Hepatitis C virus-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin

Hepatitis C virus (HCV)-RNA clearance seems to occur more slowly in HIV/HCV-coinfected patients than in HCV-monoinfected subjects treated with pegylated interferon alpha (peg-IFN) plus ribavirin (RBV). As a consequence, concern has arisen over the feasibility of following the treatment rules applied to HIV-negative patients with chronic hepatitis C. A total of 89 HIV/HCV-coinfected patients who had fully completed a course of peg-IFN plus RBV were analysed. Of these, 29 (32.6%) reached sustained virological response (SVR). Reductions >2 logs in plasma HCV-RNA occurred in 52 (58%) patients at week 12 of treatment (early virological response; EVR). None of patients who showed HCV-RNA drops <2 logs at week 12 reached SVR (negative predictive value: 100%). The positive predictive value of EVR was 56%. On the other hand, relapses occurred in 19 (39.6%) out of the 48 patients who had negative HCV-RNA at the end of treatment, and there were no differences noted when comparing patients with HCV genotypes 2/3 and 1/4. In summary, the quantitative assessment of plasma HCV-RNA at week 12 predicts the chance of SVR using peg-IFN plus RBV in HIV-positive patients with chronic hepatitis C, as it does in HIV-negative individuals. Thus, discontinuation of anti-HCV therapy, which is associated with frequent side effects, might be warranted in HIV/HCV-coinfected patients showing HCV-RNA reductions <2 logs at week 12 of treatment. On the other hand, relapses in virological responders were unexpectedly high in HIV/HCV-coinfected patients when treatment was provided following the rules applied to HIV-negative subjects. This is particularly relevant for HCV genotypes 2/3, which only rarely relapse in HIV-negative patients. Therefore, extending therapy (for 12 months in HCV genotypes 2/3 and perhaps for 18 months in HCV genotypes 1/4) might be warranted in HIV/HCV-coinfected patients showing EVR.     

Premature treatment discontinuation in HIV/HCV-coinfected patients receiving pegylated interferon plus weight-based ribavirin

BACKGROUND: Chronic hepatitis C therapy in HIV patients is often penalized by more frequent premature treatment discontinuations. It is unclear what the relative contribution of more adverse events and/or early virological failures are. METHODS: PRESCO was a prospective, multicentre, comparative trial, in which 389 HIV/HCV-coinfected patients with CD4+ T-cell counts >300 cells/ml and elevated aminotransferases received pegylated interferon-alpha2a (peg IFN-alpha2a) 180 mg per week plus ribavirin (RBV) 1,000-1,200 mg daily. Patients with HCV genotypes 1 or 4 were treated for 48 or 72 weeks while HCV genotypes 2 or 3 carriers were treated for 24 or 48 weeks. Use of didanosine was not allowed. RESULTS: Sustained virological response (SVR) was achieved by 193 (49.6%), and was significantly greater in HCV-2/3 than in HCV-1/4 patients (72.4% versus 35%; P<0.0001). Premature treatment discontinuations occurred in 174 patients (44.7%). This was due to early virological failure in 66 (17%), serious adverse events in 32 (8.2%), loss-to-follow-up in 12 (3.1%) and voluntary withdrawal in 64 (16.4%). Only 10 patients (2.6%) stopped HCV therapy due to severe anaemia. Two patients stopped HCV medication due to symptomatic mitochondrial toxicity. There were no episodes of hepatic decompensation. CONCLUSIONS: Treatment with RBV 1,000-1,200 mg/day plus peg IFN-alpha2a is relatively safe and provided SVR in nearly half of the HIV/HCV-coinfected patients, twice as many amongst the HCV-2/3 than HCV-1/4 carriers. Avoidance of didanosine, limited use of zidovudine and therapy restricted to patients with CD4+ T-cell counts >300 cells/ml most probably explains the lower and different spectrum of serious adverse events in PRESCO compared with prior trials conducted in coinfected patients.     

Rapid virological response at week 4 predicts response to pegylated interferon plus ribavirin among HIV/HCV-coinfected patients

INTRODUCTION: The clinical applicability of early viral kinetics at week 4 in predicting sustained virological response (SVR) of pegylated interferon (peg-IFN) plus ribavirin (RBV) in HIV/HCV-coinfected patients is unclear. Our objective was to determine if rapid virological response (RVR) at week 4 of therapy with peg-IFN and RBV could predict SVR among HIV/HCV-coinfected patients. METHODS: HIV/HCV-coinfected patients in whom an HCV viral load determination had been carried out at week 4 of therapy were included in the study. The positive predictive value (PPV) and the negative predictive value (NPV) of RVR (undetectable serum HCV RNA at 4 week) for SVR were calculated in the study population. Receiver operating characteristic curves were calculated to determine the best cutoff of HCV RNA decrease to predict treatment failure. RESULTS: A total of 101 HIV/HCV-coinfected patients were included. RVR and SVR were observed in 39 (39%) and in 49 (48%) individuals, respectively. Of patients with RVR, 37/39 patients achieved SVR (PPV: 95%), whereas 50/62 individuals without RVR did not show SVR (NPV: 81%). The highest NPV (96%) was reached by using a cutoff level of HCV RNA decrease of 0.6 log10. By applying this cutoff level, treatment could have been discontinued in 25 (25%) patients. CONCLUSIONS: An undetectable serum HCV RNA determination at week 4 of treatment with peg-IFN plus RBV is a reliable predictor of SVR in HIV/HCV-coinfected patients. In addition, a decrease of HCV RNA less than 0.6 log10 at this point of treatment could identify an appreciable proportion of individuals who will fail to achieve SVR.     

Evolution of HVR-1 quasispecies after 1-year treatment in HIV/HCV-coinfected patients according to the pattern of response to highly active antiretroviral therapy

Hepatitis C virus (HCV) variability is mainly attributed to the ability of the virus to respond to host immune pressure, acting as a driving force for the evolution of quasispecies. This study was aimed at studying the changes in HVR-1 heterogeneity and the evolution of HCV quasispecies in HIV/HCV-coinfected patients according to the pattern of response to highly active antiretroviral therapy (HAART). Sixteen HIV/HCV-coinfected patients harbouring HCV genotype 1 and who had been on HAART for at least 1 year, 8 showing increasing CD4+ T-cell counts (immunological responders) and 8 showing a stable or decreasing CD4+ T-cell counts (immunological nonresponders), were selected from a prospective cohort study. After 1 year of HAART, 11 patients showed HIV viral load <2.6 log10 cp/ml (virological responders), and 5 showed HIV viral load above this value (virological non-responders). Plasma samples, collected before starting therapy and after 1 year of HAART, underwent clonal sequence analysis for HVR-1 region of HCV. Nonsynonymous/synonymous substitutions ratio (Ka/Ks), aminoacidic complexity (normalized Shannon entropy) and diversity (p-distance), were considered as parameters of quasispecies heterogeneity. After 1 year of HAART, heterogeneity of HVR-1 quasispecies significantly decreased in virological non-responders, whereas the heterogeneity tended to increase in virological responders. The differences in the evolution were less stringent, when considering immunological response. On the other hand, profound qualitative modifications of HVR-1 quasispecies were observed only in patients with both immunological and virological HAART response. On the whole, these findings suggest that, in patients undergoing HAART, the extent of HCV variability and the evolution of HVR-1 quasispecies is influenced by the pattern of response to antiretroviral therapy.     

Chronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapy

HIV-infected patients are living longer since the introduction of highly active antiretroviral therapy. However, coinfection with the hepatitis C virus (HCV) leads to increased morbidity from liver disease and higher overall mortality. The prevalence of chronic hepatitis C among patients with HIV/AIDS ranges from 7% (sexual transmission of HIV) to >90% (injection drug use). Uncontrolled HIV infection seems to accelerate the progression of HCV-induced liver fibrosis. Forty-eight weeks of combination therapy with pegylated interferon alpha (2a or 2b) plus ribavirin achieves a sustained viral response in coinfected individuals in up to 38% with HCV genotype 1 and up to 73% with genotypes 2 or 3. The safety profile of this treatment is similar to therapy in HCV-monoinfected patients with influenza-like symptoms, cytopenia and neuropsychiatric symptoms dominating. However, HIV/HCV-coinfected patients who also take zidovudine develop more profound anaemia than those on other HIV nucleoside analogue therapy. Didanosine and stavudine are associated with rare but serious mitochondrial toxicity, such as pancreatitis or lactic acidosis. It does not appear that the addition of ribavirin increases that risk. There is currently no evidence that in HIV/HCV coinfection one pegylated interferon product is superior to the other. Contrary to common perception, it is also unproven that HIV/HCV-coinfected patients respond less well to therapy with peginterferon alpha plus ribavirin than HCV-monoinfected patients. Given the safety and efficacy of combination therapy with peginterferon plus ribavirin and the deleterious effects of chronic hepatitis C, all HIV/HCV-coinfected patients should be evaluated for therapy.     

Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.     

Role of viral kinetics under HCV therapy in HIV/HCV-coinfected patients

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are less responsive to anti-HCV therapies and are at a higher risk of toxicity than HCV monoinfected patients. HCV viral kinetics is the basis for the study of response to interferon-based therapy and for predicting sustained virological response (SVR). A lack of early virological response (EVR; undetectable HCV RNA or a decrease of >/=2 log(10) from baseline) after 12 weeks of pegylated interferon (peg-IFN) plus ribavirin (RBV) is an equally reliable predictor of lack of SVR in HIV/HCV-coinfected patients and in the monoinfected HCV population. Early stopping rules are particularly important in coinfected HIV/HCV patients, considering their low chances of response in the more difficult-to-treat HCV genotypes 1 and 4 (<30%). Several factors have been involved in this low efficacy, including higher baseline HCV viraemia, slower viral kinetics decay under interferon pressure and a defective immune substratum. A better understanding of HCV viral kinetics under HCV therapy may be the basis for assaying different peg-IFN plus RBV schedules, such as induction or extending strategies, and may help physicians to make tailored decisions for the management of their patients.     

Treatment of hepatitis C in HIV-coinfected patients

OBJECTIVE: To review the current management of hepatitis C virus (HCV) in persons coinfected with HIV. DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted, using key words such as HIV, human immunodeficiency virus, hepatitis C, interferon, pegylated interferon, and therapy. Article bibliographies and conference abstracts were also reviewed to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Studies that examined HCV treatment in individuals coinfected with HIV and articles that focused on HCV/HIV coinfection were considered for this review. DATA SYNTHESIS: Coinfection with HIV leads to a more rapid and severe course of HCV-related liver disease. Treatment of HCV with pegylated interferon (PEG-IFN) and ribavirin therapy is relatively well tolerated in individuals coinfected with HIV, with overall sustained virologic response (SVR) rates of 27-40%. High relapse rates and poor response in HCV-genotype 1 contribute to the lower SVR in coinfected individuals compared with HCV monoinfection. Treatment of HCV is more complicated in HIV-infected persons due to increased risk of myelosuppression, drug interactions, hepatotoxicity of antiretroviral therapy, and the relative contraindication to interferon therapy in advanced HIV disease. Current guidelines recommend that all HIV-positive patients with chronic HCV infection be considered as treatment candidates for anti-HCV therapy due to the higher risk of liver disease progression. Further studies are needed, however, to define the appropriate dose and duration of therapy in HCV/HIV-coinfected individuals. CONCLUSIONS: Response to treatment with PEG-IFN and ribavirin is poorer in patients coinfected with HCV/HIV than in those infected with HCV alone. The benefits of anti-HCV therapy, including viral eradication, need to be weighed against the risks of adverse effects and drug-drug interactions between anti-HCV and antiretroviral medications.     

Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus ribavirin therapy

BACKGROUND: Hepatitis C virus (HCV) is believed to exert a suppressive effect on hepatitis B virus (HBV) in most HBV/HCV-coinfected patients; once HCV is cured by interferon-based therapy, these patients may show HBV reactivation. However, recent evidence revealed that the virological status in HBV/HCV-untreated individuals may vary over time and may show fluctuating profiles. METHODS: To evaluate the behaviour of apparently inactive HBV infection in patients under treatment for a concurrent HCV infection, we performed a prospective study that evaluated nine consecutive patients (eight males with a median age of 45.9 years, and one female aged 62 years) longitudinally followed-up with bi-monthly evaluation of HBV/HCV viraemia levels and liver biochemistry during a 1-year treatment with interferon plus ribavirin. RESULTS: In seven cases the HBV infection maintained its inactive status independently of the HCV response to therapy. By contrast, two non-responder cases with persistently high HCV RNA levels showed HBV DNA flairs during the follow-up, indicating a status of active HBV infection with fluctuating virological profiles. CONCLUSIONS: This study suggests that the HBV behaviour may be independent of the HCV activity during anti-HCV therapy in HBV/HCV-coinfected patients, and that the HBV virological profile should be monitored to recognize possible reactivations that might lead to more proper therapeutic choices or adjustments.     

Efficacy of interferon in immunocompromised HCV patients after liver transplantation or with HIV co-infection

Background Interferon (IFN)‐based antiviral therapy is increasingly used in immunocompromised patients with chronic hepatitis C after orthotopic liver transplantation (OLT) and HIV–HCV co‐infection. Differences in early viral kinetics have not been compared in these patients. Materials and methods We retrospectively analysed 76 patients (31 OLT, 20 HIV–HCV and 25 HCV control patients) undergoing IFN sensitivity testing before starting antiviral therapy with pegylated IFN‐α2a (180 µg week^?1) plus ribavirin (0·8–1·2 g day^?1) for 48 weeks. We compared baseline parameters, response to IFN and treatment outcome between the groups and assessed the influence of specific calcineurin inhibitors in OLT patients and immune status in HIV–HCV patients on treatment response. Results Viral loads pretherapy were higher in OLT compared to nontransplanted HCV controls (P = 0·003). The same trend was present in HIV–HCV (P = 0·09). The log‐drop after test dose was less in OLT compared to HCV (P = 0·02), while no significant difference was found between HIV–HCV and HCV. In HIV–HCV patients viral load log‐drop correlated significantly with CD4⁺ cell counts (P = 0·001). No difference in viral load pretherapy, log‐drop and treatment outcome was noted between different calcineurin inhibitors in OLT patients. Sustained virological response rates were 28% in OLT, 50% in HIV–HCV and 56% in HCV patients. Conclusions Immunosuppression results in high HCV viral loads. Initial efficacy of IFN is significantly impaired in OLT patients, but not in HIV–HCV with largely preserved CD4⁺ cell counts. Sustained virological response rates of 28% in OLT patients are suboptimal, but encouraging results are shown for HIV–HCV patients with relatively high CD4⁺ cell counts.     

Open, randomized, multicentre italian trial on PEG-IFN plus ribavirin versus PEG-IFN monotherapy for chronic hepatitis C in HIV-coinfected patients on HAART

BACKGROUND: Chronic hepatitis C is common and aggressive in HIV-positive patients, so the development of a well-tolerated HCV therapy is a priority. We evaluated the efficacy and safety of pegylated interferon alpha2b (PEG-IFN) plus ribavirin (RBV) versus PEG-IFN monotherapy in HIV/HCV-coinfected patients undergoing highly active antiretroviral therapy (HAART), and analysed the predictive factors of response. METHODS: An Italian, multicentre, open-label trial including 135 coinfected patients, randomized to PEG-IFN 1.5 microg/kg/week plus RBV 400 mg twice daily (n=69, arm A) or PEG-IFN 1.5 microg/kg/week (n=66, arm B) for 48 weeks. We assessed the predictive values of early virological response (EVR) at week 8 (HCV-RNA drop >2 log10 compared with baseline or undetectable levels) on sustained virological response (SVR). RESULTS: Fifty-five patients (28 from arm A and 27 from arm B) completed 48 weeks of therapy. At the end of treatment, 20/28 patients in arm A and 11/27 in arm B had HCV-RNA <50 IU/ml. In a per-protocol analysis, SVR was reached by 54% of patients in arm A (genotype 2-3, 11/16; genotype 1-4, 4/12) and 22% in arm B (genotype 2-3, 3/15; genotype 1-4, 3/12). In an intention-to-treat analysis, the SVR was 22% in arm A (genotype 2-3, 11/32; genotype 1-4, 4/37) versus 9% in arm B (genotype 2-3, 3/32; genotype 1-4, 3/34). The best predictors of SVR were the use of combination therapy, infection with HCV genotype 3 versus genotype 1, and EVR at week 8. Thirty patients (15 from arm A and 15 from arm B) dropped out of the trial prematurely due to side effects. The positive predictive value of EVR at week 8 was 65%, the negative predictive value was 86%. CONCLUSIONS: PEG-IFN plus RBV can be considered a solid option for the treatment of HIV/HCV-coinfected patients. The key to successfully improving efficacy is strong compliance through strict overall patient monitoring, in order to best manage drug toxicity. EVR assessment at week 8 may become a useful stategy in the management of therapy.     

Standard interferon-alpha in combination with ribavirin for hepatitis C patients with advanced liver disease and thrombocytopenia

BACKGROUND AND AIM: Patients with advanced liver disease due to thrombocytopenia and chronic infection with hepatitis C virus (HCV) are difficult to treat in view of concerns about the efficacy and safety of interferon-based therapy. Nevertheless, antiviral therapy might have a substantial benefit in these patients as it potentially minimizes disease progression and prevents recurrence after liver transplantation. We evaluated the safety, efficacy and tolerability of standard interferon-alpha in an accelerating dose regimen in combination with ribavirin in patients with HCV-induced liver cirrhosis and thrombocytopenia. PATIENTS: Nine patients (M=8, age: 48.4 +/- 9.9, mean +/- SD) with HCV-related advanced liver disease and thrombocytopenia were prospectively investigated. The Child-Pugh stage was A in six patients and B in three, the MELD score was 11 [6-17] (median [range]). Four patients were interferon naive. HCV-genotype distribution was 1b (n=3), 3a (n=4) and 4 (n=2). The patients received 1-1.5 MU/d standard interferon-a2b with increasing dose regimen and weight-based ribavirin for 48 weeks (genotype 1), or 24 weeks (genotype 3), or until liver transplantation, respectively. RESULTS: The baseline platelet count was 64.3 +/- 8.7 (G/l, mean +/- SD) and remained remarkably stable during treatment (58.0 +/- 12.4 G/l at week 4, 51.7 +/- 20.5 G/l at week 8, P=0.1). All patients had adverse events such as weight loss, fever and anorexia. Hospitalization because of decompensation or infection was necessary in three patients. Three patients underwent liver transplantation. A virological response on treatment was achieved in eight patients and sustained in three (33.3%) patients. CONCLUSION: Treatment with standard interferon-alpha2b/ribavirin could be of benefit in patients with advanced liver cirrhosis and thrombocytopenia however, a vigilant monitoring of these high risk patients is mandatory.     

Antiretroviral therapy based on protease inhibitors as a protective factor against liver fibrosis progression in patients with chronic hepatitis C

Cohort studies have shown that highly active antiretroviral therapy (HAART) can improve liver-related mortality in HIV/hepatitis C virus (HCV)-coinfected patients. A reduction in the accelerated liver fibrosis progression observed in HIV infection induced by HAART could explain these findings. A few studies have assessed the impact of HAART on liver fibrosis, but with contradictory results. Therefore, we evaluated the associations between the use of different antiretroviral drug classes and HAART combinations, and liver fibrosis in HIV-infected patients with chronic hepatitis C. Six hundred and eighty-three HIV/HCV-coinfected patients, who underwent a liver biopsy and who had not received anti-HCV treatment were included. Age at HCV infection < 23years (adjusted odds ratio [AOR] = 0.7, 95% confidence interval [95% CI] = 0.3-0.9, P = 0.05) and protease inhibitor (PI)-based HAART versus no use of HAART (AOR = 0.5, 95% CI = 0.3-0.9, P = 0.01) were negatively associated with advanced fibrosis (> or = F3). PI-based HAART versus no use of HAART (AOR = 0.4, 95% CI = 0.2-0.7, P = 0.001) was negatively associated with fibrosis progression rate > or = 0.2 units/year and independently of age at HCV infection and CD4+ T-cell counts. Fifteen (17%) patients treated only with PIs and zidovudine plus lamivudine showed > or = F3, compared with 65 (37%) patients without HAART (P = 0.001). Forty (31%) patients on PI and stavudine plus lamivudine showed > or = F3 (P = 0.3, when compared with patients with no HAART). The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis. The nucleoside analogue backbone in a HAART regimen may influence this association.     

Naive HIV/HCV-coinfected patients have higher intrahepatic pro-inflammatory cytokines than coinfected patients treated with antiretroviral therapy

In the era of antiretroviral therapy, liver disease has emerged as an important cause of morbidity and mortality in HIV/hepatitis C virus (HCV) coinfected patients. It is believed that HCV is a non-cytopathic virus and that T-cell-mediated events (including the production of pro-inflammatory cytokines) have an important role in promoting both liver damage and viral clearance. Whether HIV coinfection or antiretroviral therapies influence such events is still unclear. In the current study, we compared the expression of NKp46 (a natural killer cell marker), CD3 (a T-cell marker), interferon-gamma (IFN-gamma), tumour-necrosis factor-alpha (TNF-alpha; pro-inflammatory cytokines) and interleukin-10 (IL-10; an anti-inflammatory cytokine) mRNA in the liver of naive HIV/HCV-coinfected patients (group one, n=14), coinfected patients treated with antiretroviral therapy (group two, n=23) and naive HCV mono-infected patients (group three, n=24). All three groups had comparable HCV viremia, with coinfected patients showing similar and relatively high CD4+ T-cell counts and significantly different HIV vireamia. Interestingly, when compared to groups two and three, group one showed significantly higher intrahepatic mRNA levels for CD3, IFN-gamma and TNF-alpha, whereas the expression of NKp46 and IL-10 were comparable in all three groups. Further, higher histopathological grading scores within each group were independently associated with higher mRNA contents for CD3 and IFN-gamma and higher serum alanine aminotransferase levels at the time of liver biopsy. Together, these results suggest that HIV infection may exacerbate the immune-mediated inflammatory response in the liver of patients chronically infected with HCV and antiretroviral therapy may prevent this effect.     

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4⁺ T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.     

Clinical management of patients with recurrent viral hepatitis after liver transplantation

Liver transplantation is indicated in end-stage chronic viral liver disease, but unless adequate prophylaxis is administered, the patient will in most cases develop recurrent hepatitis B (HBV) and C (HCV) virus infection. Today, patients receiving prophylaxis using nucleoside analogue drugs with or without specific immune globulin drugs in connection with orthotopic liver transplantation for HBV related cirrhosis, present low risk of relapse and high 5–10 year survival rates. Lamivudine was the first drug used in the prophylactic treatment, but this drug has increasingly been combined with or replaced by adefovir due to the low genetic barrier, which causes viral resistance. Most patients develop viral recurrence after orthotopic liver transplantation for HCV related cirrhosis, and in an elevated number of cases, cirrhosis and hepatic insufficiency set in after a few years. Prophylaxis before transplantation and pre-emptive treatment using interferon and ribavirin present numerous side effects resulting in reduction of doses and suspension of therapy, with consequently low sustained virological remission rates and risk of rejection.The treatment is better tolerated by patients with histologically confirmed chronic disease, but also in these patients virological remission rates are low. This pathology requires new therapeutic protocols and/or new drugs in order to obtain better compliance and better responses.     

Response to HAART and GB virus type C coinfection in a cohort of antiretroviral-naive HIV-infected individuals

The prognostic role of GB virus type C (GBV-C) viraemia in HIV-infected subjects treated with highly active antiretroviral therapy (HAART) is still undefined. The aim of this analysis is to assess the relationship between GBV-C infection and response to antiretroviral therapy among HIV-infected subjects initiating HAART when antiretroviral-naive. A prospective, observational study of 400 HIV-infected patients with measurements of GBV-C RNA, hepatitis C virus (HCV) antibodies and HCV RNA determined from plasma stored prior to HAART initiation. Time to virological (achieving HIV RNA < or =500 copies/ml) and immunological success (a CD4+ count increase of > or =200 cells/microl), and the time to virological relapse (confirmed HIV RNA >500 copies/ml) were assessed by Kaplan-Meier methods and Cox proportional hazard regression model. Of the subjects, 117 (29.3%) were GBV-C positive and, overall, 351 (87.8%) patients achieved virological success. After controlling for a number of confounders including HCV RNA, GBV-C viraemic patients experienced a significantly lower risk of HIV rebound than those who were GBV-C negative [relative hazard (RH)=0.56, 95% CI: 0.34-0.93, P=0.03]. Conversely, the probability of achieving initial virological success or CD4+ count response after HAART did not differ between GBV-C-negative and -positive subjects. These results suggest that GBV-C coinfection may play a role in determining the rate of HIV rebound possibly by competing with HIV replication after HIV load has been successfully suppressed by HAART.     

Results of a study of prolonging treatment with pegylated interferon-alpha2a plus ribavirin in HIV/HCV-coinfected patients with no early virological response

OBJECTIVE: To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR). METHODS: Patients received pegylated interferon (peg-INF)-alpha2a 180 microg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm). RESULTS: One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+ T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load >800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%. CONCLUSIONS: This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.