| Hepatitis C Virus (HCV) and HIV/HCV Coinfection | |||
| V. Hepatitis C Treatment Summary | Recommendations | |||
Although the duration of follow-up and baseline participant characteristics differ widely across studies of the long-term effects of interferon, the data suggest that among individuals who achieve an SVR or a biochemical response to treatment, fibrosis progression is slowed or arrested and, in some cases, pre-treatment liver damage can be reversed (Cammá 2004; Lau 1998; Marcellin 1997; Schvarcz 1999; Shiatori 2000; Shindo 2001; Yabuuchi 2000; Yoshida 2002). Lau and colleagues followed ten individuals for six to thirteen years after completion of HCV treatment (with varying regimens of interferon alfa-2b). Half of the group achieved SVR; the other five were non-responders. Liver biopsies were performed five to eleven years after therapy. All five of the sustained responders had no detectable HCV RNA in their serum or their liver at final follow-up. Biopsy samples from all five responders reflected improvements over baseline and end-of- treatment scores for fibrosis and inflammation; one individual had normal liver tissue and the other four had non-specific, mild inflammation without significant fibrosis. All five of the non-responders had detectable HCV RNA at final follow-up, and two had increased fibrosis scores. One non-responder developed hepatocellular carcinoma (HCC) five years after treatment and had a liver transplant, while another progressed to decompensated liver disease and died from an intracerebral bleed while awaiting transplantation (Lau 1998). Marcellin and colleagues evaluated the long-term benefit of interferon among 80 individuals who achieved sustained virological and biochemical responses to interferon treatment. Follow-up ranged from 1.0 to 7.6 years. HCV RNA remained undetectable in 96%, and 93% maintained persistently normal liver enzyme levels. Before treatment, 60% experienced fatigue; after treatment, none reported fatigue. Baseline liver biopsy samples were available from all 80 participants, and at least one post-treatment biopsy was performed on 69 individuals between one and six years after completion of treatment. Normal—or nearly normal—liver histology was observed after treatment in 62%, while 94% had an improvement in liver histology. No new cases of cirrhosis were diagnosed after treatment. Of the five individuals with pre-treatment cirrhosis, four had post-treatment biopsies. An improvement was seen in two; disease progression without liver decompensation or hepatocellular carcinoma was found in the other two (increases of one and two points on the Knodell HAI, respectively) (Marcellin 1997). Although achieving a sustained virological response increases the likelihood of histological benefit, a sustained biochemical response to treatment appears to reduce the risk of HCV disease progression. Shindo and colleagues studied the pre- and post-treatment liver histology of 250 individuals treated with standard interferon and a control group of 89 untreated individuals. Follow-up ranged from 8 to 11 years post-treatment. The treated cohort was categorized by response to therapy as: complete responders (defined as sustained virological and sustained biochemical response), biochemical responders, relapsers, and non-responders. The annual incidence of cirrhosis was significantly lower in complete responders, biochemical responders, and relapsers than in an untreated control group (P=0.0001). Table 19. Annual Incidence of Cirrhosis and HCC among Responders, Relapsers, Non-Responders, and Untreated Controls  *P=0.0001 for complete responders, biochemical responders, relapsers, and controls vs. non-responders. Complete responders had improvements in the grade (amount of disease activity) and stage (structural progression of disease) of liver histology at the end of treatment. Grading scores continued to decrease at one and two years after treatment, while staging scores decreased at one year after treatment and then stabilized. Biochemical responders had decreases in grading and staging scores by the end of treatment, but their scores did not change subsequently (Shindo 2001). Fibrosis does not invariably improve after hepatitis C treatment. Shiratori and colleagues performed a retrospective cohort study, assessing post-treatment changes in fibrosis and inflammatory activity in biopsy samples from 487 interferon-treated individuals and 106 untreated controls. Liver biopsy was performed within six months of treatment initiation and 1-10 years (median, 3.7) after completion of treatment. Regression of fibrosis and improvement in histological activity occurred most frequently among those who achieved sustained virological responses, although some relapsers experienced histological improvement as well (Shiratori 2000). Table 20. Post-Treatment Changes in Fibrosis among Sustained Responders and Relapsers, Plus Untreated Controls  *Lower baseline ALT level, milder histologic activity and fibrosis than treated cohort Table 21. Post-Treatment Changes in Disease Activity among Sustained Responders and Relapsers, Plus Untreated Controls  *Lower baseline ALT level, milder histological activity and fibrosis than treated cohort Poynard and colleagues used a modeled estimate of fibrosis progression (see Chapter II, Natural History of Hepatitis C) to compare baseline and post-treatment changes in fibrosis progression and disease activity by treatment regimen. Data were pooled from four randomized treatment trials with 3,010 participants. They examined rates of pre- and post-treatment fibrosis progression, liver histology after therapy, and histological response by regimen. The mean duration between baseline and post-treatment biopsies was 20 months. Figure 25. Changes in Grade of Histological Activity and Fibrosis Stage  Improvements in the histological activity grade occurred most frequently among those who received pegylated interferon alfa-2b 1.5 µg/kg plus high-dose ribavirin (73%), and least frequently (39%) among those who received 24 weeks of standard interferon alfa-2b. Worsening of fibrosis occurred least frequently in those who received pegylated interferon alfa-2b 1.5 µg/kg with high-dose ribavirin (8%), and occurred most frequently among those treated with 24 weeks of standard interferon monotherapy (23%). Among cirrhotics, 49% (75/153) had improvement in fibrosis after treatment. All of them received 48 weeks of standard interferon alfa-2b, with or without ribavirin. Improvement from stage 4 to stage 3 was observed in 23 individuals; from stage 4 to stage 2 in 26; and from stage 4 to stage 1 in 23. Three individuals improved by four stages (to stage 0; no remaining fibrosis) (Poynard 2002b). Although this is a promising report, it is preliminary, and may be limited by the use of estimated fibrosis progression rates per year, since fibrosis progression is not always linear. Cammà and colleagues performed a meta-analysis of data from three HCV treatment trials, to examine the effect of pegylated interferon alfa-2a on liver histology, using baseline and post-treatment biopsy samples from 1,013 people. All were treated for 48 weeks with pegylated interferon alfa-2a or standard interferon. Overall, 280 achieved SVR (215 from pegylated interferon vs. 65 from standard interferon; P=0.001). Reduction in fibrosis was most likely among those treated with pegylated interferon (P=0.04) and sustained virological responders (P<0.001). Sustained virological response was significantly associated with reductions in disease activity (P<0.00001). Relapse was associated with improvement in fibrosis (P=0.0007) and disease activity (P=0.004), while no significant changes were observed among virological non-responders (Cammà 2004). Table 22. Changes in Fibrosis and Disease Activity After Treatment with Standard or Pegylated Interferon  Longer-term follow-up will reveal the durability and clinical benefits of improvements in grading and staging of liver disease.
More promising results came from two uncontrolled studies of interferon therapy during acute-phase hepatitis C in which 90% and 98% of participants achieved sustained virological responses. Vogel and colleagues treated 24 individuals with acute hepatitis C with 10 MIU of subcutaneous (SQ) interferon alfa-2b per day until liver enzyme levels reached normal levels (18-43 days). Pre-treatment ALT levels ranged from 531 to 1,940 IU/liter, with a mean of 1055; normal ALT was considered to be <22 IU/liter. Twenty-two of 24 participants completed treatment; 18 (90%) of these individuals remained virus-free during a follow-up interval of 18.65 ± 9.7 months (Vogel 1996). Jaeckel and colleagues treated 44 individuals with subcutaneous injections of 5 MIU of interferon alfa-2b per day for four weeks, followed with thrice weekly dosing for 20 more weeks. Treatment was initiated at an average of 89 days (with a range of 30-112) after infection. All but one individual completed treatment. One individual was re-treated (with interferon alfa-2b and ribavirin) 89 days after finishing study treatment. After six months of follow-up, 98% (43/44) had an undetectable HCV-RNA level (including the individual who discontinued treatment at week 12 and the individual undergoing re-treatment) (Jaeckel 2001). It is important to note that both studies were uncontrolled. Without a randomized, untreated control group, it is not possible to determine how many study participants would have achieved spontaneous viral clearance without undergoing treatment. Other factors may have had contributed to the high rates of a viral clearance: homogeneity of study participants—many of whom were symptomatic and jaundiced (both of which have been associated with higher rates of spontaneous viral clearance)—and the mode of acquisition. In these two studies, all of the participants acquired their infections from occupational or nosocomial exposures, injection drug use, sexual contact, or sporadic (unknown) means. HCV infections acquired from transfusions appear to have a higher rate of chronicity than those acquired by other means (Alberti 2002). In addition, the follow-up periods may have been too brief, or RNA testing too infrequent to detect intermittent viremia. HCV RNA may have been present in levels below the threshold of detection; Jaeckel and colleagues used an assay with a lower limit of detection of 600 copies, the most sensitive available at the time (Jaeckel 2001). Gerlach and colleagues identified 60 individuals with acute hepatitis C over a seven-year interval. Each was offered HCV treatment at diagnosis; ten individuals either declined or were ineligible (due to active injection drug use or other medical conditions) and 24 others achieved spontaneous viral clearance before HCV treatment was initiated. Of the 26 who were treated, 21 (81%) achieved SVR. Risk factor and interval between diagnosis and initiation of treatment differed among individuals, as did the regimen and duration of therapy (Gerlach 2003). Table 23. Acute HCV: Risk Factor, Interval from Diagnosis to Treatment, HCV Genotype, Regimen and Response  Amid the compelling evidence that treating acute hepatitis C infection is beneficial, questions remain about the dosing and duration of treatment, choice of therapeutic agent(s), and determination of the need for treatment. Optimal dose and duration of standard interferon therapy have yet to be identified, and pegylated interferons have not been adequately explored as treatments for acute HCV. The higher response rates to pegylated interferon in chronic hepatitis C suggest that they will be more effective against acute hepatitis C. Information about dosing from studies of standard interferon may not be applicable to pegylated interferon, because it is difficult to translate the dosage of standard interferon (in millions of international units) into doses of pegylated interferon (in micrograms). Preliminary information suggests that 1.0 µg/kg may be a suboptimal dose of pegylated interferon alfa-2b for treatment of acute HCV (Wiegand 2003). Data on interferon and ribavirin during acute HCV infection are scant. Determining when to initiate treatment for acute hepatitis C is an important issue. Treatment may not be necessary for those who will achieve spontaneous viral clearance. Identifying these individuals before initiating treatment will spare them the side effects and expense of unnecessary treatment. Findings from a study of twelve individuals with acute HCV indicated a high rate of spontaneous viral clearance relatively soon after exposure and onset of symptoms. Eight individuals achieved spontaneous viral clearance by 74 ± 25.3 days after exposure and 34.7 ± 22.1 days after the onset of symptoms. HCV-RNA levels decreased rapidly in the individuals with viral clearance. In the remaining four individuals HCV-RNA levels stayed high or increased (Hofer 2003). Larghi and colleagues noted longer intervals of detectable HCV RNA among seven acutely infected individuals. Before achieving spontaneous viral clearance, these seven individuals had detectable HCV RNA for between four and thirteen months after infection (Larghi 2002). Larger studies are needed to determine when treatment of acute HCV should be initiated.
Prognostic factors—genotype, baseline HCV RNA—and ability to tolerate HCV treatment influence the likelihood of successful re-treatment. The type of response to the initial course of treatment may also contribute to the success of re-treatment. Relapsers (who become HCV RNA undetectable but do not remain aviremic after completion of treatment) are more likely to achieve an SVR after re-treatment than non-responders (Shiffman 2002a). There are two patterns of non-response to HCV therapy. A partial response indicates a decrease in HCV RNA of >2.0 log and persistently detectable HCV RNA during treatment; a flat response is characterized by a decrease of <2.0 log in HCV RNA while on treatment, which may be an indication of interferon resistance. Strategies for effective re-treatment have included higher-dose interferon monotherapy, different types of interferon, a longer duration of therapy and re-treatment with a combination of interferon plus ribavirin or pegylated interferon plus ribavirin. Data from two meta-analyses of re-treatment for non-responders to interferon monotherapy report low overall SVR rates (ranging from 13% to 20%). Individuals were re-treated with inteferon plus ribavirin. Reponse rates depended on duration of re-treatment therapy and individual prognostic factors (Cheng 2001; Cummings 2001).
Table 24. HCV-RNA Levels at Week 48 of Re-treatment 
So far, SVR data is available from 604/863 who have completed treatment and follow-up. Overall, 18% (109/604) achieved SVR. Prior interferon monotherapy, genotype 2 or 3, a lower AST:ALT ratio and no cirrhosis were associated with achievment of a sustained virological response. SVR was more likely among those who received ≥60% of the ribavirin dose (21% vs. 11%; P=0.05) (Shiffman 2004). In a sub-group of 212 HALT-C participants who completed therapy by late 2002, the likelihood of SVR was significantly greater in non-African Americans, non-1 genotypes, those with a 2.0 log decrease in HCV RNA at week 12, and persons less than 50 years old (P<0.005 for all). More than half of these the participants had dose reductions of pegylated interferon and/or ribavirin. Week 24 discontinuations for fatigue, depression, or hematologic abnormalities were reported in 5% (Shiffman 2002b).
A retrospective analysis of data from 637 cirrhotics, treated and untreated, found that treatment with interferon—regardless of the outcome—seems to affect the oncogenic mechanisms of HCV. Interferon alfa is active against a number of cancers, including AIDS-associated Kaposi's sarcoma (KS). The International Interferon-a Hepatocellular Carcinoma Study Group identified predictors of progression from compensated cirrhosis to hepatocellular carcinoma (male sex, older age, and signs of portal hypertension) and time from diagnosis of cirrhosis to development of hepatocellular carcinoma. The study compared outcomes of two matched groups, one of 356 untreated cirrhotics and one of 281 cirrhotics treated with interferon. The median duration of therapy was 7 months (range: 3-30 months). Participants were followed for at least three years. The overall risk of progression to HCC was 1.99 for untreated individuals (95% CI, 1.09-3.6; P=0.027), with 66 untreated individuals and 29 treated individuals developing HCC during an interval of 36-250 months. Among cirrhotics with HCV infection, the relative risk of progression to hepatocellular carcinoma among untreated individuals was 3.14 times that of those treated with interferon (95% CI, 1.46-6.80; P=0.004). In a subgroup of cirrhotics who were HCV-antibody-positive and anti-HBV-negative, the risk of progression to hepatocellular carcinoma for untreated individuals was 6.28 times greater (95% CI, 1.65-23.97; P<0.007) (The International Interferon-a Hepatocellular Carcinoma Study Group 1998). The effect of interferon on the clinical outcomes of 189 cirrhotics was retrospectively assessed by Benvegnù and colleagues during a mean follow-up of 71.5 ± 23.6 months; 7.9% of those who received treatment (88/189) and 21.8% of untreated individuals (101/189) had progressive liver disease (by Child's staging; see Chapter IV, Diagnostics). Hepatocellular carcinoma developed in 5.6% of treated persons vs. 26% of untreated individuals (P<0.001) (Benvegnù 1998). Imazeki and colleagues retrospectively analyzed the effect of interferon on survival rates of people with hepatitis C. Of the 459 individuals in this study, 104 were untreated. Among cirrhotics, those who achieved SVR had a reduced rate of mortality during the eight-year follow-up. Hepatocellular carcinoma accounted for 25 deaths overall; only one was a sustained virological responder (Imazeki 2003). There are particular safety concerns for cirrhotics; many are more vulnerable to side effects and adverse events, especially the hematologic toxicities of pegylated interferons. As a result, dose reductions may be more frequent, and the efficacy of treatment may be diminished. For example, there were dose reductions among 83% (44/53) of those participating in an ongoing study of the viral kinetics of pegylated interferon alfa-2a plus ribavirin in cirrhotics (Gane 2002). Interim data from an HCV treatment trial in people with advanced liver disease (bridging fibrosis or cirrhosis) suggests that full-dose pegylated interferon and weight-based dosing of ribavirin, especially in non-1 genotypes, may increase the likelihood of sustained virological responses. Participants were randomized to receive 48 weeks of treatment with either full-dose (1.5 µg/kg once weekly) or half-dose (0.75 µg/kg once weekly) pegylated interferon alfa-2b, plus 800 mg/day of ribavirin. Sustained virological response data are available from 165 of 210 participants who have completed follow-up (Abergel 2003). No information on adverse events, dose reductions, or discontinuations was provided. Table 25. Sustained Virological Response by Regimen and Genotype  A subset of individuals with bridging fibrosis and cirrhosis have participated in large HCV treatment trials. The treatment regimens and study populations differ, so it is difficult to draw conclusions from pooled data. Table 26. Sustained Virological Response Rate Among Persons With Bridging Fibrosis and Cirrhosis: Subgroup Data From Four Trials  The goals of therapy may be different for those with advanced liver disease. Averting liver transplantation, slowing disease progression, and improvement in liver histology may be relevant outcomes in the absence of achieving SVR, although histological response often correlates with virological response. Without long-term follow-up, it is impossible to know if histological improvement and/or viral eradication translate into increased quality of life and survival. Long-term studies of interferon maintenance therapy for non-responders with advanced liver disease are underway.
Everson and colleagues studied safety, efficacy, and tolerability of a gradually accelerated dosing regimen. This strategy resulted in SVR among 22% (20/91), with 40% (8/20) of those who achieved SVR remaining HCV-RNA-undetectable after liver transplantation. The regimen started with low doses of interferon (1.5 MIU thrice weekly), plus ribavirin (600 mg/day). Doses of each drug were gradually increased every two weeks, as tolerated. Growth factors were used to maintain blood cell counts when needed (Everson 2000). Information on changes in hepatic function, Child-Pugh scoring after treatment (see Chapter IV, Diagnostics), and serious adverse events was not available. Crippin and colleagues conducted a pilot study of the safety, tolerability and efficacy of interferon with or without ribavirin in individuals with decompensated cirrhosis. Fifteen participants awaiting liver transplantation were randomized to:
At the end of treatment, 33% had undetectable HCV RNA, and 55% had reduced viral loads. During the study, two individuals had liver transplants; both had recurrent hepatitis C. Adverse events were frequent and serious; 20 of the 23 adverse events were serious (severe thrombocytopenia and neutropenia, hepatic encephalopathy, and serious infections). One person died from infectious complications (Crippin 2003). The study was ended because of the frequency of severe adverse events. Garcia-Retortillo and colleagues treated 30 individuals (13 cirrhotics and 17 with hepatocellular carcinoma) awaiting liver transplantation. Treatment was initiated when the anticipated interval before transplantation was less than five months and continued until transplantation. At the time of transplantation, 9/30 had undetectable HCV-RNA levels and 6/9 remained undetectable after transplantation (median follow-up of 26 weeks; range: 5-60 weeks). The original regimen was standard interferon alfa-2b (3 MIU daily) plus ribavirin (400 mg every 12 hours). The dose of interferon was reduced in 60% (18/30); the ribavirin dose was reduced in 20% (6/30). Growth factors were given when necessary (G-CSF to 10/30; epoetin-alfa to 8/30). Treatment was discontinued permanently by four individuals and temporarily by two. There were three serious adverse events: two cases of sepsis and one case of hepatitis. Leukopenia was reported in 18/30, thrombocytopenia in 13/30, and anemia in 5/30 (Garcia-Retortillo 2002b).
The overall survival rate at one year after liver transplantation is 85%; at three years, 75.9%; and at ten years, it decreases to 59% (C. M. Smith 2000; United Network for Organ Sharing, 2000). For transplant recipients with hepatitis C, survival rates at one year, three years, and five years are 86.4%, 77.8%, and 69.9%, respectively (Forman 2002). Progression of post-transplant hepatitis C disease varies (see Chapter III, Natural History of HCV in HIV Coinfection; HCV and Immunosuppression). Cirrhosis develops in 10-25% of transplant recipients with recurrent HCV within five years (Everson 2002). Individuals with early recurrence of HCV (less than six months after transplantation) are at greater risk of progression to bridging fibrosis or cirrhosis (Shuhart 1997; Testa 2000). There are three strategies for treating recurrent hepatitis C: preemptive treatment prior to transplantation, initiating treatment as soon as possible after transplantation, or delaying treatment until post-transplantation hepatitis has recurred. The goals of preemptive treatment are to stabilize or improve hepatic function and reduce the likelihood of recurrent hepatitis C infection. Data on preemptive treatment are scarce. A retrospective analysis of outcomes of 26 cirrhotic transplant candidates treated with interferon, with or without ribavirin, reported no recurrent HCV among 6/6 individuals who achieved SVR prior to transplantation, although adverse events were frequent and severe (Alvarez 2003). Preemptive treatment carries significant risks such as serious adverse events and potential acceleration of liver deterioration (see Treatment for Decompensated Cirrhosis section in this chapter), but some individuals may benefit. More research is needed before this approach becomes the standard of care. The goal of early post-transplant therapy is to avert histological damage from recurrent HCV. Treatment is more effective in individuals with low viral loads. HCV-RNA levels are usually at their lowest immediately after transplantation, before rising to levels up to 20-fold higher than before transplantation (Feray 1994). Singh and colleagues found that early treatment with six months of interferon did delay recurrence of HCV. Recurrence occurred at a median of 408 days after transplantation in the treated group vs. a median of 193 days after transplantation in the untreated controls; P=0.05). Otherwise, no significant differences were observed, either in the frequency of recurrence or the severity of recurrent HCV disease (Singh 1998). Sheiner and colleagues randomized 86 transplant recipients to a regimen of interferon alfa-2b, 3 MIU thrice weekly, or to a control arm who did not receive interferon. Recurrent hepatitis C occurred less frequently in the interferon arm (8 vs. 22; P=0.017). HCV-RNA levels were categorized as low, moderate, or high. In the treated group, high HCV-RNA levels at one and three months were significantly associated with risk of recurrence (risk was 3.1 times greater at month one; P=0.01; at month three, risk was 3.9 times greater; P=0.006). There was no significant difference in actuarial survival between groups at one and two years (Sheiner 1998). Early treatment with standard interferon plus ribavirin has shown more promising results. Beginning three weeks after transplantation, 36 individuals were given combination therapy for one year. At 36 months after completion of therapy, 33% (12/36) achieved sustained virological and biochemical responses. Progression to severe hepatitis occurred in 11% (4/30) of non-responders (Mazzaferro 2001). Dose reductions due to hemolytic anemia occurred frequently. Terrault and colleagues have treated 25/49 eligible transplant recipients for 48 weeks; 23 have completed treatment and follow-up. Treatment was initiated 1.7-9.3 weeks (median: 5.1 weeks) after transplantation. Participants were randomized to receive an induction/maintenance regimen of standard or pegylated interferon, with or without a gradually escalating dose of ribavirin (400 mg/day to 1.0-1.2 g/day, by body weight). Only 23% received full-dose ribavirin; 84% were able to tolerate full-dose interferon. Overall, only 3/23 achieved SVR; those with undetectable HCV RNA prior to treatment were more likely to achieve SVR (P=0.0009). After completion of treatment, most had mild liver disease; 78% had stage 0 fibrosis, and 72% had ≤grade-1 disease activity, suggesting histological benefit in the absence of virological response. The discontinuation rate was high: five individuals left before starting treatment, and 19 discontinued due to adverse events. Five deaths occurred during the study, none treatment-related (Terrault 2003). Larger, randomized studies of safety, efficacy, and tolerability of combination therapy for this indication are needed. The outcome of treatment for recurrent hepatitis C varies, depending on pre-transplant HCV-RNA levels, genotype, regimen, duration of treatment, and an individual's capacity for tolerating treatment. Adverse events requiring dose modifications are common, especially hemolytic anemia due to ribavirin (De Vera 2001; Kornberg 2001; Lavezzo 2002; Narayanan 2002; Samuel 2003). Ribavirin is eliminated by the kidneys. Levels of ribavirin tend to build up when renal function is impaired, and renal impairment is common in liver transplant recipients. Jain and colleagues examined the incidence of hemolysis and renal impairment among transplant recipients on combination therapy. Serum creatinine levels were higher (median of 1.3 mg/dL vs. 1.0 mg/dL), and clearance of creatinine was significantly lower (median 66.47 vs. 96; P=0.018), among those who experienced hemolysis (Jain 2002a). Table 27. Treatment of Recurrent Hepatitis C: Outcomes/Dose Reductions/Discontinuations  *At the end of treatment, 14 of 54 participants (26%) had undetectable HCV RNA; all 14 were followed for a mean interval of three years after completion of treatment. End-of-treatment results are available from a study of safety, efficacy, and tolerability of pegylated interferon monotherapy in transplant recipients. Vogel and colleagues randomized 65 transplant recipients with recurrent HCV to either 48 weeks of treatment with 180 µg/week of pegylated interferon alfa-2a (33) or no treatment (32). Participants were stratified by high (>1,000,000) or low (<1,000,000) HCV-RNA levels. Week 48 results were available from 49 participants (23 treated and 26 contols). A total of 16 individuals discontinued participation in this study; 10 from the treatment arm and 6 from the control arm. Table 28. Hepatitis C RNA Levels During Treatment  During the study, four rejection episodes occurred in the treatment arm; two of these individuals completed the trial. In the treatment arm, 45% (15/33) had at least one serious adverse event. In the control arm, 25% (8/32) had at least one serious adverse event. There were two deaths in the treatment arm (one from hepatic and renal failure and another from pulmonary metatases); neither were considered to be related to treatment (Vogel 2002). Preliminary data from several ongoing studies of pegylated interferon alfa-2b plus ribavirin are available. Table 29. Treatment of Recurrent HCV with Pegylated Interferon and Ribavirin  *One death was reported; its cause and relationship to treatment were not described. Serious adverse events occurred frequently across these studies, including severe depression, neutropenia, thrombocytopenia, anemia, acute pancreatitis (N=1; relationship to study treatment not described), organ rejection (N=3; relationship to study treatment not described), jaundice, and severe flulike symptoms. Neff and colleagues reported using multiple therapeutic interventions in one study, where 10% were given blood transfusions, 20% received erythropoietin, 43% were given neupogen, and 43% received treatment for clinical depression (Neff 2003b). Each investigator concluded that efficacy and tolerability were poorer in transplant recipients. Initiation of treatment with lower doses, and gradual dose escalation are current strategies for increasing the efficacy and tolerability of treatment for recurrent hepatitis C in transplant recipients. Higher doses of pegylated interferon appear to be more effective, based on interim reports of week-12 and week-24 virological responses from 30 transplant recipients treated with two different doses of pegylated interferon alfa-2b (0.5 µg/kg or 1.5 µg/kg) plus 600 mg/day of ribavirin, increased to 800 mg/day at week 4. Growth factors were used to decrease dose reductions, although 18% (3/17) in the high-dose arm and 21% (4/19) in the low-dose arm had reductions of their pegylated interferon doses. Both arms had reductions in ribavirin doses (41% and 37%). No differences in toxicity by pegylated interferon dose have been reported (Ghalib 2003a; Ghalib 2003b). Figure 26. Week-12 and Week-24 Virological Response by Treatment Arm 
Interferon treatment for HCV in kidney transplant recipients has resulted in episodes of graft rejection (Kakimoto 1994; Rostaing 1996; Takahara 1995). Due to the risk of acute renal failure during treatment, and the frequency of relapse after completion of treatment for HCV, treatment of hepatitis C after kidney transplantation is contraindicated (Pol 2002).
Izopet and colleagues treated 23 dialysis recipients with 3 MIU of interferon thrice weekly for either 6 (N=12) or 12 months (N=11). Sustained viral clearance was achieved by 42% (5/12) of those treated for 6 months and 64% (7/11) of those who received 12 months of treatment (Izopet 1997). Another prospective, controlled study evaluated the outcome of kidney transplantation in 30 individuals with HCV infection awaiting transplantation. A year of interferon monotherapy (3 MIU thrice weekly) was given to 15 individuals; another 15 were untreated. Kidney transplantation was performed in 11/15 who received HCV treatment, and in 10/15 controls. A year after transplantation, HCV RNA was undetectable in 4/11 treated individuals, and liver biopsy was performed on all transplant recipients. Those who had received HCV treatment had significantly lower mean HAI scores than untreated controls (1.82 ± 0.6 vs. 5.5 ± 1.35; P<0.0001) (Huraib 2001). In another study of efficacy and tolerance of interferon monotherapy in 19 HCV-infected individuals with renal impairment, treatment was discontinued in 9/19. Of those who completed treatment, 7/10 achieved SVR. Renal transplantation was performed in 10 individuals; 3 of them had undetectable HCV RNA at the time of transplantation, and 2 of the 3 remained virus-free 24 months after transplantation (Campistol 1999).
Some treatment-related adverse events may be life-threatening. A range of severe adverse events have been recorded and are categorized below, with current strategies for their management.
The most serious neuropsychiatric adverse events are severe depression, suicidal ideation, and suicide attempts. Suicidal behavior (attempts and suicide) has occurred in <1% (Roche) to 2% (Schering) of trial participants (Roche package insert, 2002; Schering package insert, 2001). Treatment with interferon must be discontinued if an episode of severe depression with suicidal ideation occurs. Suicides and attempted suicide have been reported during interferon therapy in individuals with no prior history of mental illness (Fattovich; Janssen 1994; Schering package insert, 2001). One case report of a 50-year-old woman with no significant psychiatric history provides a harrowing illustration of interferon-induced depression. During treatment with interferon, she developed irritability, anxiety, insomnia, and depression; she poured lamp oil on herself and set herself on fire. Fortunately, she survived (Fukunishi 1998). Severe interferon-related depression may not always disappear after treatment discontinuation. In one study, prevalence of suicide attempts among 306 individuals during and after interferon therapy increased from 0% (during therapy) to 1.3% in the six months after therapy (Rifflet 1998). Clinical trials have used different instruments to assess depression, or have relied upon self-reporting of depression, which may not reflect the true incidence of depression among those on treatment (estimated at 20-30%) (Fried 2002b). It may be difficult for people on HCV treatment and their clinicians to distinguish clinical depression from other common side effects from interferon (such as insomnia and fatigue). Although there is no specifically validated instrument to assess interferon-related depression, different instruments have been used to measure interferon-induced depression. The Montgomery-Asberg Depression Rating Scale (MADRS) was used in a small (N=33) prospective evaluation of the incidence of, and predictive factors for, depression prior to starting interferon. Participants with a high baseline MADRS (≥3) had more intense depressive symptoms than those with low baseline scores (<3) (Castéra 2002). Another group used the Minnesota Multiphasic Personality Inventory (MMPI) at baseline and three months after initiation of interferon to identify individuals at risk for depression. Three months after initiation of interferon, 64% (9/14) of those with a baseline score of ≥60/100 developed a depressive mood, and 11% (5/44) with baseline scores <60/100 showed medium-level depression after three months on treatment (Scalori 2000). Sanchez and colleagues used the Beck Depression Inventory (BDI) to predict and identify HCV-treatment-related depression in a study of 76 individuals from three HCV treatment trials. Depression increased significantly during HCV treatment, regardless of the regimen used (P≤0.001). The severity of treatment-induced depression correlated with the baseline BDI score (P≤0.001). Individuals with severe depression had a greater incidence of early withdrawal from treatment trials than those with no, or mild-to-moderate depression (34% vs. 11% and 15% respectively). Those with severe depression who continued treatment had lower rates of week-12 viral response than did those with mild-to-moderate depression (34% vs. 62%) (N. Sanchez 2002). When mild-to-moderate interferon-induced depression is identified, it can often be managed, thus improving quality of life and, possibly, treatment adherence and outcomes. Because they appear to be safe and easily tolerated in individuals with liver disease, selective serotonin reuptake inhibitor (SSRI) antidepressants are often used to treat interferon-induced depression (Gleason 2002; Hauser 2002: Krauss 2002; Schramm 2000). Some individuals and their clinicians may choose to start preemptive treatment for depression before the initiation of interferon. Schafer and colleagues evaluated the effect of pre-treatment with citalopram (an SSRI) among 25 methadone recipients with psychiatric histories. Episodes of major depression were significantly less frequent during four months of HCV treatment in the citalopram group than in those who were not pre-treated (14% vs. 64%; P=0.028) (Schafer 2003b). Careful assessment of baseline depression and an ongoing screening process during therapy should be a routine part of HCV treatment. Exploration of the pathophysiology of interferon-induced depression is needed, so that better interventions may be developed. Although uncommon, other severe, interferon-induced neuropsychiatric adverse events have been reported, including acute psychosis, confusion and coma, memory loss, neuropathy, panic attacks and personality changes, and seizures in persons with and without a history of such disorders (Ahmed 2003a; Anton 2000; Fried 2002b; Hosoda 2000; Kanno 1999; Schafer 2000; Shakil 1996).
Pegylated interferon-based therapy has been linked with serious ophthalmologic side effects. Ahmed and colleagues reported serious ophthalmic adverse events in 20/4800 people who received at least one dose of pegylated interferon alfa-2b and fixed or weight-based dosing of ribavirin. Ophthalmic damage was diagnosed in 16; 1 needed surgery for a detached retina. Treatment was discontinued in 17/20; 3 had persistent symptoms after treatment discontinuation (Ahmed 2003b). Assessment of ocular problems at baseline, and regular monitoring, including color vision testing, are recommended.
Data from chemotherapy recipients have been used to evaluate the risk of infection from interferon- induced neutropenia. Low neutrophil counts have been a criterion for exclusion in many HCV treatment trials, and used as triggers for dose reductions of interferon, both in clinical trials and clinical practice. Individuals with chronic hepatitis C, however, may not be at the same risk for infections as immunosuppressed chemotherapy recipients, with the possible exceptions of cirrhotics and coinfected persons. A retrospective analysis of data from 119 persons treated for HCV with interferon and ribavirin found that no bacterial infections occurred in neutropenic individuals during treatment (Soza 2002). Additionally, Blacks have significantly lower neutrophil counts than Whites (Freedman 1997; Reed 1991; Zezulka 1987). Soza and colleagues have estimated that there may be 76,000 black Americans with HCV and constitutional neutropenia. Using a universal neutrophil cutoff for hepatitis C treatment trials may result in the exclusion of many black volunteers. Research to identify an appropriate neutrophil threshold for Blacks, and a safe threshold for triggering dose reductions is needed. Dose reduction is the standard of care for interferon-induced neutropenia, yet suboptimal dosing of interferon may impair treatment outcomes. Maintaining doses of at least 80% of both drugs, for at least 80% of the course of therapy, increases the likelihood of achieving an SVR (McHutchison 2002). Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) can be used to boost neutrophil counts. Clinical trials of G-CSF as a therapy for hepatitis C, either alone or with interferon, have demonstrated safety, but not antiviral efficacy (Carreno 1996; Carreno 2000; Schiffman 1998). It is not current clinical practice to use G-CSF for neutrophil rescue therapy during hepatitis C treatment. More information is needed to determine if G-CSF rescue therapy is a viable option. Thrombocytopenia (low platelets) may be a manifestation of untreated hepatitis C itself, especially among cirrhotics and those with advanced liver damage, or may be induced by interferon therapy (Giannini 2002; Pockros 2002; Ramos-Casals 2003). Interferon has been used as a treatment for the thrombocytopenia caused by HCV, and platelet counts have increased after therapy (Benci 2003; Rajan 2001). If platelet counts drop markedly during therapy with pegylated interferon, dosing may need to be modified or treatment discontinued, as there is growing concern among clinicians about spontaneous intracranial bleeding in patients with fewer than 50,000 platelets/mm³. Hemolytic anemia (destruction of red blood cells) is a common, usually reversible side effect of ribavirin. Dose reduction is one strategy used for management of ribavirin-induced anemia, but suboptimal dosing may result. Epoetin-alfa, a genetically engineered version of erythropoietin (EPO), a human protein that stimulates production of red blood cells, has been used to maintain or restore full doses of ribavirin, resulting in significantly higher hemoglobin levels (Dieterich 2001; Dieterich 2002; Gergely 2002; Senkbeil 2003; Wasserman 2000; Weisz 1998). When ribavirin is used with pegylated interferon, the recovery period from treatment-induced anemia may be longer than that observed with ribavirin and standard interferon; use of epoetin-alfa may contribute to recovery (Azzam 2003).
Table 30. HCV Treatment Outcomes for Hemophiliacs  *Biochemical non-responders or those with persistently detectable HCV RNA discontinued treatment at week 24.
There have not been any randomized, controlled trials of the safety, efficacy, and tolerability of HCV treatment in children, although data from several small studies of interferon monotherapy have yielded SVR rates ranging from 33% to 50% (Bortolotti 1995; Jonas 1998; Marcellini 1997; Nakashima 2003; A. Sawada 1998; Yuce 2000). Wirth and colleagues conducted an uncontrolled pilot study of efficacy and tolerability of 3 or 5 MIU of interferon thrice weekly plus ribavirin (15 mg/kg per day) in 41 children. Those with detectable HCV RNA after six months of treatment discontinued. When HCV RNA was undetectable at week 24, treatment continued for another 24 weeks. One child discontinued treatment because of severe anemia, and 12 discontinued due to week-24 non-response. Of the 25 children who completed treatment without virological breakthrough, all achieved SVR; the overall SVR rate was 61% (25/41). The rate of SVR in children with genotype 1 was 53% (18/34); all children with non-1 genotypes achieved SVR (Wirth 2002). Two other studies of interferon plus ribavirin in children have yielded sustained virological response rates of 41-45% (Kelly 2001; Süoglu 2002). Wirth and colleagues reported that children were better able to tolerate combination therapy than adults, although all of them experienced flulike symptoms during the first weeks of treatment. Thyroid autoantibodies developed in 21% (6/28) after six months of treatment, and 11% (3/28) had markedly increased levels of thyroid-stimulating hormone. Dry skin and hair loss developed in three children. All side effects resolved after treatment was ended (Wirth 2002). Encouraging data on safety and efficacy of pegylated interferon alfa-2a monotherapy in children have been reported from a multicenter, open-label study. The 14 participants were given 180 µg/kg once weekly for 48 weeks. Figure 27. Virological Response to Pegylated Interferon Monotherapy at Weeks 24, 48, and 72  No serious adverse events were reported; the adverse events most frequently reported—fever, headache, vomiting, appetite loss, and abdominal pain—were described as "mild in intensity." There were four withdrawals from this study: one for week-24 virological non-response, two from elevations in liver enzymes, and one from an exacerbation of preexisting hypertriglyceridemia (K. B. Schwarz 2003). Wirth and colleagues have reported interim results from an open-label pilot study of a 12-month course of pegylated interferon alfa-2b (1.5 µg/kg) plus ribavirin (15 mg/kg per day) in 52 children and adolescents (mean age: 11.3 years; range: 2-17). Treatment was discontinued at week 24 if HCV RNA was detectable. Of the 46 participants with six month follow-up data, 61% (28/46) achieved SVR. All participants with non-1 genotypes achieved SVR; 52.6% (20/38) with genotype 1 achieved SVR. The remaining 39% (18/46) were primary non-responders, relapsers, and one treatment discontinuation for side effects. No serious adverse events were reported; treatment was characterized as "well tolerated" (Wirth 2003). More study of pegylated interferon, with and without ribavirin, is needed in pediatric populations.
Treatment of HCV infections should not be withheld from patient populations with complicated social problems.
Many patients with chronic hepatitis C have been ineligible for trials because of injection drug use, significant alcohol use, age, and a number of co-morbid medical and neuropsychiatric conditions. Efforts should be made to increase the availability of the best current treatments to these patients. Recent, albeit limited, experience has demonstrated the feasibility and effectiveness of treating chronic hepatitis C in people who use illicit injection drugs, known as injection drug users (IDUs). This is potentially important because injection drug use is the most common risk factor for new HCV infections in the United States, and successful treatment may reduce transmission. Management of HCV-infected IDUs is enhanced by linking these patients to drug treatment programs. Treatment for drug and alcohol abuse should be made available to all patients who want and need it. Access to methadone treatment programs should be fostered for HCV-infected IDUs whether or not they are receiving treatment for HCV. Methadone treatment has been shown to reduce risky behaviors that can spread HCV infection, and it is not a contraindication to HCV treatment. Efforts should be made to promote collaboration between experts in HCV and healthcare providers specializing in substance-abuse treatment. HCV therapy has been successful even when the patients have not abstained from continued drug or alcohol use or are on daily methadone. However, few data are available on HCV treatment in active IDUs who are not in drug treatment programs. Thus, it is recommended that treatment of active injection drug use be considered on a case-by-case basis, and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy.
Clinicians approach these patients from a perspective reflecting their respective training and background. Medical clinicians typically address the toxic effects (such as seizures or alcoholic cirrhosis) of a particular substance or the health consequences of a high-risk lifestyle (such as infectious hepatitis or HIV infection). Psychiatrists and other mental health clinicians focus on the mental health issues prevalent among substance-dependent patients. Chemical dependency counselors typically focus on the individual's destructive preoccupation with obtaining and consuming a psychoactive chemical substance and the negative consequences thereof. For the patient, the issues from all of these perspectives are pressing, often inseparable problems, yet health care providers operate in separate systems of care. The shortcoming of these parallel approaches is that the patient's problems are interrelated and require input from all systems for optimal treatment. Providing opportunities for hepatitis C care and treatment in populations for which it was formerly contraindicated is complicated. Encouraging results have emerged from different studies of active drug users and individuals with dual diagnoses (mental illness and addiction), as well as those on methadone maintenance. All speak to the need for patient-centered, multidisciplinary care. Schafer and colleagues found no rationale for continued contraindications to interferon therapy if psychiatric evaluation and multidisciplinary care are provided before and during interferon therapy. They prospectively assessed efficacy, psychiatric side effects, and adherence to hepatitis C treatment (standard interferon 3 MIU, thrice weekly, plus ribavirin 1,000-1,200 mg/day; duration according to genotype and week-24 response) in four groups: individuals with a history of psychiatric disorders; individuals receiving methadone maintenance; former injection drug users; and controls (no past or present psychiatric disorders or drug use). Preexisting and interferon-induced depression did not have a significant impact on the dropout rate or treatment outcomes. All participants were seen by a psychiatrist twice weekly during their first eight weeks on interferon, and on a monthly basis thereafter. Although five individuals were admitted to the psychiatric ward, not one of these admissions could be directly linked with interferon. Suicidal thoughts were reported in 4-6% of participants, and two individuals dropped out for this reason. In every instance, suicidal thoughts vanished during psychiatric care. Overall, 16% (13/81) developed new depression during treatment and were treated with antidepressants. Six individuals (four with a history of addiction and two from the methadone group) were treated for alcohol abuse during the study; only one of these individuals dropped out of the study (Schafer 2003a). Table 31. SVR, Adherence, Discontinuation, Depression, and Suicidal Thoughts 
Despite the significant prevalence of these co-morbidities among veterans with hepatitis C, treatment for hepatitis C using a multidisciplinary model has produced encouraging results. A team of providers, including a hepatologist, psychiatrist, pharmacologist, and nurses, assessed prevalence of co-morbid behavioral emotional disorders (BED) in veterans with hepatitis C at the Cincinnati VA Medical Center. Over 95% had experienced or been diagnosed with a BED (67% had one or more disorders, and 89% had been diagnosed with drug or alcohol addiction). At the time of publication, 90% ( 83/92) had completed six months of treatment; 50% (47/92) had completed the entire course of therapy and 28% (26/92) remained on treatment. Withdrawals and dropouts (29%) were attributed to personal problems (9%), psychiatric adverse events (7%), disappearance due to suspected drug/alcohol relapse (6%), medical adverse events (5%), and known drug/alcohol relapse (2%). Overall, 20% achieved sustained virological responses, with the highest rate of SVR seen in white males (42%) (Goldsmith 2002). Nguyen and colleagues looked at the medical records of 206 veterans with hepatitis C who received care at a multidisciplinary medical and psychiatric chronic hepatitis clinic. Psychiatric disorders and/or drug/alcohol addiction were prevalent; 89% had been diagnosed with one or both. Treatment was not given to individuals with minimal liver fibrosis or persons with worsening medical, psychiatric, or drug/alcohol problems. Of the 206, 145 (71%) were treated for hepatitis C with interferon or interferon plus ribavirin. Sustained virological responses were within expected parameters: 16% of those on interferon monotherapy, and 28% of those on interferon plus ribavirin (H. A. Nguyen 2002).
Backmund and colleagues studied the feasibility of initiating hepatitis C treatment during inpatient detoxification treatment. HCV treatment was not withheld or discontinued if relapse to injection drug use occurred during the study. Fifty individuals enrolled in the study. Hepatitis C treatment was initiated two weeks before discharge. After discharge, participants either attended a weekly outpatient program or were sent to an inpatient clinic. Relapse to active drug use occurred in 80% of study participants; 30% began replacement therapy with methadone or dihydrocodeine. After 12 weeks of treatment, 54% discontinued (10% due to side effects, 10% because of non-adherence and 34% because of virological non-response). Week-12 responders to interferon monotherapy continued treatment for another 36 weeks. The duration of combination therapy was assigned according to genotype: 24 weeks for genotypes 2 and 3, and 48 weeks for genotype 1. Overall, 36% achieved a sustained virological response to treatment (Backmund 2001). This rate of response is within the range from two pivotal clinical trials of interferon monotherapy and combination therapy in non-drug users, although baseline characteristics were different in these trials. Table 32. SVR After Treatment with Combination Therapy or Interferon: Data from Two Large Clinical Trials  Table 33. SVR in Current/Former IDUs by Regimen, Setting, Appointment Attendance, and Baseline Characteristics  *After October 1998, all participants received combination therapy.
Interim data from the Organization to Achieve Solutions in Substance Abuse (OASIS) reported that 54% achieved an ETR after a six or twelve month course of interferon and ribavirin. A subset of 59/105 achieved SVR (Sylvestre 2002a). Table 34. Sustained Virological Response Rates from 59/105 Study Participants*  *Data on the remaining participants will be available at completion of study. HCV treatment is feasible for recent drug users, and methadone maintenance may support adherence to treatment. Van Thiel and colleagues treated 120 recent drug users, 52 on methadone maintenance. Their baseline characteristics, preclinical parameters and treatment outcomes were compared to those of 120 non-drug using controls. Discontinuation rates were astonishingly low, despite a grueling regimen of 5 MIU of interferon daily for a minimum of one year (virological responders were continued on therapy until their HCV RNA was undetectable for fifteen consecutive months). Only 15% (18/120) of drug users discontinued (vs. 7% [112/120]) of the control group). Sustained virological response rates did not differ significantly between drug and methadone users (33%) and controls (37%). Access to methadone during this study may have increased adherence to treatment, because some participants initiated methadone maintenance as a side effects management strategy. Methadone dosing remained stable or increased by 10-15% (Van Thiel 2003). Two other studies demonstrated the safety, feasibility, and efficacy of providing HCV treatment with methadone maintenance. Buggisch and colleagues retrospectively analyzed data from 39 individuals on methadone maintenance who were treated for HCV with standard interferon plus ribavirin. Participants had to be drug-free (with the exception of methadone) for six months before enrolling. The SVR rate was 46% (18/39)—comparable to that seen in non-methadone-using populations (Fried 2002a; McHutchison 1998; Poynard 1998). Many participants had genotype 2 or 3 (31% or 12/39), and SVR occurred more frequently among these individuals (75% vs. 33% for genotype 1) contributing to the overall SVR rate. There were four discontinuations, two each for side effects and relapse to active drug use (Buggisch 2002). Mauss and colleagues compared HCV treatment outcomes between 50 individuals using methadone maintenance and 50 matched controls. Participants received pegylated interferon plus ribavirin according to genotype. The end-of-treatment response rate in the control arm was 74% (37/50) vs. 50% (25/50) in the methadone arm. In the control group, 54% (27/50) achieved SVR vs. 39% (19/49) in the methadone group. Discontinuation rates for side effects or lack of adherence were 18% (8/45) in the control arm vs. 42% (18/43) in the methadone arm. Most of the discontinuations in the methadone arm occurred before week eight. There was no significant difference in the response rates for those who remained on treatment after week eight; 50% (19/38) of methadone users achieved SVR, as did 56% (27/48) of the control arm. No serious psychiatric side effects were reported in either arm. No information was provided about care and ancillary psychiatric services available to study participants (Mauss 2003a; Mauss 2003b). The pharmacokinetics of methadone and pegylated interferon alfa-2a (180 µg/week) were evaluated in 24 individuals receiving concomitant methadone maintenance. Baseline levels of methadone were compared with serum samples after single (week 1) and multiple doses (week 4) of pegylated interferon, and pegylated interferon levels were compared with historical data from non-methadone users. The levels of pegylated interferon at week 1 and week 4 were similar to levels in non-methadone users, and methadone levels were similar at baseline and at week 4. No signs of opioid withdrawal were observed. The most frequently reported adverse events—headache, myalgia, fever, fatigue, and appetite loss—were mild or moderate (Sulkowski 2003a).
A case-controlled study evaluated the effect of different amounts of alcohol on treatment efficacy in 65 individuals. Alcohol use per day was categorized into four groups: none, ≤40 g/day, 41-80 g/day, and >80 g/day. HCV-RNA levels were significantly higher in drinkers, with the heaviest drinkers having the highest titers of HCV RNA. Response to treatment decreased with heavier alcohol intake. Fewer than 5% of those reporting alcohol use of any amount achieved SVR, and non-response to treatment occurred at a significantly greater rate among drinkers (63.1% vs. 10.7%; P<0.001) (Loguercio 2000). Specific information about the effect of light-to-moderate alcohol intake (<20 g/day) on HCV treatment efficacy is unavailable. Decreasing or eliminating alcohol intake during treatment is recommended.
Correctional facilities are critical settings for the efficient delivery of prevention and treatment interventions for infectious diseases. Such interventions stand to benefit not only inmates, their families, and partners, but also the public health of the communities to which inmates return. |
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