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Is HCV Curable?
 
Reported by Jules Levin
 
  Over 90% of HCV mono-infected patients who have negative HCV viral load (undetectable) 6 months after stopping therapy remain undetectable. Small studies of perhaps 200 hundred patients in total have followed patients for 3-11 years and find over 90% of these patients continue to have undetectable HCV in the blood. Small studies have shown that these patients do not have HCV in the liver either. The study discussed below found that 98% of patients achieving a sustained viral response (undetectable HCV viral load) did not have HCV in the liver. This of course is good news. Most doctors feel that a patient who achieves and sustains undetectable viral load is likely to remain healthy. Many patients who achieve a sustained viral response (SVR) are able to improve the condition of the liver (fibrosis and inflammation). Studies have also found that a percentage of patients who are not able to achieve an SVR are still able to slow disease progression (inflammation and fibrosis). However, we still need long-term studies which follow large numbers of patients for many years to evaluate long-term clinical outcomes: the development of cirrhosis and other severe complications of HCV, and longevity.
 
This past year HCV researchers (Poynard, McHutchison, Lindsay et al) reported on the effect of HCV therapy on fibrosis and inflammation. They followed patients who received various regimens including interferon and Pegylated interferon, and they evaluated the outcomes in terms of improved fibrosis and inflammation. They found that inflammation and fibrosis improves in many patients whether or not they achieve an SVR, but of course achieving an SVR results in greater likelihood of improving the liver. They also found that 49% of the 150 patients with cirrhosis in this study were able to "reverse" cirrhosis.
 
Here is link to full article: http://www.natap.org/2002/may/050902_2.htm
 
When doctors refer to HCV being "curable" it is often said that this is analagous the situation with cancer. In cancer if they can't find cancer for a certain number of years after therapy has been finished they call the person cured. Does cancer ever re-emerge? We need long-term studies in HCV to evaluate the outcomes of patients who sustain undetectable HCV viral load in order to confirm this.
 
In summary, if a patient can sustain an undetectable viral load for 6 months to 1 year after stopping HCV therapy this gives them the best opportunity to remain healthy. It's important to bear in mind that these study results apply to patients with HCV mono-infection. We are not certain if these findings apply precisely to HCV/HIV coinfected patients. Studies in coinfected patients are ongoing and soon we will have additional information on them. There is much research going on now into new drugs for treating HCV. For patients who do not achieve a sustained viral response with the current therapy, they may want to consider maintenance therapy if they have advanced liver disease. Maintenance therapy consists of continuing interferon at a half-dose. Studies have found that this slows disease progression. The first study data on a new HCV drug that appears promising was presented recently at the large annual liver conference (AASLD). They studies and reported for the first time results from patients with HCV who received an HCV protease inhibitor (BILN 1061). Patients received this new drug for 2 days and achieved potent reductions in viral of 2-3 logs. There were no apparent safety concerns. Phase II studies are expected to begin in early 2003.
 
Study title: Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin
 
"...Of the 400 sustained responders, 393 (98%) had undetectable hepatic HCV RNA, whereas the other 7 (2%) had detectable viral RNA in the liver... Seven (2%) patients with a SVR had persistent hepatic HCV RNA; of these, 5 were followed late after treatment, and 2 relapsed... Five of these 7 patients have subsequently been followed annually. To date, 2 with high and low hepatic HCV-RNA levels, respectively, have relapsed (patients 2 and 7), with serum HCV RNA reappearing 12 months after completion of therapy. Two others (patients 3 and 6) have a durable response at 3.5 years' posttreatment. Patient 5 was still virus-free at 12 months' posttreatment, but has not been followed further. Patients 1 and 4 achieved a sustained response at 24 weeks after treatment, but have not been followed subsequently.."
 
Abstract summary: The clinical use of measuring hepatic hepatitis C virus (HCV) RNA before and after therapy in patients with chronic hepatitis C has been assessed in a number of small clinical trials. Viral clearance from the liver may be a better marker of long-term response than eradication of serum HCV RNA. The aim of this study was to evaluate quantitative hepatic HCV-RNA measurements before and after antiviral therapy. Two thousand eighty-nine chronic hepatitis C patients were enrolled in 3 published clinical trials evaluating interferon alfa-2b alone or with ribavirin either as initial therapy or for interferon relapse. Hepatic HCV-RNA quantitation was performed with a modified reverse-transcription polymerase chain reaction (RT-PCR) before and 24 weeks after therapy in 951 and 1,316 patients, respectively. Pretherapy hepatic HCV-RNA concentrations correlated best with serum HCV-RNA concentrations (R = .236, P = .0001) and negatively correlated with alanine transaminase (ALT) values (-0.178, P = .0001), duration of infection (-0.09, P = .02), parenchymal injury (-0.135, P = .0001), histologic activity index (HAI) inflammatory score (-0.085, P = .01), Knodell fibrosis score (-0.072, P = .03), and body weight (-0.078, P = .02). In paired liver biopsy specimens (n = 534), change in hepatic HCV RNA correlated with the change in the HAI (R = .346, P = .0001). Of 400 sustained virologic responders (SVR), 393 (98%) had undetectable hepatic HCV RNA, whereas 7 (2%) had detectable hepatic HCV RNA; 5 have been followed and 2 have had reappearance of serum HCV RNA 12 months after therapy. In conclusion, measurement of hepatic HCV RNA before or after therapy reflects changes observed in serum HCV RNA, and correlates inversely with hepatic inflammation and fibrosis, but otherwise has minimal clinical use. (HEPATOLOGY 2002;35:688-693. Author: McHutichison et al)
 
Hepatitis C is an important cause of chronic liver disease, with an estimated 2.7 million persons infected in the United States and 150 million persons worldwide. Recent studies have shown that 35% to 40% of patients who receive the combination of interferon plus ribavirin achieve the long-term benefits of sustained viral eradication from serum. Therapy, however, is costly and associated with side effects that require discontinuation or dose reductions in up to 20% of patients. Thus, identification of factors that would allow selection of patients most likely to respond or maintain their response would be clinically valuable. Before treatment, young age, female gender, absence of cirrhosis, low levels of pretreatment serum hepatitis C virus (HCV) RNA, and infection with HCV genotypes 2 or 3 have been associated with response. Unfortunately, these variables cannot be used clinically to accurately predict response in any individual patient, rendering it difficult to use these prognostic indicators to deny therapy.
 
The clinical use of quantifying hepatic HCV RNA before and after interferon therapy in patients with chronic hepatitis C infection has been assessed retrospectively in a number of small clinical studies. Viral clearance from the liver has been thought to be a better marker of long-term response than sustained eradication of serum HCV RNA, and most patients with a sustained virologic response (SVR) after therapy have also been shown to have undetectable liver HCV RNA.
 
The aim of this study was to prospectively evaluate the clinical use of assessing liver HCV-RNA quantitation before therapy as a predictor of sustained response, and after therapy as an indicator of durable response, in patients with chronic hepatitis C infection.
 
Two thousand eighty-nine patients with chronic hepatitis C infection were enrolled in 3 published clinical trials, comparing the safety and efficacy of interferon alfa-2b (INTRON A, Schering-Plough, Kenilworth, NJ) alone or combined with ribavirin (REBETOL, Schering-Plough) for 24 or 48 weeks for initial therapy or for relapse after interferon. At the time of liver biopsy (before and 24 weeks after therapy), a portion of liver tissue was immediately snap-frozen in liquid nitrogen and stored at -70íC for HCV-RNA analysis.
 
A SVR was defined as loss of serum HCV RNA by reverse-transcription polymerase chain reaction (RT-PCR) 24 weeks after completion of therapy. Pre- and posttherapy liver tissue was available for analysis from 951 and 1,316 patients, respectively.
 
RESULTS
 
Of the 2,089 patients evaluated, pre- and posttherapy liver tissue was available for analysis from 951 and 1,316 patients, respectively. The discrepancy in the lower number of patients with pretreatment biopsies available for this study resulted from the fact that this protocol was introduced after some patients had already undergone their pretreatment liver biopsy. Thus, patients with a biopsy obtained within a few months of these clinical trials did not undergo a repeat pretreatment liver biopsy before study entry. Most pretreatment liver-biopsy specimens (903 of 951 [95%]) contained detectable HCV RNA.. Of the remaining 48 (5%) that were negative, 37 (77%) were associated with reduced amplification of the internal assay controls, indicating that there was insufficient remaining viable tissue to perform RT-PCR.
 
Of the 1,316 liver biopsies tested for HCV RNA 24 weeks after therapy, 400 were from sustained responders and 916 from nonresponders (those who did not achieve a sustained response). Of the 400 sustained responders, 393 (98%) had undetectable hepatic HCV RNA, whereas the other 7 (2%) had detectable viral RNA in the liver. The remaining 916 liver biopsies tested were from nonresponders, of which 850 (93%) had detectable HCV RNA, but in 66 (7%) biopsies, HCV RNA was undetectable. However, 34 (52%) of these specimens from nonresponders, and 17 of 393 (4%) from sustained responders, had reduced amplification of internal controls, consistent with viable tissue inadequate to assess whether HCV RNA was present or absent.
 
Pretreatment hepatic HCV-RNA values correlated closely with baseline serum HCV-RNA levels (r = 0.236, P = .0001).
 
A significant negative correlation was observed with the baseline ALT ratio (ALT value at baseline expressed as a ratio to the upper limit of normal) (r = -0.178, P = .0001), body weight (r = -0.078, P = .019), and duration of infection (r = -0.088, P = .017). However, the date of acquisition of infection was based on the patient's reporting; therefore, the duration of infection represents an estimated value in the majority of cases. Analysis of subgroup means by ANOVA also showed a statistical association between hepatic HCV-RNA levels and the reported mode of acquisition (P = .0001), as well as a higher hepatic HCV-RNA level in patients with genotype 1 compared with non-1 ( P = .0007).
 
When we evaluated the relationship between hepatic HCV-RNA concentrations and histologic changes before treatment, we found a negative correlation between pretreatment hepatic HCV-RNA values and parenchymal injury (r = -0.135, P = .0001), HAI inflammatory score (r = -0.085, P = .012), and Knodell fibrosis score (r = -0.072, P = .034); however, we found no association with other components of the HAI.
 
Although pretreatment hepatic HCV-RNA values were predictive of response to antiviral therapy when analyzed alone or after controlling for treatment, when other prognostic factors such as genotype and serum HCV RNA were included in the logistic regression, the effect of the hepatic HCV RNA in predicting response became nonsignificant.
 
There were 534 patients with paired liver biopsies available before and after therapy. Of these, 364 (68%) were nonresponders and 170 (32%) sustained responders. Overall, the observed change in liver HCV RNA correlated significantly with the change in the HAI (r = .346, P = .0001). However, this correlation was not observed when either nonresponders (r = .026, P = .62) or sustained responders (r = -.062, P = .42) were analyzed separately. Seven patients achieved a SVR to therapy but had detectable hepatic HCV RNA at the 24-week posttreatment biopsy. One of these (patient 3) was from the interferon-relapse retreatment trial, and most had low levels of detectable hepatic HCV RNA at follow-up.
 
Five of these 7 patients have subsequently been followed annually. To date, 2 with high and low hepatic HCV-RNA levels, respectively, have relapsed (patients 2 and 7), with serum HCV RNA reappearing 12 months after completion of therapy. Two others (patients 3 and 6) have a durable response at 3.5 years' posttreatment. Patient 5 was still virus-free at 12 months' posttreatment, but has not been followed further. Patients 1 and 4 achieved a sustained response at 24 weeks after treatment, but have not been followed subsequently.
 
Discussion By Authors
 
When this study was initiated, the clinical value of measuring hepatic HCV RNA as a predictor of response, relapse, or disease severity was unclear. Smaller studies have demonstrated that changes in hepatic HCV RNA with therapy reflect changes in serum HCV RNA, and that the persistence of hepatic HCV RNA at the end of therapy may predict relapse. Other studies using non-PCR-based techniques for the detection of intrahepatic HCV RNA, such as branched-chain DNA target amplification or in situ hybridization, have also demonstrated a correlation between hepatic HCV-RNA levels and serum HCV RNA. This large trial allowed a careful prospective evaluation of these issues.
 
Our results indicate that measurement of hepatic HCV RNA before or after therapy reflects levels of serum HCV RNA.
 
Seven (2%) patients with a SVR had persistent hepatic HCV RNA; of these, 5 were followed late after treatment, and 2 relapsed. Combination therapy for previously untreated patients with chronic hepatitis C results in posttreatment virologic relapse rates of 20% to 40% depending on the duration of therapy. Accurate, early identification of these relapsing patients is not possible and cannot be predicted at this time. Most relapses occur during the first 3 months following treatment. After this period, the late relapse rate over several years in patients with a SVR is approximately 5% to 10%. Small studies of hepatic HCV RNA have documented that hepatic viral clearance correlates with long-term SVR. In our study, only 2 of 7 patients with a SVR, but detectable posttreatment hepatic HCV RNA, have relapsed within 12 months.
 
In this study, the posttreatment liver biopsies were obtained 24 weeks after the end of therapy. Whether earlier relapse, within the first 6 months after therapy, could be predicted by assessing hepatic HCV RNA at the end of treatment was not evaluated in this study. Presumably, residual virus within the liver (or other extrahepatic reservoirs) is responsible for most early relapses, and this might have been detectable if hepatic HCV-RNA estimation had been performed at the end of treatment, as indicated in a previous small trial. Larger prospective trials would be required to further evaluate this concept, but end-of-therapy biopsies are rarely obtained either in clinical trials or in routine clinical practice.
 
Hepatic HCV-RNA concentrations before treatment correlated with both serum HCV-RNA concentrations and HCV genotype, and were higher in genotype 1-infected patients, as previously noted. In addition, hepatic HCV-RNA concentrations were associated with certain demographic variables. A strong inverse correlation existed between pretreatment hepatic HCV-RNA concentrations and the degree of liver parenchymal injury, and with baseline ALT values; a weaker correlation was found with the estimated duration of infection, body weight, HAI inflammatory, and Knodell fibrosis scores. Reasons for these negative correlations are speculative. The precise mechanisms of hepatocyte injury in chronic hepatitis C are unknown but presumably immune-mediated. This study did not indicate an association between hepatic HCV-RNA levels and the degree of histologic activity as would be expected if a direct viral cytopathic mechanism were the predominant factor in hepatic injury.
 
In this study, 5% of pretreatment and 7% of posttreatment liver specimens were falsely negative (HCV RNA detected in the serum but not in the liver), and most of these could be explained by reduced amplification within the assay. Whereas sampling could be a potential explanation, other studies suggest that HCV is distributed evenly throughout the liver, but may only infect 5% to 25% of hepatocytes. Technical factors could explain these occasional negative samples, but in most instances, the accompanying internal controls were also negative, suggesting that the liver tissue was insufficient or improperly stored to maintain nucleic-acid viability.
 
 
 
 
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