Sustained viral responses

Sustained viral response rates substantially better when combined with ribavirin (genotype 1 40%-50% genotype 2 or 3 70%-80% for combination therapy overall response rate 40% for monotherapy)... 

HCV RNA (early virologic response defined as HCV RNA undetectable or >2 logjo lower than baseline at 12 weeks and 24 weeks) for patients who lack an early viral response at 12 weeks, chance of sustained viral response is 13% for patients who lack an early viral response at 24 weeks, chance of sustained viral response is near zero in consultation with experts, consider stoppi ng peginterferon therapy if vi ro-logic response absent at 12-24 weeks... 

In contrast to the treatment of patients with chronic HBV infection, the primary goal of treatment in patients with HCV infection is viral eradication. In clinical trials, the primary efficacy end point is typically achievement of sustained viral response (SVR), defined as the absence of detectable viremia for 6 months after completion of therapy. SVR is associated with improvement in fiver histology and reduction in risk of hepatocellular carcinoma and occasionally with regression of cirrhosis as well. Late relapse occurs in less than 5% of patients who achieve SVR. 

The relation between interferon alfa-induced depressive disorders and the viral response to treatment has been examined in 39 patients with hepatitis C infection and no history of active psychiatric disease (359). After treatment with interferon alfa-2b and ribavirin for 6-12 months, 13 developed major depressive disorders requiring treatment with citalopram. The end-of-treatment response rates and sustained viral response rates were significantly greater in patients who developed a major depressive disorder than in those who did not (62% versus 27% and 39% versus 12% respectively). Despite the small sample, these results suggest that interferon alfa-induced depression occurs at doses or concentrations that... 

Half the patients with normal transaminases sometimes show both increased values and histological activity scores. Therefore, it is necessary to recheck the indications for these patients, especially because their sustained viral response (SVR) is comparable to that of patients with elevated transaminases. (225)... 

Interferon was used in the treatment of chronic hepatitis NANB as early as 1986 by J.A. Hoofnagel et af, i. e. three years before HCV was identified. The efficacy of IFNa for chronic hepatitis C could be proven in many studies. (213, 216, 219, 227, 229, 234, 241, 242, 245, 248, 251) The pegy-lation of IFNa (= coupling to polyethyleneglykol) leads to reduced enzymatic degradation, diminished antigenicity and delayed renal clearance thus its half-life is prolonged. As a result, a constant efficient level is achieved with only 1 (-2) injection(s) per week. This newly developed Peg IFNa led to a further improvement in the sustained viral response. (214, 229, 231, 232)... 

Lee SS, Heathcote EJ, Reddy KR, Zeuzem S, Fried MW, Wright TL, et al. Prognostic factors and early predictability of sustained viral response with pegin-terferon alfa-2a (40KD). J Hepatol 2002 37 500-6. 

Systematic reviews In a systematic review of antiviral drug therapy in 16 studies, in which pegylated interferon alfa was used in combination with ribavirin for recurrent hepatitis C after liver transplantation, the mean sustained viral response rate was 30% (range 8-50%) [34 ]. Dosage reduction and withdrawal of treatment were common (73% and 28% respectively). 

A meta-analysis of eight studies that compared 24- and 48-week sustained viral responses (SVR) and drug-related adverse events between telaprevir (5 studies) and boceprevir (3 studies involving 2020 patients) triple-therapy regimens in the treatment of chronic HCV infection, also reported increased prevalence of anaemia and dysgeusia associated with boceprevir [70 ]. It was calculated that treating 100 (naive or experienced) HCV patients with boceprevir-based triple therapy would result in 21 additional instances of anaemia and 26 of dysgeusia linked to treatment. 

Interferon alfa-2a (Roferon A), interferon alfa-2b (Intron-A), and interferon alfacon-1 (Infergen) are approved for chronic hepatitis C. However, they are not prescribed alone because only 12% to 16% of patients achieve a sustained virologic response (SVR). Adding ribavirin, a synthetic guanosine analogue that inhibits viral polymerase, increases the SVR rate to 35% to 45%. 

Encourage medication compliance with viral hepatitis treatments to increase sustaining virologic response. 

Subsequent analysis of stored serum samples showed reduction of HCV RNA levels during treatment and durable eradication of virus in some cases [38]. These early results were confirmed by randomized controlled trials in patients with chronic hepatitis C [39-41]. Durable viral eradication (termed sustained virologic response, or SVR) was achieved in 6% to 15% of patients after six months of treatment with recombinant interferon at doses of 3 to 6 MU administered subcutaneously three times per week. SVR increased to 13% to 25% if treatment was extended to 12 months [41]. The combination of the oral nucleoside analogue ribavirin with recombinant interferon increased SVR to 41% [42-44]. Ribavirin, however, is potentially embryotoxic and induces a dose-dependent hemolytic anemia, a situation that calls for close monitoring during therapy. 

Tan LK, Gilleece Y, Mandalia S, Murungi A, Grover D, Fisher M, Atkins M, Nelson M. Reduced glomerular filtration rate but sustained virologic response in HIV/hepatitis B co-infected individuals on long-term tenofovir. J Viral Hepat 2009 16(7) 471-8. 

Similar to HBV, infections with hepatitis C virus (HCV) have a high rate of progression from an acute to a chronic state that frequently leads to cirrhosis or hepatocellular carcinoma [2]. Monotherapy for HCV infection with IFN-a or combined therapy with ribavirin and IFN-a is associated with initial rates of response as high as 40%. The rates of sustained responses are, however, lower and also depend on the viral genotype. In patients infected with HCV genotype 2 or 3, the response was maximal after 24 weeks of treatment, whereas patients infected with genotype 1 -the most frequent in the USA and Europe - required a minimum treatment course of 48 weeks for an optimal outcome. 

Interim results from the SPRINT-1 phase 2 trial of boceprevir (SCH 503034) have been released. In subjects who received boceprevir plus interferon-a and ribavirin, viral RNA loads were suppressed at week 12 in between 70 and 79% of subjects infected with genotype 1 HCV, compared with only 34% in the interferon-o/ ribavirin standard of care arm (www.sch-plough.com/schering plough/news/release. jsp releaseID = 1064540). However, it is not yet known if this enhanced early response will translate into sustained response. 

Interferon-a is currently the only agent of proven clinical efficacy in the treatment of hepatitis C however, only 10 to 51% of patients enrolled in clinical trials showed a sustained improvement (Davis et al., 1989 Di Bisceglie et al, 1989). Current interferon-a therapy is, typically, 3 million units, thrice weekly, given subcutaneously for 12 months. Both HCV genotype and pretreatment viral load have been shown to influence the response to interferon (Lau et al., 1993 Yoshioka et al., 1992). 

Substances such as promoters that interfere with cell-to-cell communication allow cancer cells to proliferate wildly. But cell proliferation can be induced by other means as well. Toxicity or other types of injury to tissues can result in a proliferative response. So can certain natural and synthetic hormones, such as estrogens, cause proliferation of certain tissues, such as the breast. Chronic viral infections may cause cell killing and its consequence is cell proliferation. It appears that sustained chronic proliferation induced in any of these ways, either by agents foreign to the body or some, such as the estrogens, that are natural to it, can increase tumor growth. 

E. Therapeutic response According to the product label, studies have shown that Rofewn-A can normalize serum transaminases, improve Uver histology, and reduce viral load in patients with chronic hepatitis C virus (HCV) infection. Other studies have shown that Roferon-A can produce clinically meaningful tumor regression or disease stabilization in patients with hairy-cell leukemia or in patients with AIDS-related Kaposi s sarcoma. In Ph-positive CML, Roferon-A supplemented with intermittent chemotherapy has been shown to prolong overall survival and to delay disease progression compared to patients treated with chemotherapy alone. In addition Roferon-A has been shown to produce sustained complete cytogenetic responses in a small subset of patients with CML in chronic phase. 

An immune response is produced against the viral vectors that make subsequent administration of viral vectors less feasible, specifically when a sustained expression of the gene is a major issue. 

Lamivudine achieves almost universal HBV DNA suppression, with decreases in viral replication by about 3-4 log copies in most patients. Response to lamivudine is more rapid than to interferon (see below), with HBV DNA levels decreasing by approximately 97% after 2 weeks of therapy and 98% by 1 year. However, evidence of viral replication recurs in over 80% upon discontinuation of therapy. Seroconversion of HBeAg antigen from positive to negative occurs in only about 20% of patients yet in patients who do achieve seroconversion with lamivudine, the response is typically sustained. Progression to liver fibrosis is less frequent in patients treated with lamivudine compared with placebo. The height of the pretreatment serum ALT level may be the best predictor of HBeAg seroconversion. 

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