HIV/HCV coinfection: re-treating hepatitis C in people coinfected with HIV
13 April 2006. Related: Pipeline report, Hepatitis coinfection.
Tracy Swan, for HIV i-Base
Prevalence and severity of HIV/HCV coinfection
Coinfection with hepatitis C virus (HCV) is a common co-morbidity of HIV disease, due to overlapping routes of transmission. Worldwide, four to five million people are HIV/HCV coinfected.  In the UK, an estimated 9% of HIV-positive individuals are coinfected with hepatitis.  HIV accelerates hepatitis C disease progression, particularly in people with a CD4 cell count of <200 cells/mm3. [3, 4] A meta-analysis of HCV progression among different cohorts of coinfected people reported that the risk for cirrhosis was doubled, and the risk of hepatic decompensation was six times greater for coinfected people than those with HCV alone.  HCV-associated end-stage liver disease has become a leading cause of death among HIV-positive people in Europe and the United States. [6, 7, 8, 9, 10]
Hepatitis C can be treated effectively in HIV-positive people (see Table 1), although response rates are lower than with HCV monoinfection. The primary goal of HCV therapy is a sustained virological response (SVR), defined as undetectable HCV RNA six months after completion of therapy. SVR is an indication that hepatitis C virus will remain undetectable; many experts consider it a cure. The secondary goal of hepatitis C treatment is histological benefit, which may occur in the absence of an SVR. Decreases in liver inflammation have been reported among a proportion of coinfected virological non-responders, even those with bridging fibrosis or cirrhosis. [11, 12, 13]
Table 1. HCV treatment recommendations for people coinfected with HIV/HCV
|Source, date and online access||Recommendation|
|British HIV Association (BHIVA). Guidelines for treatment and management of HIV and HCV coinfection. October 2004. http://www.bhiva.org||Moderate to severe disease without cirrhosis is the main indication for treatment. HCV testing is recommended for all HIV-positive individuals.|
|Veteran Affairs. Management and treatment of HCV infection in HIV-infected adults: recommendations from the Veterans Affairs HCV resource center program and national HCV program office. September 2005. http://hepatitis.va.gov/vahep?page=tp04-gd-01||Consider HCV treatment in all HIV/HCV-coinfected patients Consider the decision to treat the HIV/HCVcoinfected patient on an individual basis including information on the severity of liver disease, genotype, viral quantification, and the state of any co morbid conditions|
|American Association for the Study of Liver Diseases (AASLD) Strader DB, Wright T, Thomas DL et al. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004 Apr;39(4):1147-71. https://www.aasld.org/eweb/DynamicPage.aspx?Site=AASLD3&webcode=ViralHepatitis||Hepatitis C should be treated in the HIV/HCV coinfected person in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy.|
|European Consensus Conference, May 2005. Journal of Hepatology (2006, Vol 44 Supp 1) http://www.jhep-elsevier.com||Treatment for HCV offers the chance to eradicate infection and is advantageous for the subsequent management of the patient with HIV. Every patient should be considered for the treatment when the benefits of therapy will outweigh the risks.|
|Management of hepatitis C: 2002 National Institutes of Health Consensus Conference Statement http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm||All HIV-infected people should be screened for HCV. Patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of HCV disease. Therefore, although there are no HCV therapies specifically approved for patients co-infected with HIV, these patients should be considered for treatment. [Since these guidelines were written, Roche has been granted a coinfection indication for Pegasys (pegylated interferon alfa-2a) and Copegus ( ribavirin) in Europe and the US.]|
Efficacy of HCV therapy in HIV/HCV coinfection vs HCV monoinfection
Data from three pivotal clinical trials of HCV therapy in people coinfected with HIV/HCV showed that HCV treatment is less effective in HIV/HCV coinfected people versus those with HCV alone (see Table 2).
This raises specific issues for coinifection: how to improve this response by earlier treatment (perhaps both for HIV and HCV), longer duration of treatment and different dosing regimens. It also highlights the higher proportion of coinfected patients for whom effective retreatment strategies are essential.
Table 2: SVR and treatment failure rates In HCV/HIV coinfection vs HCV-monoinfection
All studies 48 week duration.
|Regimen||Overall||Genotype 1 & 4||Genotype 2 & 3|
|Peginterferonalfa-2a: 180 µg weekly Ribavirin: 1000-1200 mg/day Fried, NEJM 2002 ||SVR: 56% Failure rate: 44%||SVR: 44% Failure rate: 56%||SVR: 70% ** Failure rate: 18%|
|Peginterferon alfa-2b: 1.5 µg/kg weekly Ribavirin: 800 mg/day Manns, Lancet, 2001 ||SVR: 54% Failure rate: 46%||SVR: 42% Failure rate: 58%||SVR: 82% Failure rate: 18%|
|Peginterferon alfa-2a: 180 µg/kg weekly Ribavirin: 600 mg/day, escalated to 1000-1200 mg/day, as tolerated Chung, NEJM 2004 ||SVR: 27% Failure rate: 73%||SVR: 14% Failure rate: 86%||SVR: 73% Failure rate: 27%|
|Peginterferon alfa-2a: 180 µg/kg weekly Ribavirin: 800 mg/day Torriani, NEJM 2004 ||SVR: 27% Failure rate: 73%||SVR: 17% Failure rate: 83%||SVR: 44% Failure rate: 56%|
|Peginterferon alfa-2b: 1.5 µg/kg weekly Ribavirin: 800 mg/day Carrat, JAMA 2004 ||SVR: 40% Failure rate: 60%||SVR: 29% Failure rate: 71%||SVR: 62% Failure rate: 38%|
* Genotype 4 response rates were included when available. ** Includes genotypes 2-6.
Avoiding treatment failure
Now that pivotal clinical trials have demonstrated safety and efficacy of HCV treatment in HIV/HCV coinfection, the number of HIV/HCV coinfected individuals treated for HCV is likely to increase. Given the higher non-response rates among people with coinfection, the pool of HIV/HCV coinfected candidates for retreatment is also likely to increase.
In some cases, retreatment might be avoided by optimising the initial HCV treatment regimen. There are five strategies for optimisation:
- Increasing the dose of peginterferon
- Increasing the dose of ribavirin
- Extending duration of therapy (by genotype: 24 vs. 48 weeks for 2 & 3; 48 vs 72 weeks for 1 & 4)
- Aggressive side effect management (use of anti-depressants, other strategies, informing patients, proactive vs reactive)
- Adherence support.
Increasing the dose of pegylated interferon
Data on safety and efficacy of high-dose pegylated interferon are available from studies of HCV monoinfection. The RENEW (Retreatment of Non-responders with Escalating Weight-Based Therapy) evaluated safety and efficacy of a 48-week regimen of double dose (3.0 ug/kg weekly) vs. standard dose (1.5 ug/kg weekly) of pegylated interferon alfa-2b plus weight-based ribavirin (800-1400mg/day), among 704 non-responders to interferon plus ribavirin. Almost all had genotype 1 (91%), 40% had bridging fibrosis or cirrhosis, and 18% were African-American. Sustained virological response (SVR) rates were significantly higher in the 3.0 ug/kg arm than the standard dosing arm (17% versus 12%; p=0.03). The rate of SVR in the doubled-dose arm did not differ significantly by race or liver histology. Discontinuation rates were similar in each arm; 13% versus 11%. No significant differences in adverse events were reported, although there was a trend towards more frequent events in the double dose arm. The authors concluded high-dose antiviral treatment deserves further study as initial therapy for patients with inherently low response rates. 
An ongoing trial, the REPEAT study (Retreatment with Pegasys in patients not responding to prior peginterferon alfa2b/ribavirin combination therapy) is evaluating four different treatment strategies in previous non-responders to 12 or more weeks of treatment with pegylated interferon alfa-2b plus ribavirin:
A) 12 weeks of induction therapy with 360ug of pegylated interferon alfa-2a plus weight-based ribavirin, followed by 36 weeks of 180µg of pegylated interferon plus ribavirin; B) 12 weeks of induction therapy with 360ug of pegylated interferon alfa-2a plus weight-based ribavirin, followed by 48 weeks of 180µg of pegylated interferon plus ribavirin; C) 180µg of pegylated interferon plus weight-based ribavirin for 48 weeks; D) 180µg of pegylated interferon plus weight-based ribavirin for 72 weeks.
Early virological response (EVR) rates from 856 participants, that combined pegylated interferon dose (360ug vs 180ug) showed that the rate of EVR was significantly greater among those who received high-dose induction dosing of pegylated interferon in arms A and B than the standard dosing arms (B and C). This difference was seen whether response was defined as getting 2 log decrease from baseline (62% vs. 45%; p<0.001) or by achieving HCV RNA <50 copies/mL (20% vs 13%; p=0.003). There was a trend towards more discontinuations and dose modifications in the high-dose arms than the standard dosing arms (19% vs 13%, respectively). Adverse events did not differ significantly by treatment arm.  Final results, expected in 2007 according to information on the Roche website, will clarify the value of induction dosing and duration of treatment.
Increasing the dose of ribavirin
Anaemia is common among people with advanced HIV, and has been linked to poorer survival, particularly among HIV-infected women. [21. 22] It is also a common side effect of HCV treatment, since ribavirin induces hemolytic anaemia, and interferon is myleosuppressive. Concomitant use of AZT and ribavirin increases the risk for anaemia.  Thus, concerns about ribavirin-induced anaemia among coinfected people led to the use of a fixed dose of 800 mg/day in APRICOT, ACTG 5071 and RIBAVIC coinfection trials, regardless of weight or HCV genotype. However, data are accumulating on superior efficacy of weight-based ribavirin in both mono-and coinfection.
Results from the WIN-R (Weight-based Dosing of Peg-Intron and Rebetol) study evaluated safety and efficacy of weight-based vs. fixed-dose ribavirin, combined with pegylated interferon alfa-2b in 4913 individuals with HCV monoinfection. Participants with HCV genotype 1 were treated for 48 weeks; those with genotypes 2 and 3 were randomised to 24 or 48 weeks of treatment. In people with genotype 1, weight-based dosing (WBD) was significantly more effective than the 800 mg/day fixed dose of ribavirin (SVR of 34% vs. 29%; p=0.004). WBD was also more effective for treating those with genotype 1 and high baseline viral load (32% vs. 27%; p=0.047). In genotypes 2 and 3, there was no significant difference in the rate of SVR by duration of treatment or ribavirin dose. Per protocol, the dose of ribavirin was reduced if Hgb decreased to <10 gm/dL. Dose reductions for anaemia occurred more frequently in the WBD group vs. the fixed-dose group (46% vs. 32%, respectively), although the discontinuation rate was similar with weight-based and fixed-dose ribavirin. 
In HIV/HCV coinfection, two studies have provided some insight on weight-based ribavirin dosing. Laguno and colleagues used weight-based ribavirin with pegylated or standard interferon. 
Duration of treatment varied according to genotype. In the pegylated interferon arm, the SVR rate was 38% for genotype 1 (vs. 7% for interferon), representing the highest SVR rate for genotype 1 reported from coinfection treatment trials. [16, 17, 18]
The PRESCO trial is evaluating safety and efficacy of pegylated interferon alfa-2a (180 ug per week) plus 1000-1200mg/day of ribavirin (according to weight). Participants with HCV genotype 1 or 4 were randomised to either 12 or 18 months of treatment; those with genotype 2 or 3, to either 6 or 12 months of treatment. So far, end-of-treatment (EOT) response rates have been presented: overall, 63%; genotype 1, 50%; genotype 3, 85%; genotype 4, 44%. 
Extending duration of treatment
The rationale for extending duration of HCV treatment is based on the premise that, during therapy, HCV RNA must remain undetectable for a certain interval to reduce the risk of relapse. Drusano and colleagues used patient data to develop a model predicting treatment efficacy for HCV genotype 1. They determined that an average of just over 30 weeks of HCV therapy was necessary to render HCV genotype 1 undetectable. Once undetectable HCV RNA was achieved, it should be maintained by continuing treatment for an additional 32-36 weeks for an 80% to 90% probability of SVR.  In HCV monoinfection, the TeraViC-4 study extended HCV treatment to 72 weeks in people with detectable HCV RNA at week 4. Extended duration of treatment was associated with significantly increased SVR in genotype 1 (44% vs. 28% for 48 weeks; p<0.001), and lower relapse rates (13% vs. 48%; p=0.005). Although the incidence of adverse events did not differ significantly by duration of treatment, discontinuations occurred more frequently in the 72-week arm (18% vs. 4.8%). 
Poor tolerability may make it difficult to extend duration of HCV therapy in people with coinfecion. Zanini and colleagues studied 24 vs. 48 weeks of therapy for coinfected people with genotype 2 or 3. They reported that 48 weeks of treatment, although difficult to tolerate, was significantly more effective than 24 weeks, resulting in SVR of 90% (vs. 61% for 24-week therapy).  However, Uriel and colleagues reported that a >50% dropout rate made it impossible to assess the impact of duration of treatment on SVR in a group of 61 coinfected people. At 24 weeks of treatment, individuals with undetectable HCV RNA were randomised to continue treatment for either 24 or 48 weeks. There was no significant difference in the SVR rate by treatment duration (50% for 48 weeks of treatment vs. 54.8% for 72 weeks of treatment),  Final data from PRESCO, expected in the next few months, will be help to assessing the efficacy of extending treatment for coinfected people with HCV genotype 1.
Managing side effects
The side effects and toxicities of HCV therapy make treatment challenging, as reflected by high discontinuation rates reported from some clinical trials of in HIV/HCV coinfection. Cargnel and colleagues reported that only 55 of 135 coinfected participants in their open-label study of pegylated interferon plus ribavirin completed 48 weeks of therapy, and concluded the key to successfully improving efficacy is strong compliance through strict overall patient monitoring, in order to best manage drug toxicity. 
Aggressive, proactive management of side effects supports adherence to HCV treatment in HIV/HCV coinfected patients. 
Anaemia and depression are two common and potentially treatment-limiting side effects of hepatitis C treatment. Both have been associated with diminished quality of life during HCV therapy.  Anaemia is managed by reducing the dose of ribavirin, or adjunctive therapy with epoetin-alfa, a hematopoetic growth factor. Since adequate ribavirin dosing is associated with increased SVR rates, dose reduction may not be the preferable strategy. In HCV monoinfection, epoetin alfa is associated with improved quality of life, and maintenance of ribavirin dose, and may increase the likelihood of SVR [34, 35 36] Sulkowski and colleagues conducted a 16-week, open-label randomised study of epoetin vs. standard of care (dose reduction) in 66 HIV/HCV coinfected individuals undergoing HCV treatment. They reported that epoetin alfa was effective at rectifying ribavirin-induced anaemia, even in people using AZT, and that it significantly reduced fatigue. Premature withdrawals (14 directly after randomisation and an additional 31 during the study) made it difficult to assess the impact of epoetin on ribavirin dosing. 
Interferon is associated with the development of neuropsychiatric side effects, particularly depression, irritability and mood swings. [38,39] People with a history of depression are at increased risk for developing interferon-associated depression.  Interferon-associated depression can be managed with antidepressant medication. A baseline psychiatric evaluation should be conducted prior to initiation of HCV therapy, especially for people with a psychiatric history. Some clinicians prefer to treat depression if necessary, while others use a proactive approach, by prescribing prophylactic antidepressant therapy to ensure selection of an effective agent and identification of medication-related side effects before HCV treatment is initiated.
Fatigue is commonly reported during HCV treatment, and it may be difficult to distinguish fatigue from depression. A recent study by Raison and colleagues suggested that interferon-associated fatigue is associated with poorer HCV treatment outcomes in monoinfected people.  Fatigue may occur often in coinfected people; Jones and colleagues reported that fatigue was twice as common as depression in a group of 93 coinfected people undergoing HCV therapy (see Table 3). They underscored the importance of differentiating between fatigue and depression, as their management strategies differ. 
Table 3. Management of fatigue and depression during HCV treatment 
|Consider psychostimulants||Consider antidepressants|
Adherence to at least 80% of the full dose of pegylated interferon and ribavirin, for at least 80% of the duration of therapy has been associated with SVR in HCV genotype 1, and in HIV/HCV coinfection [43, 44 ] Patients who are fully informed of the risks and benefits of HCV treatment may be more likely to adhere to demanding regimens, and patient education and support groups have been identified as an important element of adherence support in mono-and coinfected people. [32, 45, 46]
Defining treatment failure: relapse versus non-response
Early response to an initial HCV treatment regimen predicts ultimate response. For those who do not achieve SVR, the nature of the response to HCV therapywhether partial, virologic breakthrough, relapse or null provides key information for developing the retreatment strategy. Response can be assessed as early as four weeks after commencement of anti-HCV therapy. A rapid virological response (RVR) occurs when HCV RNA is detected in the bloodstream at week four of HCV treatment. Torriani and colleagues reported that participants in the APRICOT trial who achieved RVR were very likely to achieve SVR. In HCV genotype 1, the positive predictive value of an RVR was 82%; it increased to 94% for genotypes 2 and 3. 
The more common time point for assessing response to treatment is 12 weeks after initiation of HCV therapy. In contrast to the RVR, the early virological response (EVR) is associated with a high negative predictive value. Coinfected patients who do not achieve either a <2 log decrease in HCV RNA, or undetectable HCV RNA, are very unlikely to achieve an SVR. Clinical trials of HCV therapy in coinfected people have reported negative predictive values for failure to achieve EVR ranging from 94 to 100%. [48, 49, 50]
Partial responders are defined as achieving a <2 log decrease in HCV RNA after 12 weeks of treatment, but do not achieve an undetectable HCV RNA after 24 weeks of treatment. Virologic breakthrough occurs during treatment, when HCV RNA reappears in the blood of people who previously achieved undetectable HCV RNA. If virologic breakthrough occurs during treatment, a repeat HCV RNA should be performed to rule out specimen contamination or error.
Relapsers have an end-of-treatment response (ETR, with no detectable HCV RNA in the bloodstream at the end of therapy), but HCV RNA reappears after completion of treatment. Non-responders do not have a significant reduction in HCV RNA levels (< 2 log after 12 weeks of HCV treatment, or never become HCV-RNA undetectable during treatment. Non-responders are less likely to achieve SVR upon retreatment than partial responders, relapsers, or people with virologic breakthrough. 
Considering retreatment: current guidelines and recommendations
Current guidelines for retreatment of coinfected people are limited, due to lack of coinfection-specific data (see Table 4). Regardless of HIV status, relapsers, partial responders, people who experience virologic breakthrough, and non-responders should not be re-treated with the same regimen, unless they received suboptimal doses of either agent, were not adherent, or the duration of initial therapy was insufficient.
Table 4: Guidelines for retreating coinfected non-responders
|Source, date and weblink||Recommendation|
|British HIV Association (BHIVA) Guidelines For Treatment and management of HIV and Hepatitis C Coinfection; 2004. http://www.bhiva.org||Treatment options are limited No data is available in the coinfected patient on the best strategy of care in those who have failed previous interferon based therapy.|
|Short Statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients; May 2005. Alberti A, Clumeck N, Collins S, et al. J Hepatol. 2005 May;42(5):615-24. [The full proceedings and statements from the 1st European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients, May 2005 are published online in free issue of Journal of Hepatology (2006, Vol 44 Supp 1).] http://www.jhep-elsevier.com||The decision to retreat should be considered based on the type of response and tolerability to the previous treatment, the extent of liver damage and HCV genotype.|
|Management of Hepatitis C: 2002 National Institutes of Health Consensus Conference Statement http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm||Selected patients who fail to achieve an SVR may benefit from re-treatment with pegylated interferon-based regimens. Decisions regarding re-treatment should be based on (1) previous type of response, (2) the previous therapy and the difference in potency of the new therapy, (3) the severity of the underlying liver disease, (4) viral genotype and other predictive factors for response, and (5) tolerance of previous therapy and adherence.*|
|American Association for the Study of Liver Diseases, Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004 Apr;39(4):1147-71. https://www.aasld.org/eweb/DynamicPage.aspx?Site=AASLD3&webcode=ViralHepatitis||Retreatment with peg interferon plus ribavirin should be considered for nonresponders or relapsers who have significant fibrosis or cirrhosis and who have undergone previous regimens of treatment using non-pegylated interferon… Retreatment with peg interferon plus ribavirin with the aim of eradicating HCV is not indicated in patients who have failed to respond to a prior course of peg interferon plus ribavirin, even if a different type of peg interferon is administered.|
*Recommended in the context of HCV monoinfection; no coinfection-specific recommendation provided.
The clinical management strategy for coinfected non-responders is based on liver histology. HCV therapy may be deferred in people with minimal liver disease, as many novel anti-HCV therapies are currently being evaluated. For this population, a biopsy every two years is suggested. People with more serious liver disease may be candidates for retreatment or maintenance therapy, and should be monitored; those with bridging fibrosis or cirrhosis should be screened for hepatocellular carcinoma and signs and symptoms of end-stage liver disease.
Retreatment with pegylated interferon and ribavirin should be considered for coinfected non-responders to interferon, with or without ribavirin, or pegylated interferon monotherapy. One study reported on safety and efficacy in a group of 32 HIV/HCV coinfected relapsers and non-responders. Myers and colleagues evaluated a 48-week course of pegylated interferon alfa-2b plus 600 to 1200 mg/day of ribavirin in relapsers (25%; N=6) and nonresponders (75%; N=24). All were previously treated with at least 12 weeks of interferon monotherapy (6%; N=2) or ribavirin plus interferon (94%;N=30). The majority (94%; N=30) received antiretroviral therapy during treatment, and the mean CD4 cell count was 478 cells/mm3 (SD+/= 208). More than a third (38%; N=12) had bridging fibrosis or cirrhosis.
They reported an overall SVR rate of 16% (N=5). By genotype, SVR rates were as follows: 33% (1 of 3) in genotype 4; 29%, (3 of 7) in genotype 3, and 9%, (2 of 22) in genotype 1. None of the participants with bridging fibrosis or cirrhosis achieved SVR. Although not statistically significant, SVR occurred more frequently in people with lower baseline HCV RNA, higher baseline ALT, and higher baseline CD4 cell count.
Safety and tolerability issues were significant, leading to premature discontinuation among almost half of the study participants (47%; N=15). The most frequently reported side effects were neuropsychiatric, hematological, and generalised symptoms such as fatigue, insomnia and weight loss. 
Data on safety and efficacy of retreatment regimens in coinfected non-responders to pegylated interferon plus ribavirin are scant. Only one study, from Leevy and colleagues, has evaluated a novel regimeninterferon alfacon-1 (consensus interferon; CIFN; a synthetic type 1 interferon, developed from a consensus sequence of natural alfa interferons) plus weight-based ribavirinand extended duration of therapy in 61 HIV//HCV coinfected non-responders. Most patients (93%; N=57) had HCV genotype 1, and 53% (N=32) were African-American. HCV treatment began with a 12-week lead-in of pegylated interferon and weight-based ribavirin. None of the study participants achieved EVR. At week 12, pegylated interferon was immediately replaced with interferon alfacon-1 (consensus interferon). Daily treatment with 15ug of interferon alfacon-1 and weight-based ribavirin continued for 72 weeks. SVR was achieved by 30% (N=18). There were no discontinuations; the most common side effects reported were flu-like. Growth factors were used to treat hematologic toxicities; 53% (N=32) received epoetin, 44% (N=27) were given fillagrastim; and 16% (N=10) received both. None of the study participants discontinued treatment. 
Many promising new HCV therapies, such as oral protease and polymerase inhibitors and new formulations of interferon, are currently in development, but so far, none have been studied in coinfected people. Early data from HCV monoinfected non-responders are promising. Unfortunately, coinfected non-responders may face a long wait before trials of these agents are launched, despite pressure from patients and advocates.
Preventing HCV progression: maintenance therapy
Interferon has anti-fibrotic properties. The use of long-term, low-dose pegylated interferon is currently being evaluated in several ongoing studies as a maintenance therapy, to prevent progression to hepatic decompensation, hepatocellular carcinoma, and death. EPIC, Co-Pilot and HALT-C are three ongoing studies assessing safety and efficacy of interferon maintenance in HCV monoinfection.
Another group of studies, SLAM-C, Endure, and HRN-004, HIV/HCV are studying interferon maintenance therapy in HIV/HCV coinfected non-responders (Table 5).
Table 5. Maintenance therapy trials in HIV/HCV coinfection 
|HRN-004||SLAM-C (ACTG 5178)||ENDURE|
|Population and study size||Non-responders to IFN or IFN/RBV >Stage 0 fibrosis. N=100||Non-responders or treatment naive, with = Stage 1 fibrosis. N=100||Cirrhotic (Child-Pugh =8) nonresponders or intolerant to full dose peg interferon and ribavirin. N=468|
|Treatment arms||Peg interferon alfa-2a 90 µg/week vs. observation||Peg interferon alfa-2a 180 µg/week vs. observation||Peg interferon alfa-2b 0.5 µg/kg/week vs. observation|
|Duration||1.5 years||1.5 years||1.5 years|
|Lead-in phase||24 weeks of peg interferon alfa-2a plus 800-1200 mg of ribavirin per day||12 weeks of peg interferon alfa-2a plus 800-1200 mg of ribavirin per day||None|
|Trial status||Enrollment complete||Currently enrolling||Launch 2006|
The initial course of HCV therapy should be optimised, by using adequate doses of pegylated interferon and ribavirin, and aggressively managing side effects. When HCV therapy is unsuccessful, the retreatment regimen should be more effective than the initial regimen.
Current approaches to re-treating HCV either using high-dose therapy to eradicate HCV, or low-dose maintenance therapy to prevent progression to cirrhosis, hepatic decompensation, or hepatocellular carcinoma.
Ultimately the hope is that new therapies will improve response rates in all populations, and access to experimental HCV treatment in coinfected patients, and earlier trials in coinfected populations should carry urgency as an advocacy issue.
Tracy Swan is the Hepatitis C coinfection project director at Treatment Action Group (TAG), New York and co-author of TAGs Hepatiits C Coinfection Report.
Treatment Action Group (TAG)
- Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44 Suppl 1:S6-9
- Mohsen AH, Murad S, Easterbrook PJ. Prevalence of hepatitis C in an ethnically diverse HIV-1-infected cohort in south London. HIV Med. 2005 May;6(3):206-15.
- Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999 Oct;30(4):1054-8.
- Goedert JJ, Eyster ME, Lederman MM, et al. End-stage liver disease in people with hemophilia and transfusion-associated infections. Blood. 2002 Sep 1;100(5):1584-9.
- Graham CS, Baden LR, Yu E, et al. Influence of HIV infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001 Aug 15;33(4):562-9.
- Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001 Feb 1;32(3):492-7.
- Crum NF, Riffenburgh RH, Wegner S, et al; on Behalf of the Triservice AIDS Clinical Consortium. Comparisons of Causes of Death and Mortality Rates Among HIV-Infected People: Analysis of the Pre-, Early, and Late HAART (Highly Active Antiretroviral Therapy). J Acquir Immune Defic Syndr. 2006 Feb 1;41(2):194-200.
- Lewden C, Salmon D ,Morlat P. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol. 2005 Feb;34(1):121-30.
- Macias J, Melguizo I, Fernandez-Rivera FJ, et al. Mortality due to liver failure and impact on survival of hepatitis virus infections in HIV-infected patients receiving potent antiretroviral therapy. Eur J Clin Microbiol Infect Dis. 2002 Nov;21(11):775-81.
- Rosenthal E, Poiree M, Pradier C, et al; GERMIVIC Joint Study Group. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS. 2003 Aug 15;17(12):1803-9.
- Chung RT, Andersen J, Volberding P, et al; AIDS Clinical Trials Group A5071 Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004 Jul 29;351(5):451-9.
- Lissen E, Clumeck N, Sola R, et al. Histologic response to peginterferon alpha-2 a (40KD) (Pegasys®) plus ribavirin (Copegus®) in patients with HIV-HCV co-infection: results of the AIDS Pegasys ribavirin international coinfection trial (APRICOT). 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 – November 2, 2004; Boston, Massachusetts. Abstract 174.
- Lissen E, Clumeck N, Sola R, et al. Histological response to peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in HIV-HCV co-infected patients with bridging fibrosis or cirrhosis in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT). 3rd IAS Conference on HIV Pathogeneis and Treatment. Rio De Janiero, Brazil. 24-27 July 2005. Abstract TuPe1.1C21.
- Fried MW, Shiffman ML, Reddy KR, et al. Peg interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347(13):975-82.
- Manns MP, McHutchison JG, Gordon SC, et al. Peg interferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001 Sep 22;358(9286):958-65.
- Chung RT, Andersen J, Volberding P, et al; AIDS Clinical Trials Group A5071 Study Team. Peg interferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004 Jul 29;351(5):451-9.
- Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al; APRICOT Study Group. Peg interferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 Jul 29;351(5):438-50.
- Carrat F, Bani-Sadr F, Pol S, et al; ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomised controlled trial. JAMA. 2004 Dec 15;292(23):2839-48.
- Gross J, Johnson S, Kwo, P, Afdhal N, Flamm S, Therneau T. Double-dose peginterferon alfa-2b with weight-based ribavirin improves response for interferon/ribavirin non-responders with hepatitis C: final results of RENEW. 56th Annual Meeting of the American Association for the Study of Liver Diseases; November 11- 15, 2005; San Francisco, CA. Abstract 60.
- Marcellin P, Freilich B, Andreone P, et al. Interim safety analysis of patients enrolled in the randomised, international REtreatment with PEgasys in pATients not responding to prior peginterferon alfa-2b/ribavirin (RBV) combination therapy (REPEAT) study. 56th Annual Meeting of the American Association for the Study of Liver Diseases; 11-15 November 2005; San Francisco. Abstract 72557.
- Berhane K, Karim R, Cohen MH, et al. Impact of highly active antiretroviral therapy on anaemia and relationship between anaemia and survival in a large cohort of HIV-infected women: Womens Interagency HIV Study. J Acquir Immune Defic Syndr. 2004 Oct 1;37(2):1245-52.
- Moore RD, Forney D. Anaemia in HIV-infected patients receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002 Jan 1;29(1):54-7.
- Brau N, Rodriguez-Torres M, Prokupek D, et al. Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin. Hepatology. 2004 Apr;39(4):989-98.
- Jacobson I, Brown RS, Freilich B, et al. Weight-based ribavirin dosing (WBD) increases sustained viral response rates in patients with chronic hepatitis C (CHC): final results of the WIN-R Study, a U.S. community-based trial. 56th Annual Meeting of the American Association for the Study of Liver Diseases; November 11- 15, 2005; San Francisco, CA. Abstract LB03.
- Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004 Sep 3;18(13):F27-36.
- Ramos B, et al. High ribavirin doses and early virological response in HCV/HIV- coinfected patients. 2nd International Workshop on HIV and Hepatitis Co-infection; January 12-14th; Amsterdam, The Netherlands. Abstract 36.
- Drusano GL, Preston SL. A 48-week duration of therapy with pegylated interferon alpha 2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype-1 hepatitis C. J Infect Dis. 2004 Mar 15;189(6):964-70.
- Sanchez-Tapias JM, Escartin P, Enriquez J, et al. Longer treatment duration with peginterferon alfa-2a (40KD) (Pegasys) and ribavirin (Copegus) in naive patients with chronic hepatitis C and detectable HCV RNA by week 4 of therapy: final results of the randomised, multicenter TERAVIC-4 Study. 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 – November 2, 2004; Boston, Massachusetts. Abstract 126.
- Zanini B, Puoti M, Quiros Roldan E, et al. The optimal duration of treatment for HIV-infected patients with chronic hepatitis C (CHC) and genotype 2 or 3 is 48 weeks: results of a randomised controlled trial. 3rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract MoPpLB0103.
- Uriel A, Moorehead L, Carriero D, Sulkowski M, Dieterich D. A Multicenter, Randomised Trial of 48 vs 72 Weeks of Peg-Interferon Alfa -2b + Ribavirin in HIV/HCV-co-infected Subjects: Longer Therapy Does Not Correlate with Improved Sustained Virological Response. 13th Conference on Retroviruses and Opportunistic Infections; 5-8 February 2006, Denver, CO. Abstract 854.
- Cargnel A, Angeli E et al; Italian Co-infection Study (ICOS) Group. Open, randomised, multicentre italian trial on PEG-IFN plus ribavirin versus PEG-IFN monotherapy for chronic hepatitis C in HIV-coinfected patients on HAART. Antivir Ther. 2005;10(2):309-17.
- Clanon KA, Johannes Mueller J, Harank M. Integrating treatment for hepatitis C virus infection into an HIV clinic. Clin Infect Dis. 2005 Apr 15;40 Suppl 5:S362-6.
- Dan AA, Martin LM, Crone C, et al. Depression, anaemia and health-related quality of life in chronic hepatitis C. J Hepatol. 2006 Mar;44(3):491-8.
- Afdhal NH, Dieterich DT, Pockros PJ, et al; Proactive Study Group. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomised controlled study. Gastroenterology. 2004 May;126(5):1302-11.
- Pockros PJ, Shiffman ML, Schiff ER, et al;; PROACTIVE Study Group. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology. 2004 Dec;40(6):1450-8.
- Spiegel BM, Chen K, Chiou CF, Robbins S, Younossi ZM. Erythropoietic growth factors for treatment-induced anaemia in hepatitis C: a cost-effectiveness analysis. Clin Gastroenterol Hepatol. 2005 Oct;3(10):1034-42.
- Sulkowski MS, Dieterich DT, Bini EJ, et al; for the HIV/HCV Coinfection Study Group. Epoetin alfa once weekly improves anaemia in HIV/hepatitis C virus-coinfected patients treated with interferon/ribavirin: a randomised controlled trial. J Acquir Immune Defic Syndr. 2005 Aug 1;39(4):504-6
- Constant A, Castera L, Dantzer R, et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005 Aug;66(8):1050-7.
- Kraus MR, Schafer A , Faller H, Csef H, Scheurlen M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry. 2003 Jun;64(6):708-14.
- Raison CL ,Demetrashvili M, Capuron L, Miller AH . Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19(2):105-23.
- Raison CL, Pariante CM, Capuron L, et al. The association of fatigue with poor virologic response in patients receiving interferon alpha plus ribavirin for the treatment of hepatitis C. 56th Annual Meeting of the American Association for the Study of Liver Diseases; November 11- 15, 2005; San Francisco, CA. Abstract 62918.)
- Jones K, Kadam J, Talal A, Peterson R, Luckett P, Ferrando S. High prevalence of fatigue and depression in HIV/ High prevalence of fatigue and depression in HIV/hepatitis C coinfected patients treated with interferon and RBV. Second International Workshop on HIV and Hepatitis Coinfection; 12-14 January 2005. Amsterdam. Abstract 38.
- McHutchison JG, Manns M, Patel K, et al; International Hepatitis Interventional Therapy Group. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002 Oct;123(4):1061-9.
- Opravil M, Torriani FJ, Sasadeusz J, et al. Treatment exposure and sustained virological response (SVR) in genotype 1 patients treated with peginterferon alfa-2a (40KD) plus ribavirin (RBV) in APRICOT (AIDS PEGASYS Ribavirin (RBV) International Co-infection Trial). Program and abstracts of the 45th Interscience Conference of Antimicrobial Agents and Chemotherapy; December 16-19, 2005; Washington, DC. Abstract V-1179.
- Fleming CA, Tumilty S, Murray JE, Nunes D. Challenges in the treatment of patients coinfected with HIV and hepatitis C virus: need for team care. Clin Infect Dis. 2005 Apr 15;40 Suppl 5:S349-54.
- Litwin AH, Soloway I, Gourevitch MN. Integrating services for injection drug users infected with hepatitis C virus with methadone maintenance treatment: challenges and opportunities. Clin Infect Dis. 2005 Apr 15;40 Suppl 5:S339-45.
- Torriani FJ, Rodriguez-Torres M, Lissen E, et al. Predictability of virologic response at week 4 and 12 of peginterferon alfa-2a (40KD) plus ribavirin (RBV) therapy in HIV-HCV co-infection: AIDS PEGASYS Ribavirin International Co-Infection Trial (APRICOT). 45th Intl Conference on Antimicrobial Agents and Chemotherapy; December 16-19; Washington, DC. Abstract V-1178.
- Chung RT, Anderson J, Volberding P, et al; AIDS Clinical Trials Group A5071 Study Team. A randomised, controlled trial of PEG-interferon-alfa-2a plus ribavirin vs interferon-alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-co-infected persons: follow-up results of ACTG A5071. 11th Conference on Retroviruses and Opportunistic Infections; 8-11February 2004, San Francisco. Abstract 110.
- Perez-Olmeda M, Nunez M, Romero M, et al. Pegylated IFN-alpha2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients. AIDS. 2003 May 2;17(7):1023-8.
- Rodriguez-Torres M, Torriani FJ, Lissen E, et al. Predictability of sustained virological response (SVR) in patients with HCV/HIV co-infection during combination therapy with peginterferon alfa-2A (40KD) (Pegasys) plus ribavirin (Copegus) in the APRICOT trial. XV International AIDS Conference; 11-16 July 2004, Bangkok. Abstract MoPeB3304.
- Shiffman ML. Chronic HCV: treatment of PEG interferon/ribavirin nonresponders. Curr Gastroenterol Rep. 2006 Feb;8(1):46-52.
- Myers RP, Benhamou Y, Bochet M, Thibault V, Mehri D, Poynard T. Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy. AIDS. 2004 Jan 2;18(1):75-9.
- Leevy C, Chalmers C, Blatt LM. Sustained virologic response (SVR) to retreatment with IFN alfacon 1 + ribavirin in HCV/HIV coinfected patients who had failed 12 weeks of PEG IFN alpha 2 + ribavirin therapy. 56th Annual Meeting of the American Association for the Study of Liver Diseases; 11-15 November 2005, San Francisco. Abstract 1268.
- Adapted from: Sulkowski M. Treatment of Hepatitis C in non-responders and maintenance therapy: pros and cons. Second International Workshop on HIV and Hepatitis Coinfection; 12-14 January, 2005. Amsterdam. Session 3.