care, and addressed in future research studies of HIV-infected individuals.”
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HIV and Perinatal HCV Transmission
While the overall likelihood of mother-to-child (perinatal) HCV transmission is low -- around 5% in most studies -- various factors can increase the risk. In the April 15, 2007 issue of Clinical Infectious Diseases, C.B. Polis and colleagues reported on a meta-analysis of perinatal HCV transmission studies to date. They identified 10 published articles that met the inclusion criteria, each of which included at least 20 HIV/HCV coinfected women; seven were from Italy, two were from elsewhere in Europe, and one was from the United States. In total, the data covered 4,424 mother/child pairs, and 858 of the mothers (19.3%) were coinfected. Overall, 287 infants became infected with HCV. When the investigators restricted their analysis to the five studies that included more than 50 coinfected women, they found that having HIV nearly doubled the risk of perinatal HCV transmission. Among mothers with detectable HCV RNA, coinfection nearly tripled the transmission risk. “HIV/HCV coinfected women have significantly higher odds of transmitting HCV to their infants than do women who are infected with HCV alone,” the researchers concluded.
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Mitochondrial Toxicity Due to Ribavirin Plus NRTIs
Mitochondrial damage is a potential side effect of ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) used to treat HIV -- especially d4T (Zerit) and ddI (Videx). Mitochondrial toxicity, indicated by low cellular levels of mitochondrial DNA (mtDNA), can cause symptoms including lactic acidosis, lipoatrophy (fat loss), and pancreatitis. As reported in the March 12, 2007 issue of AIDS, C. de Mendoza and colleagues conducted a retrospective analysis of 59 HIV/HCV coinfected patients who started treatment with pegylated interferon plus ribavirin. Among the 43 individuals on antiretroviral therapy, all were taking two NRTIs plus either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor; seven were taking d4T, but none were on ddI (as per guidelines for patients receiving ribavirin). At baseline, there was an inverse correlation between serum HCV RNA level and mtDNA in peripheral blood mononuclear cells. After starting anti-HCV therapy, there was an overall increase in the amount of mtDNA in blood cells, which was most pronounced among patients with the highest baseline HCV RNA levels. HCV suppression was associated with a significant increase in mtDNA among patients who were not on anti-HIV therapy, but not among those taking antiretroviral drugs; changes in mtDNA did not differ significantly, however, when comparing the various NRTIs. The researches hypothesized that HCV eradication might reduce mitochondrial damage, but that this benefit does not occur in individuals taking both anti-HCV and anti-HIV therapy, “probably because of a deleterious interaction of these drugs on mitochondria.” They suggested that to avoid such interactions, “HCV therapy should ideally be administered to [HIV/HCV coinfected] patients before beginning antiretroviral therapy.”
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