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In This Issue:
• HCV Genotype 4 Treatment
• Genotype 2 and 3 Differences
• Growth Hormone Deficiency
• CD4 Count and Treatment Response in Coinfected Patients
HCV Genotype 4 Treatment
Genotype 4 hepatitis C virus (HCV), which is the most common type in parts of the Middle East and North Africa, is often classified as “hard to treat” like genotype 1, but prior studies have produced conflicting results and the optimal duration of interferon-based therapy is unknown. In a study by S.M. Kamal and colleagues, reported in the December 2007 issue of Hepatology, 358 Egyptian patients with genotype 4 chronic hepatitis C were treated with 1.5 mcg/kg/week pegylated interferon alpha-2b (PegIntron) plus weight-based ribavirin for variable durations. A control group of 50 participants was treated for a fixed duration of 48 weeks regardless of early response. Among the remainder, 69 individuals with undetectable HCV RNA at Week 4 were treated for 24 weeks (Group A), 79 with undetectable viral load at Week 12 were treated for 36 weeks (Group B), and 160 with continued detectable HCV RNA at Week 12 were treated for 48 weeks.
Sustained virological response (SVR) rates were 86% for Group A, 76% for Group B, 56% for Group C, and 58% for the fixed-duration control group. The incidence of adverse events and frequency of treatment discontinuation were higher for patients treated for the longest duration. Factors associated with SVR were milder liver injury at baseline (for all groups) and, for Group C, older age, higher body mass index, and low baseline viral load. These findings suggest that genotype 4 falls somewhere between hard-to-treat genotype 1 and easier-to-treat genotypes 2 and 3, and that the factors predicting treatment success are similar, especially early virological response. “In patients with chronic hepatitis C genotype 4 and undetectable HCV RNA at weeks 4 and 12, treatment with [PegIntron] and ribavirin for 24 weeks and 36 weeks, respectively, is sufficient,” the authors concluded.
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Genotype 2 and 3 Differences
HCV genotypes 2 and 3 are often grouped together in clinical trials, since both respond better to interferon-based therapy than genotype 1 and perhaps genotype 4. But data is accumulating that these two types are not the same, suggesting they should be analyzed separately. As reported in the January 2008 Journal of Viral Hepatitis, J. Powis and colleagues conducted a retrospective analysis of 180 treatment-naive patients – 72 (40%) with genotype 2 and 108 (60%) with genotype 3 – in a non-randomized, expanded-access trial of 180 mcg/week pegylated interferon alpha-2a (Pegasys) plus 800 mg/day ribavirin for 24-48 weeks; baseline characteristics, including fibrosis severity, were similar in the two genotype groups.
Overall, SVR was less common among genotype 3 patients. Along with genotype 3, more advanced fibrosis also predicted lack of sustained response, and the negative impact of cirrhosis on treatment response was more pronounced in the genotype 3 patients. These findings support those of the POWeR study, presented at the 2007 AASLD meeting (R.J. Bailey et al, abstract 246), which showed that individuals with genotype 2 responded better to PegIntron plus 800-1,200 mg/day weight-based ribavirin than those with genotype 3 (79% vs 72%); here too, advanced fibrosis, as well as high baseline HCV viral load, had a larger negative effect on response in the genotype 3 group.
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Growth Hormone Deficiency
HCV infection and its treatment can affect levels of growth hormone (GH) in chronic hepatitis C patients, according to a study published in the December 2007 American Journal of Gastroenterology. GH is one of several hormones produced by the pituitary gland in the brain that control the activity of endocrine glands and influence other bodily functions. U. Plockinder and colleagues prospectively assessed basal and stimulated pituitary hormone secretion in 21 German hepatitis C patients before and during treatment with pegylated interferon plus ribavirin or the related drug levovirin.
Before starting treatment, 17 patients (81%) had severe GH insufficiency and 9 of these had low levels of insulin-like growth factor-1 (IGF-1), a cytokine that regulates cell growth. Basal and stimulated GH levels increased significantly while on pegylated interferon, though IGF-1 levels remained low. Thyroid-releasing hormone concentrations also rose during therapy. By contrast, levels of prolactin, thyroid-stimulating hormone, adrenocorticotropic hormone, gonadotropin, and testosterone were normal before and during treatment. “While GH secretion improves during antiviral therapy, IGF-1 remains low, indicating persistent GH resistance of hepatocytes,” the researchers concluded. “Whether improvement in GH secretion during treatment is due to a direct drug effect or related to the suppression of viral load could not be differentiated, as most patients demonstrated a positive virologic response.”
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CD4 Count and Treatment Response in Coinfected Patients
While HIV/HCV coinfected patients tend to experience more rapid liver fibrosis progression and respond less well to interferon-based therapy than HCV monoinfected individuals, some past research suggests this may not be the case for coinfected people with well-preserved immune function. Two studies in the January 1, 2008 Journal of Acquired Immune Deficiency Syndromes explored the association between CD4 T-cell count and percentage – key measures of immune system health – and response to pegylated interferon plus ribavirin.
M. Opravil and an international team of colleagues analyzed CD4 counts and treatment outcomes in the pivotal APRICOT trial, in which 860 coinfected patients who had never been treated for hepatitis C were randomly assigned to receive Pegasys monotherapy, Pegasys plus 800 mg/day fixed-dose ribavirin, or conventional interferon plus ribavirin for 48 weeks; 857 participants with available CD4 cell data were included in the present analysis. Overall, Pegasys plus ribavirin produced a higher SVR rate (40%) than Pegasys alone (20%) or conventional interferon plus ribavirin (12%). SVR rates were highest with Pegasys plus ribavirin for patients at all CD4 cell levels. Within the Pegasys plus ribavirin arm, sustained response was not associated with CD4 count in genotype 2 or 3 patients, but the SVR rate was slightly higher in genotype 1 patients with a higher CD4 cell count or percentage. Adverse events occurred with similar frequency regardless of CD4 count or percentage, but more participants with a CD4 cell count below 200 required dose reduction or treatment discontinuation for safety reasons. “[N]either the efficacy nor the safety profile of [Pegasys plus ribavirin] therapy seems to be significantly compromised by a low baseline CD4 count,” the researchers wrote.
In the second study, L. Valerio and colleagues assessed 75 HIV/HCV coinfected French patients to assess whether a baseline CD4 cell count at of least 350 would predict sustained response to pegylated interferon plus ribavirin. They found that among genotype 1 patients, the overall SVR rate was 13%, and was not related to baseline CD4 count. Among participants with other genotypes, the overall SVR rate was 46%, and also was not significantly higher among those with 350 or more CD4 cells. “Higher CD4 cell count at treatment initiation with pegylated interferon plus ribavirin did not improve treatment success probability, regardless of HCV genotype,” the investigators concluded.
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