Department of Medicine, Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA and the Veterans Affairs Medical Center, Bronx, NY, USA
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Abstract |
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Keywords: pegylated interferon , ribavirin , highly active antiretroviral therapy , drug interactions
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Introduction |
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The prevalence of HCV coinfection among patients with HIV disease varies greatly and is largely dependent on the mode of transmission of HIV itself. It is high with parenteral transmission such as injection-drug use (91%) or transfusions (71%) but low with sexual transmission (7%).6
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Therapy of chronic hepatitis C in HIV/HCV-coinfected patients in 2005 |
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In the same year, four RCTs were reported on therapy with pegylated IFN plus ribavirin, two with 40 kDa peginterferon alpha-2a (PEG-IFN-2a; Pegasys®) plus ribavirin and two with 12 kDa peginterferon alpha-2b (PEG-IFN-2b; PEG-Intron®) plus ribavirin (see Table 1). The largest trial to date (APRICOT, n = 868)9 compared 48 weeks of treatment with PEG-IFN-2a 180 µg once weekly plus ribavirin 800 mg/day with standard IFN-2a 3 three times per week MIU TIW plus ribavirin 800 mg/day and PEG-IFN-2a plus placebo as safety control group. The SVR rate was higher in the pegylated than in the standard IFN arm, both overall (40% versus 12%, P < 0.001) and by HCV genotype (GT-1, 29% versus 7%, P < 0.001 and GT-2/3, 62% versus 20%, P < 0.001). Independent factors associated with SVR rate were genotype non-1 and baseline HCV RNA level <800 000 IU/mL. Indeed, in GT-1 with high HCV viral load (>800 000 copies/mL), the most common scenario in HIV/HCV-coinfected patients, the SVR rate was only 18%, compared with 61% with those having GT-1 and low viral load (800 000 IU/mL) or 6163% in GT-2/3 with any viral load. Failure to achieve an early viral response (EVR), defined as a decline in HCV viral load by at least 2 log10 or 100-fold or to <50 IU/mL led to an SVR in only 3%, giving the EVR measure a negative predictive value (NPV) for SVR of 97%. This rate is similar to the 97% NPV of the EVR measure found in the same therapy of PEG-IFN-2a plus ribavirin for HCV monoinfection.10 A smaller pilot study (ACTG A5071, n = 133)11 also found a superior SVR rate with 48 weeks of PEG-IFN-2a plus ribavirin compared with standard IFN-2b plus ribavirin (27% versus 12%, P = 0.02).
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Toxicity of HCV therapy |
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Interactions between peginterferon plus ribavirin and HAART |
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Both zidovudine and IFN are myelosuppressive and cause mild anaemia when given alone. When ribavirin causing haemolytic anaemia is combined with IFN which inhibits the bone marrow's capacity to make up for the loss in red blood cells, profound anaemia may develop. This anaemia is more pronounced when zidovudine is taken concomitantly than when patients do not take zidovudine (maximum haemoglobin level drop 3.9 versus 3.1 g/dL in PEG-2a + ribavirin9 and 2.5 versus 1.0 g/dL with IFN-2b + ribavirin7). The rate of anaemia-related dose reductions of ribavirin is much higher in patients on zidovudine (60%) than in subjects not taking zidovudine (16%).7 Use of zidovudine does not influence the degree of IFN-induced neutropenia.
HIV dideoxynucleoside analogues (didanosine and stavudine), ribavirin, and mitochondrial toxicity
Since the first report in 2001,16 cases of mitochondrial toxicity such as pancreatitis or lactic acidosis (some fatal) have been observed by multiple authors in HIV/HCV-coinfected patients undergoing combination therapy with IFN + ribavirin. In almost all instances, this toxicity was associated with the concurrent use of didanosine, stavudine or both. The US Food and Drug Administration collected reports of 52 such events and found mitochondrial toxicity to be associated with the use of didanosine [odds ratio (OR) = 12.4], with didanosine plus stavudine (OR = 8.0), and with stavudine alone (OR = 3.3). The report points out that ribavirin leads to increased intracellular levels of didanosine-triphosphate.17 This led to a warning label in the didanosine prescribing information urging clinicians to use didanosine and ribavirin together only with great caution.
It is thus evident that co-administration of didanosine or stavudine during ribavirin therapy increases the risk of mitochondrial toxicity. But these data do not permit the reverse conclusion that addition of ribavirin to an existing HAART regimen with didanosine or stavudine increases mitochondrial toxicity. Indeed, a substudy of the APRICOT trial showed that this is not the case. Comparing the two groups who received PEG-IFN-2a plus either ribavirin or placebo, the incidence of pancreatitis, lactic acidosis and symptomatic hyperlactataemia was similar in both groups (2.4% versus 2.8%, P = 0.78). Among the 15 patients with such events, 11 were concurrently taking didanosine or stavudine.18 These data show that while didanosine and stavudine are associated with mitochondrial toxicity, the addition of ribavirin does not increase this risk.
Competition of ribavirin for intracellular phosphorylation enzymes
Before the recent studies of PEG-IFN plus ribavirin therapy were published, there was concern about the interaction between ribavirin and HIV nucleoside analogues. In vitro, ribavirin competes with intracellular phosphorylation enzymes and inhibits the conversion of zidovudine and stavudine into their active triphosphate forms. However, this in vitro observation was not confirmed in patients. A nested pharmacokinetic substudy of APRICOT found that in patients receiving ribavirin, there is no significant decrease in plasma levels of zidovudine, stavudine and lamivudine and no inhibition of intracellular phosphorylation of zidovudine, stavudine and lamivudine.19
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Influence of HCV therapy with peginterferon plus ribavirin on HIV infection |
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Influence of HIV disease on HCV viral response |
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Comparison of randomized controlled trials of HCV therapy in HIV/HCV coinfection |
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Similarly, there is a widespread belief that SVR rates to PEG-IFN plus ribavirin are lower in HIV/HCV-coinfected than in HCV-monoinfected patients. This notion may be suggested by a direct comparison of treatment with PEG-IFN-2a at 180 µg per week plus ribavirin at 800 mg/day in HCV monoinfection (Hadziyannis trial,15 GT-1, 41%; GT-2/3, 79%) and in HIV/HCV coinfection (APRICOT,9 GT-1, 29%; GT-2/3, 63%). Similar differences in SVR rates are seen with PEG-IFN-2b at 1.5 µg/kg per week plus ribavirin at 800 mg/day in HCV monoinfection (Manns trial,13 GT-1, 42%; GT-2/3, 82%) and in HIV/HCV coinfection (RIBAVIC,12 GT-1, 17%; GT-2/3, 44%). However, again, this assumption is based on the comparison of SVR rates between separate studies with many differences in study population other than HIV status. Only a casecontrol study between two trials with the same treatment could provide the answer to the open question of whether HIV/HCV-coinfected patients have a different SVR rate than patients with chronic hepatitis C alone. One small casecontrol study examining viral kinetics during treatment with PEG-IFN plus ribavirin found a slower phase 1 and 2 viral decline in HIV/HCV-coinfected versus HCV-monoinfected patients but was too small to adequately control for confounding factors.21
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Open questions for future research |
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Similarly, the Hadziyannis study showed that in GT-1, PEG-IFN-2a combined with a ribavirin dose of 10001200 mg/day leads to a higher SVR rate than with 800 mg/day of ribavirin (52% versus 41%). The same effect may apply to HIV/HCV-coinfected patients, but a higher ribavirin dose may also lead to more profound anaemia, especially in patients who take zidovudine as part of their HAART regimen. Randomized controlled studies addressing the issue of ribavirin dosing are currently being planned. The role of growth factors such as recombinant granulocyte-colony stimulating factor (G-CSF, filgrastim) and recombinant human erythropoietin (EPO, epoetin alpha) in the treatment of cytopenia during HCV therapy has also not been well defined. One randomized controlled study of HIV/HCV-coinfected patients with anaemia during combination HCV therapy found that, compared with standard of care, epoetin alpha at 40 000 IU weekly is able to raise the haemoglobin level at week 16 by 2.8 g/dL in patients receiving zidovudine, and by 1.3 g/dL in subjects not on zidovudine. The ribavirin doses at week 16 were similar in both groups.22 It is unclear if the use of epoetin alpha has an influence on the SVR rate, and the drug is not currently approved for treatment of anaemia during HCV therapy.
Patients who do not achieve a viral cure after optimal HCV therapy may benefit from agents that can slow down or perhaps reverse the development of hepatic fibrosis. Based on a retrospective study that suggests a possible antifibrotic effect of IFN,23 three ongoing randomized controlled studies examine the effect of half-dose PEG-IFN versus no treatment on fibrosis progression and clinical progression to end-stage liver disease in HCV-monoinfected patients (CO-PILOT, HALT-C and EPIC-3). Two similar randomized controlled studies (HRN-004 and SLAM-C) are currently being conducted in HIV/HCV-coinfected patients.
Promising new anti-HCV agents include oral HCV enzyme inhibitors, notably RNA-dependent RNA polymerase inhibitors and HCV protease inhibitors. Several investigational drugs are currently in phases I and II of clinical development. Conference abstracts of pilot studies in HCV-monoinfected subjects have reported a 1.2 log10 decrease in HCV viral load with 14 days of therapy with the RNA polymerase inhibitor NM283 at 800 mg/day (Idenix, Cambridge, MA, USA),24 and a 4.3 log10 decline with 14 days of treatment with the protease inhibitor VX-950 at 2250 mg/day (Vertex, Cambridge, MA, USA) (Press Release, Vertex Pharmaceuticals, Chicago, 17 May 2005). It is hoped that, if successful, these new agents are also tested in HIV/HCV-coinfected patients in short order.
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Conclusion |
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Transparency declarations |
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Acknowledgements |
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References |
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