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In This Issue:
• Distribution of HCV Genotypes in the U.S.
• Caution Regarding Extra-Strength Acetaminophen
• Fibrosis Progression
• Neurocognitive Functioning
• Delayed Virological Response
Distribution of HCV Genotypes in the U.S.
Hepatitis C virus (HCV) genotype and viral load are important predictors of response to interferon-based therapy. As reported in the August 2006 issue of Gastroenterology, O. Nainan and colleagues from the Centers for Disease Control and Prevention conducted a study to determine genotypes and viral load levels in the HCV positive population in the U.S. The study included 275 HCV-infected participants in the Third National Health and Nutrition Examination Survey (NHANES), conducted between 1988 and 1994. Genotype 1a was most common (found in 142 patients), followed by 1b (73), 2b (27), 3a (17), 2a (8), 6 (5), and 4 (3). Genotype 1 was predominant in all age groups, and was the most common genotype among blacks (90.9%), Mexican-Americans (71.2%), and non-Hispanic whites (69.6%). More than half the participants had HCV RNA levels above 2 million IU/mL. The authors concluded that, “Persons with chronic hepatitis C in the United States who may require treatment in the foreseeable future are predominantly infected with genotype 1, including a disproportionate number of non-Hispanic blacks.” Since genotype 1 HCV responds less well to treatment, they added, “These features emphasize the need for improved therapies that reduce or eliminate complications from genotype 1 infections.”
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Caution Regarding Extra-Strength Acetaminophen
It is often assumed that liver toxicity related to acetaminophen (found in Tylenol and many other products) occurs primarily among individuals who take overdoses, drink alcohol, or have pre-existing liver disease. However, a study in the July 5, 2006 Journal of the American Medical Association showed that 4 grams of acetaminophen daily – the maximum recommended dose of Extra-Strength Tylenol – can cause ALT elevations even in healthy people who use the drug as directed. P. Watkins and colleagues randomly assigned 145 healthy adult volunteers to receive placebo tablets, 1000 mg acetaminophen alone every six hours, or the same dose of acetaminophen in combination with oxycodone, hydromorphone, or morphine. In the acetaminophen monotherapy and combination arms, 39% of participants had a maximum ALT level greater than 3 times the upper limit of normal (x ULN), 25% had ALT greater than 5 x ULN, and 8% had levels above 8 x ULN; in contrast, no one in the placebo arm had an elevation above 3 x ULN. AST elevations were generally smaller, but followed a similar pattern. After acetaminophen was stopped, ALT continued to increase for up to four days; ALT eventually normalized, but this took up to 11 days after discontinuation. Medical and demographic characteristics generally did not predict who would develop ALT elevations, though Hispanic subjects were at somewhat higher risk. The results of this study suggest that acetaminophen should be used with caution at the highest recommended doses.
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HIV/HCV Coinfection News
Several journal articles have recently reported on various aspects of HIV/HCV coinfection. On the whole, past studies have shown that coinfected patients experience more rapid liver disease progression than individuals with HCV alone. In the July 2006 American Journal of Gastroenterology, however, A. Monto and colleagues from the San Francisco Veterans Affairs Medical Center reported that in a cohort of 92 HIV/HCV coinfected patients and 372 HCV monoinfected individuals, the coinfected patients did not have uniformly worse liver disease. Disease severity was similar in the two groups, with mean fibrosis scores of 1.45 and 1.53, respectively. Among coinfected patients, having a lower current or nadir (lowest-ever) CD4 cell count was the only variable independently associated with worse fibrosis, confirming data from previous studies suggesting that patients on antiretroviral therapy with well-controlled HIV and relatively good immune function may not experience the accelerated progression associated with coinfection in more heavily immunocompromised individuals.
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In the August 1, 2006 issue of Clinical Infectious Diseases, B. McGovern and colleagues reported that in a retrospective study of 183 coinfected patients at four New England medical centers, 69% had some degree of hepatic steatosis (accumulation of fat in the liver): 31% minimal, 27% mild, 18% moderate, and 1% severe. Presence of steatosis was associated with higher body weight and elevated blood glucose and triglyceride levels. Steatosis was also strongly associated with the use of use of two anti-HIV drugs, ddI (didanosine, Videx) and d4T (stavudine, Zerit), which accounted for a nearly five-fold increase in risk. As expected, steatosis was associated with more severe fibrosis. In an accompanying editorial, M. Zeremski and A. Talal noted that several previous studies have found a similar association between antiretroviral drugs and steatosis. Drugs such as ddI and d4T appear to cause steatosis related to mitochondrial toxicity. “In the clinical treatment of HCV/HIV coinfected patients, and especially for those with steatosis,” the authors concluded, “the D-drugs should be used cautiously.” Fortunately, several other drugs in the same nucleoside reverse transcriptase inhibitor class may be substituted that are not linked with mitochondrial toxicity.
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Past research has shown that HIV positive patients and those with HCV have similar patterns of neurocognitive abnormalities, and that coinfected individuals may be at higher risk for cognitive problems than people with either virus alone. As reported in the August 1, 2006 issue of AIDS, T. Parsons and colleagues analyzed the effect of antiretroviral therapy for HIV on neurocognitive functioning in 20 HIV/HCV coinfected patients and 45 HIV monoinfected participants. At baseline, neurocognitive function tests revealed significantly worse performance in the coinfected group in the areas of visual memory and fine motor functioning. “[P]ersons with HCV/HIV coinfection may have greater neurocognitive declines than persons with HIV infection alone,” the authors concluded, adding that, “HCV/HIV coinfection may accelerate the progression of HIV-related neurocognitive decline.” After six months on antiretroviral therapy, “there was a general trend for improvement in the coinfected group,” suggesting “that the neurocognitive difficulties associated with HCV may be amenable to treatment with antiretroviral therapy.” The authors also suggested that the specific visual deficits observed in the coinfected group might be associated with pegylated interferon therapy, which can cause visual side effects.
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Delayed Virological Response
Finally, a study in the July 2006 Journal of Viral Hepatitis added to the conflicting data about whether HIV/HCV coinfected individuals clear HCV more slowly after starting hepatitis C treatment. A. Moreno and colleagues conducted a study in which 36 coinfected patients and 70 with HCV alone (all with genotypes 1 or 4) were treated with weight-based pegylated interferon (Peg-Intron) plus ribavirin. Despite having similar baseline HCV RNA levels, the HCV monoinfected patients had significantly lower HCV viral load at week 4 (rapid virological response), week 12 (early virological response), and week 24, and were more likely to have undetectable HCV viral load at week 24 (60% vs 30%), week 48 (end-of-treatment response; 46% vs 25%), and week 72 (sustained virological response; 37% vs 17%). Failure to achieve at least a 1-log decrease in HCV RNA by week 4 predicted treatment failure for HCV monoinfected individuals, but not for coinfected patients. The authors concluded that coinfection is associated with slower HCV clearance after starting therapy. While some other studies have suggested that 4-week rapid virological response predicts sustained response in coinfected patients, as it does in people with HCV alone, further research is needed to determine the most appropriate response cut-off for HIV/HCV coinfected individuals.
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