Mario G. Pessoa

A Sustained Virologic Response Is Durable in Patients With Chronic Hepatitis C Treated With Peginterferon Alfa-2a and Ribavirin

BACKGROUND & AIMS A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown. METHODS The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years). RESULTS Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse. CONCLUSIONS In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.

Histological response to pegifnα-2a (40kd) plus ribavirin in Hiv–hepatitis C virus co-infection

Objective:Paired liver biopsies from patients enrolled in the multinational AIDS PEGASYS Ribavirin International Co-infection Trial were analysed to investigate a possible correlation between virological and histological responses. Design and methods:A total of 860 HIV–hepatitis C virus (HCV)-co-infected patients were randomly assigned to receive pegIFNα-2a (40KD) 180 μg/week plus 800 mg daily ribavirin, pegIFNα-2a (40KD) plus placebo or conventional IFNα-2a 3 MIU three times a week plus ribavirin for 48 weeks. Paired biopsies were obtained from 401 patients and scored locally using the Ishak-modified histological activity index (HAI). The second biopsy was obtained, on average, 26 weeks or more after the end of treatment. Histological response was defined as a 2-point or greater reduction in the HAI score. Results:The histological response rate was significantly higher in patients receiving pegIFNα-2a (40KD) plus ribavirin (57%) than in patients receiving pegIFNα-2a (40KD) plus placebo (39%; P < 0.017) or IFNα-2a plus ribavirin (41%; P = 0.04). Histological response was correlated with virological response, with the histological response rate ranging from 62 to 74% in patients who achieved a sustained virological response (SVR). Histological response was also seen in 32–43% of patients not achieving an SVR. A higher total HAI score was the only prognostic factor for achieving histological response. Conclusion:The histological response rate was significantly higher in HIV–HCV-co-infected patients who received pegIFNα-2a (40KD) plus ribavirin than in those receiving pegIFNα-2a (40KD) plus placebo or IFNα-2a plus ribavirin. Histological response was correlated with virological response, although a substantial proportion of patients who did not achieve an SVR experienced histological improvement.

Hepatic steatosis in HIV/HCV co-infected patients: Correlates, efficacy and outcomes of anti-HCV therapy: A paired liver biopsy study

BACKGROUND/AIMS Hepatic steatosis is caused by the complex interaction of host and viral factors, such as metabolic syndrome (MS), alcoholism and HCV genotype, and in HIV-HCV co-infected patients, antiretroviral therapy may also play a role. A large population of patients from the AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT) had paired liver biopsies interpreted and graded for steatosis along with lipid measurements and anthropometric data. METHODS We analyzed these patients to determine the prevalence of steatosis, baseline factors associated with steatosis, effect of steatosis in HCV therapy efficacy and the impact of anti-HCV treatment on steatosis. RESULTS A total of 65/283 (23%) patients with paired biopsies were positive for steatosis. Patients with steatosis were significantly more likely to have HCV genotype 3, bridging fibrosis/cirrhosis, higher HCV RNA levels, increased triglycerides and lower cholesterol levels. The only different body measurement was neck circumference which was greater in patients with steatosis and significantly decreased from baseline during the study. Hip circumference was predictive of steatosis at baseline. CONCLUSIONS Factors associated to the metabolic syndrome are important in co-infected patients. Treatment outcome affected steatosis in that viral eradication reduced steatosis in genotype 3 patients, but altogether steatosis did not affect efficacy of treatment in any genotype.

The presence of resistance mutations to protease and polymerase inhibitors in Hepatitis C virus sequences from the Los Alamos databank

Several new direct‐acting antiviral (DAA) drugs are in development for chronic hepatitis C viral (HCV) infection, and NS3‐NS4A serine protease and the NS5B RNA‐dependent RNA polymerase have been the major targets. HCV variants displaying drug‐resistant phenotypes have been observed both in vitro and during clinical trials. Our aim was to characterize amino acid changes at positions previously associated with resistance in protease (NS3) and polymerase (NS5B) regions from treatment‐naïve HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS5B polymerase sequences (genotypes 1a = 471, 1b = 329, 3a = 6) were collected from Los Alamos databank. Genotype 3a protease sequences showed the typical low‐level resistance mutation V36L. NS3 sequences from other genotypes presented mutations on positions 36, 39, 41, 43, 54, 80, 109, 155 and 168 in a frequency lower than 2%, except for the mutation Q80R found in 35% of genotype 1a isolates. Polymerase sequences from genotype 3a patients showed five typical mutations: L419I, I424V, I482L, V499A and S556G. Two positions presented high polymorphism in the NS5B region from genotype 1a (V499A) and genotype 1b (C316N) subjects. Our results demonstrated a natural profile of genotype 3a that can be associated with the pre‐existence of HCV variants resistant to first‐generation protease inhibitors and to non‐nucleoside polymerase inhibitors. Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre‐existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively.

Efficacy and safety of entecavir for chronic HBV in HIV/HBV coinfected patients receiving lamivudine as part of antiretroviral therapy

Background:Prolonged use of lamivudine in patients coinfected with HIV and hepatitis B virus (HBV) leads to an increasing risk of lamivudine resistance in both diseases. We investigated the addition of entecavir, a potent inhibitor of HBV polymerase, to lamivudine-containing highly active antiretroviral therapy (HAART) in patients who experienced rebound in HBV viremia while maintaining suppression of plasma HIV RNA less than 400 copies/ml. Methods:Sixty-eight patients were randomized to entecavir 1 mg (n = 51) or placebo (n = 17) once daily for 24 weeks; 65 patients continued the study with entecavir for an additional 24 weeks. Lamivudine-containing HAART was continued throughout. Results:At week 24, the mean HBV DNA in entecavir-treated patients was 5.52 log10 copies/ml versus 9.27 log10 copies/ml for placebo, and at week 48, it was 4.79 log10 copies/ml versus 5.63 log10 copies/ml, respectively. The mean HBV DNA change from baseline for entecavir was −3.65 log10 copies/ml (versus + 0.11 for placebo, P < 0.0001) and alanine aminotransferase normalization in 34% of patients (versus 8% for placebo, P = 0.08). At 48 weeks, mean change in HBV DNA reached −4.20 log10 copies/ml in patients who received entecavir for the entire 48 weeks. The frequency of adverse events with entecavir and placebo was comparable. Through 48 weeks, no clinically relevant changes in HIV viremia or CD4 cell counts were identified. Conclusion:In this study, entecavir was associated with rapid, clinically significant reductions in HBV DNA, with maintenance of HIV viremia suppression, in HIV/HBV coinfected patients with HBV viremia while on lamivudine treatment.

Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy

Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a (40KD) plus ribavirin has given an overall sustained virological response of 18% in F3/F4 previous nonresponder US patients. We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.

52-Week Efficacy and Safety of Telbivudine with Conditional Tenofovir Intensification at Week 24 in HBeAg-Positive Chronic Hepatitis B

Background and Aims The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. Results 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. Conclusions Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B. Trial Registration ClinicalTrials.gov NCT00651209

HEPATITIS C INFECTION IN TRANSPLANTATION

This review emphasizes the role of HCV in the transplant setting. Prolonged HCV infection results in end-stage liver disease and as such represents a common indication for liver transplantation. Recurrence of infection is almost universal after transplantation in those with viremia before transplantation. Acquired disease is uncommon but nevertheless important, particularly in organ populations in whom screening for infection is not routine. The natural history of post-transplantation disease suggests that the effect on graft or patient survival is minor, at least during short-term follow-up. Long-term follow-up is needed, as well as more detailed study of the factors contributing to severity of post-transplantation disease. Kidney transplant recipients are commonly infected with HCV prior to transplantation. HCV infection after transplantation is associated with an increased risk of liver disease and infectious complications, but its effect on survival is still controversial. Similarly, observations in recipients of other solid organ transplants, such as heart and lung, and bone marrow patients suggest that HCV infection usually is not a major cause of mortality in the first 5 to 10 years of follow-up. Many issues still need to be addressed. The most important is the identification of factors that contribute to disease progression. Finally, effective therapies to eradicate infection and prevent disease progression are awaited.

Antienvelope antibodies are protective against GBV-C reinfection: Evidence from the liver transplant model

An assay for the detection of antibody against the second envelope (E2) protein of GB virus type C (GBV‐C) has been developed. Early reports suggested that this antibody was a marker of viral clearance, yet it is unknown whether anti‐E2 is protective against further GBV‐C infection. The primary aims were to determine (1) if posttransplantation immunosuppression alters the prevalence of anti‐E2; and (2) if anti‐E2 positivity pretransplantation protects against acquisition of GBV‐C infection posttransplantation. Fifty‐four recipients who underwent orthotopic liver transplantation for end‐stage liver disease of nonviral etiologies were tested for GBV‐C RNA using a PCR‐based assay and anti‐E2 antibodies by an enzyme‐linked immunoassay. Anti‐E2 was present in 35% and in 46% of patients pre‐ and posttransplantation, respectively. Anti‐E2 positivity pretransplantation was strongly associated with anti‐E2 positivity after transplantation (P < 0.001); 83% of patients with anti‐E2 prior to transplantation remained anti‐E2–positive after transplantation. A negative association between presence of GBV‐C viremia and presence of anti‐E2 was found in all patients tested either prior to or following transplantation (P = 0.03). Acquisition of GBV‐C infection was significantly lower in patients who were anti‐E2–positive prior to transplantation (2/13) compared to those who were antiE2–negative (12/26) (P = 0.05). It is concluded that immunosuppression does not reduce the prevalence of anti‐E2 after transplantation in those who are seroreactive prior to transplantation. Anti‐E2 appears to be a neutralizing antibody whose presence at the time of liver transplantation protects against acquisition of GBV‐C infection in the peritransplantation period. J. Med. Virol. 56:253–258, 1998.

Update on clinical trials in the treatment of hepatitis B

Chronic hepatitis B infection is a worldwide public health problem, which is particularly important in countries of Asia. Interferon has long been available for the treatment of patients with active replication (hepatitis B virus (HBV) e antigen and HBV‐DNA positive) with evidence of chronic liver disease (elevated serum alanine aminotransferase and chronic hepatitis on liver biopsy). Doses of interferon of 10 MU, t.i.w. or 5 MU, q day for 16 weeks result in e antigen and HBV‐DNA loss in approximately one‐third of individuals who meet these treatment criteria. The major limitations of interferon are: (i) side effects of influenza‐like symptoms; (ii) need for parenteral administration; and (iii) concerns about safety in patients with hepatic decompensation. Nucleoside and nucleotide analogues have potent antiviral activity. The largest experience is with lamivudine (3‐thiacytadine), a reverse transcriptase inhibitor that was recently approved by the USA Federal Drug Administration. At doses of 100 mg/day for 52 weeks, suppression of HBV replication is almost universal, with e antigen loss and improvement in histology being achieved in one‐third and two‐thirds of patients, respectively. The major advantages of lamivudine are: (i) good tolerability; (ii) oral route of administration; and (iii) safety in patients with hepatic decompensation. The major disadvantage is drug resistance, which is observed with increasing frequency following prolonged administration. New agents, such as adefovir dipivoxil, offer promise either alone or in combination with lamivudine in the treatment of individuals who are ‘treatment naive’ as well as in the treatment individuals who have developed lamivudine resistance.