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Does Liver Disease Improve for HCV Therapy Nonresponders?
Reported by Jules Levin
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Maribel Rodriguez, MD, (hepatologist in Puerto Rico and the Ponce School of Medicine) reported results of a study in viral nonresponders to HCV therapy, evaluating the effect of therapy on liver disease progression.
Background
A significant number of coinfected patients will not be able to achieve a sustained undetectable viral response. Preliminary results from several studies show coinfected patients can achieve a sustained viral response but they suggest the overall viral response rate to therapy is lower than in patients with HCV monotherapy.
In the US, 70% of individuals infected with HCV monoinfection have genotype 1, and persons with genotype 1 are less likely to achieve a sustained viral response. Among coinfected patients it appears that 80-90% have genotype 1. In addition, side effects and potential toxicities (anemia, reduced platelets, reduced white and red blood cell counts) appear to occur more often for a number of coinfected patients. HCV therapy can be difficult to tolerate for all patients, but coinfected patients may have a little more difficulty in tolerating therapy. Due to the reasons listed just above coinfected patients on the whole face more challenges in achieving a sustained undetectable viral load. As well, there are few support services currently in place targeting specifically coinfected patients.
The results of this study show nonresponders achieved an improvement in necroinflammatory score (disease activity), but only suggest an improvement in fibrosis progression. These results suggest HCV therapy may slow disease progression in coinfected patients.
In HCV monoinfected patients studies show viral responders can improve disease and perhaps normalize liver histology in the long term. There are a number of studies suggesting that inteferon therapy has an antifrobotic effect which may slow or stop disease progression in patients who do not achieve a viral response (nonresponders).
Therefore, since several studies show HIV can accelerate HCV proggresion the effect of HCV therapy on disease progression becomes important. It is important if therapy can slow disease progression until more effective drugs are developed. New HCV antivirals are in early research development. Currently, several HCV protease inhibitors and polymerase inhibitors are in early stages of development.
Rodriguez evaluated the liver biopsies in 40 coinfected patients before and after interferon (IFN) therapy. 23 patients received IFN therapy. HCV therapy was given for at least 6 months. Histology (the liver condition) measurements were performed and described using the Ishak score. The average duration of therapy was 20 months. Rodriguez assessed fibrosis score (0-6), necroinflammatory score (0-18), fibrosis progression rate (FPR), and necroinflammatory progression rate (NPR).
The average duration of HCV infection was estimated to be 18 years (range: 9-42 years). 82% of patients were men. Average age was 42. 76% of patients had genotype 1. No significant alcohol ingestion was documented before and between both biopsies. 67% of patients were on HAART. Average CD4 count was 477. The average viral load was low- 2.5 log and 50% had undetectable HIV viral load.
The average HCV viral load was 5.9 log (1 million copies). 88% of patients had fibrosis and 24% had cirrhosis.
RESULTS
In patients who received interferon but who were nonresponders, there was a significant improvement (p=0.026) noted from biopsies in necroinflammatory score (liver disease activity) from an average of 8.39 before treatment to 3.55 after treatment. The fibrosis score was 2.76 before treatment vs 3.14 after treatment (p=0.025). The necroinflammatory progression rate significantly decreased from +0.48 to -0.72 in biopsies before and after treatment. The FPR was the same before and after treatment. Although the fibrosis score and progression rate did not improve, the progression rate did not get worse and the fibrosis score did not get too much worse. We are unable to draw conclusions about whether or not fibrosis is improved from this information, it merely suggests benefit to fibrosis. Still, the improvement in necroinflammatory score and NPR suggest the possibility of clinical benefit. This suggests that even if a coinfected patient does not achieve a sustained viral response they may still be able to slow disease progression until more effective therapy is available.
Although the treated & untreated patients had the same fibrosis score (2.85 vs 2.76) before treatment, the treated patients had a lower fibrosis score on biopsy after treatment (4.28 vs 3.14), and the progression rate (FPR) was about the same (.38 vs .40).
Also, the ALT levels did not correlate with changes in necroinflammatory score.
So, what does this mean? Rodriguez concluded:
--nonresponder patients had a significant improvement in disease (histology) activity.
--no definite conclusions can be reached, regarding fibrosis progression, but the data suggest that fibrosis progression can be diminshed by IFN.
--further follow-up is needed of liver histology and additional patients are required to assess the long-term impact of treatment.
Currently, the NIH is conducting a 5 year study to evaluate the effect of Pegasys maintenance therapy in nonresponders to interferon plus ribavirin.
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