Long-term Antiviral Therapy Research Articles

Herpes Simplex and Herpes Zoster Eye Disease

To further define the spectrum of clinical disease and treatment among patients with herpes zoster ophthalmicus (HZO) and ocular herpes simplex viral (HSV) infection presenting at a large city hospital for the underserved in the United States. Retrospective review of medical records of 64 patients (40 HZO and 24 ocular HSV infection) presenting to the Bellevue Hospital Emergency Department for the management of herpetic eye disease for which an ophthalmologic consultation was obtained from January 1, 2006, to December 31, 2011. The mean age of patients with HZO was 51 ± 15 years (n=40) versus 33 ± 16 years for patients with ocular HSV infection (n=24; P<0.0001). Overall, 73% of patients with HZO were aged <60 years (n=29 of 40), of whom, 90% (26 of 29) were immunocompetent. The most common decade of onset of HZO was 50 to 59 years (11 of 40, 28%). Four patients with HZO were immunocompromised (n=4 of 40; 10%), with 3 aged <60 years attributable to human immunodeficiency virus (n=3 of 29, 10%). The study included 12 patients eligible to receive the herpes zoster vaccine. None of these patients had a history of vaccination. Of the 24 patients with ocular HSV infection, corneal stromal disease was present in 7 patients and infectious epithelial keratitis in 10 patients. No patients were treated with long-term oral antiviral prophylaxis. Acute HZO was seen more commonly than ocular HSV infection. Patients with HZO were significantly older than those with ocular HSV infection. Available prevention modalities, such as the vaccine against herpes zoster and long-term oral antiviral therapy to reduce ocular HSV infection recurrence, were underused.

Presumed Herpetic Anterior Uveitis: A Study with Retrospective Analysis of 79 Cases

To describe the clinical features, visual outcome, medical treatment, and complications of presumed herpetic anterior uveitis. We retrospectively analyzed the clinical data related to 79 eyes of 77 patients with presumed herpetic anterior uveitis seen at the Uveitis Unit of the Ulucanlar Eye Training and Research Hospital from 1996 to 2011. Age at onset of disease, sex, follow-up duration, existence of corneal involvement, posterior synechiae, distorted pupil, iris atrophy, characteristic of keratic precipitates, elevated intraocular pressure (IOP), medical treatment, recurrence rate, complications, visual acuities (VA), and surgery for complications were recorded. The complication rates in patients with and without corneal involvement were compared. There were 38 (49.4%) female and 39 (50.6%) male patients. The mean age at presentation was 48.5 ± 14.8 (20-82) years. The follow-up period was 26.5 (2-127) months. Two patients had bilateral involvement. Ocular findings were a corneal scar or active keratitis in 37 (46.8%) eyes, secondary glaucoma in 14 (17.7%), iris atrophy in 39 (49.4%), distorted pupil in 16 (20.3%), posterior synechiae in 23 (29.1%), and granulomatous anterior uveitis in 30 (40%) eyes. Eight (10.1%) eyes had a posterior subcapsular cataract. Glaucoma surgery was required for uncontrolled IOP with maximum medical treatment in 2 (2.4%) eyes. Long-term oral acyclovir was used in 9 (11.3%) patients. Final VA was ≤ 0.1 in 8 (10.1%) eyes; of these, 6 had either corneal scarring or cataract and 2 preexisting amblyopia. Presumed herpetic anterior uveitis with or without keratitis has characteristic clinical findings that enable the diagnosis. Long-term prophylactic antiviral therapy should be considered especially in patients <50 years old.

Vaccine and immunotherapeutic interventions

As we enter the fourth decade in HIV epidemic, advances in understanding HIV pathogenesis and development of potent and safer antiretroviral drugs have been spectacular. More than 30 antiviral drugs have been registered and the impact of combination antiviral therapy on morbidity and mortality has been dramatic. However, despite long-term virus suppression, HIV invariably rebounds after interruption of therapy. Long-term antiviral therapy does not cure HIV infection nor does it induce restoration/development of virus-specific immune responses capable of controlling HIV replication. Therefore, development of immune-based interventions is needed to restore effective defenses that can lead to HIV functional cure and ultimately eradication. Therapeutic vaccination and immune interventions that generate de-novo or that boost preexisting HIV-specific T-cell responses are being investigated as a potential means to achieve a 'functional HIV cure'. One major hurdle in the quest of an HIV cure is control and elimination of the HIV latent reservoir. Several immune interventions that target the latent reservoir have been tried in recent years. In parallel, several therapeutic vaccination strategies have been developed and tested in early clinical studies. Recent encouraging studies show for the first time that vaccination can have an impact on HIV load. This review summarizes the main immune interventions evaluated over the last years. Ways to improve them, as well as challenges in monitoring/evaluating effects of such strategies, are being discussed. In addition, clinical efficacy and potential clinical benefits of immunotherapeutic interventions are particularly difficult to measure. This review highlights current assays used and their shortcoming.

Virology and clinical sequelae of long-term antiviral therapy in a North American cohort of hepatitis B virus (HBV)/human immunodeficiency virus type 1 (HIV-1) co-infected patients

There are limited recent data worldwide on clinical and virological outcomes in hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfected patients on dual active antiretroviral therapy (ART). MethodsWe completed a retrospective review of 53 coinfected patients. HBV DNA in plasma was tested by PCR (sensitivity <20–<55IU/ml or ∼100–300copies/ml, Roche Diagnostics). Quantitative hepatitis B surface antigen (qHBsAg) was measured by an in-house assay (calibration range 0.24–62.5IU/ml). HBV genotyping was done by line probe assay, and HBV variants determined by sequencing the HBV polymerase (P)/overlapping surface (S) gene. ResultsThere were 7% (4/53) non-liver related deaths, ∼11% (6/53) had >F2 fibrosis, including 3 with cirrhosis. The median CD4+ T cell count was 415cells/mm3 (range 60–1310). 54% (28/51) were HBeAg-positive, and 81% (43/53) on ART had undetectable HBV DNA but only 5% (3/51) lost HBeAg. In 11/53 with HBV sequencing, 90% (10/11) were found to have HBV genotype A (HBV-A) and/or 27% (3/11) had a mixed A/G infection. Anti-HBV drug resistant mutations were detected in 54% (6/11) (i.e., any combination of rtV173L, rtL180M, M204V) and 45% (5/11) had an immune escape mutation (sP120S). In 12 with qHBsAg testing, the majority (9/12) had low-level qHBsAg ∼1–3log10IU/ml. SummaryLiver disease occurs in ∼10% of coinfected patients on ART and many have low-level HBV DNA and qHBsAg. In those sequenced most were HBV-A or mixed A/G genotype, and several carry P and S mutants highlighting the complex molecular virology of HBV during HIV coinfection.

A novel method for the analysis of drug-resistant phenotypes of hepatitis B virus

Chronic hepatitis B virus (CHB) infection is a major cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogs (NAs) are popularly used to treat chronic hepatitis B virus (HBV) infections; however, the anti-HBV effect is attenuated by drug-resistant viral mutations selected during long-term antiviral therapy. The timely analysis of drug-resistance mutations is essential in order to adjust treatment regimes. In this study, a T1699C substitution was introduced into the x gene of pHBV1.3 to generate an additional XhoI site, termed pHBV1.3‑XhoI, which is a nonsense mutation and does not influence protein expression, HBV replication ability, or NA susceptibility. Based on co-transfection with weak or non-replicative HBV plasmids and pHBV1.3-XhoI or pHBV1.3 and -XhoI-P-null plasmids into hepatocellular carcinoma cells, PCR was used to amplify 1176‑bp segments of T/C1699 using the isolated HBV encapsulated DNA as a template, modified by XhoI digestion and subjected to agarose gel electrophoresis. Different bands composed of different virions were used to distinguish the replication capacities of the plasmids. Our results demonstrated no significant effects when different virions co-existed. A novel resistance test method was developed by co-transfection with pHBV1.3-XhoI and -rtL180M/M204V and treatment with various NA concentrations. Different bands composed of pHBV1.3-XhoI or -rtL180M/M204V were used to distinguish NA susceptibility. The bands composed of pHBV1.3 were more sharply reduced by lamivudine (LMV) than -rtL180M/M204V. The data demonstrate that the method established in our study may be used for the analysis of drug-resistant phenotypes at the cellular level.

Maternal and Neonatal Herpes Simplex Virus Infections

Genital herpes infections are extremely common worldwide and ~22% of pregnant women are infected with herpes simplex virus. Eighty percent of those affected with genital herpes are unaware of being infected. The most devastating consequence of maternal genital herpes is neonatal herpes disease. Fortunately, neonatal herpes simplex infections are uncommon but due to the morbidity and mortality associated with the infection are often considered in the differential diagnosis of ill neonates. The use of polymerase chain reaction assay for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy have revolutionized the diagnosis and management of these infants. Most recently, the initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity. This review will summarize the epidemiology of maternal and neonatal herpes infections and discuss clinical presentation, diagnosis, management, and follow-up of infants with neonatal herpes disease.

Histological improvement of long‐term antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase levels

The aim of this study was to evaluate the histological outcomes of chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (ALT) levels after long-term antiviral therapy. Paired liver biopsies before and after lamivudine (LAM) treatment in CHB patients with normal and elevated ALT levels were compared. Histological response was defined as a 1-point decrease according to the Scheuer scoring system, without worsening of fibrosis between pretreatment and posttreatment biopsies. Among the 48 patients who underwent paired liver biopsies, 17 had persistently normal baseline ALT level and 31 had elevated ALT level. The median age of the patients was 44years and 72.9% of the patients were male. The median duration of antiviral treatment was 44.5months (range 14-104). Long-term follow-up of liver biopsies revealed that 82.4% of patients in the normal ALT group and 61.3% in the elevated ALT group had a baseline fibrosis score of 4, which was reduced to 17.6% and 38.7% after long-term therapy, respectively, indicating reversal of cirrhosis in a large proportion of both groups, especially in patients with normal baseline ALT levels. Long-term antiviral treatment could achieve significant histological improvement in CHB patients with fibrosis or cirrhosis, regardless of ALT level.

Development of a novel DNA sequencing method not only for hepatitis B virus genotyping but also for drug resistant mutation detection

BackgroundIn HBV-infected patients, different genotypes of the hepatitis B virus influence liver disease progression and response to antiviral therapy. Moreover, long-term antiviral therapy will eventually select for drug-resistant mutants. Detection of mutations associated to antiviral therapy and HBV genotyping are essential for monitoring treatment of chronic hepatitis B patients.ResultsIn this study, a simple method of partial-S gene sequencing using a common PCR amplification was established for genotyping clinical HBV isolates sensitively, which could detect the drug-resistant mutations successfully at the same time.ConclusionsThe partial S gene sequencing assay developed in this study has potential for application in HBV genotyping and drug resistant mutation detection. It is simpler and more convenient than traditional S gene sequencing, but has nearly the same sensitivity and specificity when compared to S gene sequencing.

Utilization of hepatitis B core antibody-positive donor liver grafts

BackgroundThe inclusion of hepatitis B core antibody-positive (HBcAb+) liver donors is a strategy utilized to increase organ availability. This study examined HBcAb+ transplantation practices to identify specific factors influencing outcomes. MethodsTwenty-five HBcAb+ liver transplants were identified retrospectively among 868 adult transplants performed between 1 January 1997 and 31 December 2009. Twelve (48%) recipients had hepatitis C and five (20%) had hepatitis B. Patient and donor demographics, preoperative morbidity, transplant data and outcomes were examined. Statistical analysis was completed using Student's t-test or the Kaplan–Meier method. A P-value of <0.05 was considered significant. ResultsThere was no difference in age, body mass index or comorbidities between HBcAb+ liver recipients and control subjects. Model for End-stage Liver Disease (MELD) scores of >30 were significantly more frequent in HBcAb+ liver recipients (32% vs. 15%; P= 0.04). All patients received immunoglobulin and longterm antiviral therapy as prophylaxis against graft hepatitis B resurgence. No patients who received HBcAb+ livers developed hepatitis B infection on follow-up. Overall survival at 30 days, 1 year and 5 years in HBcAb+ liver recipients was 92%, 74% and 74%, respectively, compared with 96%, 89% and 76%, respectively, in the control group (P= not significant, log-rank test). All except one of the deaths in the HBcAb+ liver recipient group occurred within 90 days postoperatively and in patients with MELD scores >30. ConclusionsThe practice of transplanting HBcAb+ grafts incurs low risk for infection using current methods of prophylaxis. The highest mortality risk was in the early postoperative period, specifically in patients with very high MELD scores. This probably reflects the practice of using positive serology grafts in emergent situations.

Management of treatment failure in chronic hepatitis B

Antiviral therapy of chronic hepatitis B remains a clinical challenge. The primary goal of therapy is to prevent liver disease progression. Because of the mechanism of viral persistence in infected hepatocytes, long-term antiviral therapy is needed in the majority of patients. Incomplete viral suppression and emergence of drug resistance is a major concern. The correct choice of a first-line potent therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and drug resistance. Clinical studies have demonstrated that drugs with a high barrier to resistance, such as entecavir and tenofovir, have significantly lower rates of resistance when compared with those with a low barrier to resistance such as lamivudine, adefovir, or telbivudine. Management of treatment failure requires a precise clinical and accurate virologic monitoring as well as an early treatment intervention with appropriate complementary drugs with respect to their cross-resistance profile. Long-term surveillance for treatment efficacy and possible emergence of drug resistance is necessary for those patients who have been sequentially treated with multiple antivirals. Finally, the identification of novel treatment targets remains a major research challenge to improve the efficacy of current antiviral therapy.

The therapeutic response of antiviral therapy in HBsAg-positive renal transplant recipients and a long-term follow-up

Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB). We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed. HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P=0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65weeks. The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.

Evaluation of peptide nucleic acid array for the detection of hepatitis B virus mutations associated with antiviral resistance

A major problem of long-term antiviral therapy in chronic hepatitis B patients is the emergence of hepatitis B virus (HBV) mutations associated with drug resistance. Recently, a new array using peptide nucleic acids (PNAs), which are synthetic nucleic acid analogues, was developed for the detection of HBV mutations at six different codon positions associated with lamivudine (LAM) and adefovir (ADV) resistance. We compared the PNA array with direct sequencing and reverse hybridization (INNO-LiPA) in 73 samples obtained from chronic hepatitis B patients. The PNA array detected mutations associated with LAM and/or ADV resistance in 60 (82.2%) of the 73 samples. The overall concordance rate of PNA array and INNO-LiPA compared with direct sequencing was 99.5% and 98.2%, respectively. The rate of complete concordance between PNA array and INNO-LiPA was 92.7%. The PNA array assay results were comparable with INNO-LiPA for detection of HBV mutations associated with antiviral resistance.

404 Differential Phenotype and Distribution of CMV-Specific T Cell Effector Memory between the Lung Allograft and Blood in High-Risk Lung Transplant Recipients

CMV infection remains a serious opportunistic infection in lung transplant recipients (LTRs), with donor+/recipient- (D+/R-) LTRs particularly at increased risk. We have previously shown that CMV-specific CD8+ T cell responses are immunodominant during acute primary CMV infection, with lung allograft CD8+ T cell effector responses predominant over the blood. The relationship between CMV-specific compartmental phenotype and immunologic memory in LTRs during chronic infection and durable viral control remain largely undefined. Studies of CMV-specific compartmental immunity are critical to establish whether viral control is achievable in this population without long-term antiviral therapy.

Antiviral Therapy: Analysis of Long-term Efficacy and Safety

Despite the adoption of universal vaccination in many countries, chronic hepatitis B virus (HBV) infection continues to be a global problem. Morbidity and mortality from this infection, although possibly declining, remains significant. Fortunately, our treatment armamentarium has expanded exponentially in the past decade. Newer antiviral agents are not only effective against HBV infection, but they also confer a lower risk for virologic resistance than the first-generation oral nucleoside, lamivudine. In this article, the long-term efficacy and safety of available antiviral therapy in the treatment of chronic hepatitis B are reviewed, and differences in drug potencies, side-effect profiles, and risks of development of virologic resistance are discussed to provide guidance for optimal choices for long-term antiviral therapy.

Cytomegalovirus infection/disease after hematopoietic stem cell transplantation

Cytomegalovirus (CMV) disease has historically been a main cause of death after allogeneic hematopoietic stem cell transplantation (HSCT). Since the introduction of prophylactic or preemptive therapy against CMV, the incidence of CMV disease has been successfully reduced. However, breakthrough CMV disease, particularly CMV gastrointestinal disease, remains one of the major infectious complications. Administration of an antiviral agent, ganciclovir, is often associated with myelotoxicity in HSCT recipients, and delayed immune reconstitution against CMV. Delayed immune reconstitution is a possible cause of the increasing incidence of late (more than 3 months after transplant) CMV disease after HSCT in this era of preemptive therapy. Foscarnet and valganciclovir are the available alternatives to intravenous ganciclovir. Foscarnet is not myelotoxic and has a toxicity profile different from ganciclovir. Valganciclovir, a prodrug of ganciclovir, has a higher bioavailability than oral ganciclovir and could be of clinical use, particularly in the outpatient setting or for patients requiring long-term antiviral therapy. Recent technological developments have enabled the visualization and isolation of CMV-specific T cells. Using these techniques, an individualized approach could be conducted based on each patient's immune reconstitution against CMV. In this review, we summarize the recent progress and current knowledge of CMV infection and disease after allogeneic HSCT.

Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers

Epstein-Barr virus (EBV) establishes a latent infection in B cells in the blood, and the latent EBV load in healthy individuals is generally stable over time, maintaining a "set point." It is unknown if the EBV load changes after long-term antiviral therapy in healthy individuals. We treated volunteers with either valacyclovir (valaciclovir) or no antiviral therapy for 1 year and measured the amount of EBV DNA in B cells every 3 months with a novel, highly sensitive assay. The number of EBV-infected B cells decreased in subjects receiving valacyclovir (half-life of 11 months; P = 0.02) but not in controls (half-life of 31 years; P = 0.86). The difference in the slopes of the lines for the number of EBV-infected B cells over time for the valacyclovir group versus the control group approached significance (P = 0.054). In contrast, the number of EBV DNA copies per B cell remained unchanged in both groups (P = 0.62 and P = 0.92 for the control and valacyclovir groups, respectively). Valacyclovir reduces the frequency of EBV-infected B cells when administered over a long period and, in theory, might allow eradication of EBV from the body if reinfection does not occur.

Side effects of long-term oral antiviral therapy for hepatitis B #

The aim of this review is to summarize the safety profile of the five approved oral nucleoside analogs used to treat chronic hepatitis B virus (HBV) infection, focusing on both the class adverse effects and those that have been reported with individual agents, as well as their safety in pregnancy. All nucleoside analogs have a "Black Box" warning because of their potential for inhibition of human DNA polymerase gamma involved in mitochondrial DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying clinical manifestations of mitochondrial toxicity (i.e., neuropathy, myopathy, lactic acidosis), but these side effects are rarely reported with the oral antiviral agents active against HBV. Adefovir and tenofovir are associated with a dose-dependent but usually reversible proximal renal tubular toxicity. For these reasons, patients receiving these agents should be monitored for renal toxicity and the dose modified for renal insufficiency. Prolonged use of tenofovir has also been reported to lead to reduced bone mineral density in patients with human immunodeficiency virus infection, but prospective studies in patients with HBV infection are lacking. Telbivudine treatment is associated with moderate serum creatine phosphokinase elevations in up to 12% of patients. There have been few prospective studies on the safety of nucleoside analogs during pregnancy. According to the Antiretroviral Pregnancy Registry, the incidence of birth defects associated with lamivudine and tenofovir use during pregnancy is not increased. Studies on the safety of long-term therapy with the nucleoside analogs, alone and in combination, are needed as are further studies of children, the elderly, pregnant women, and patients with renal insufficiency.

Hepatitis B immunoglobulin in preventing reinfection following liver transplantation

Before the availability of hepatitis B immunoglobulin (HBIG) in hepatitis B-positive transplant recipients, the acute mortality was very high, in many centers up to 50% within 60 days post-transplant. The overall reinfection rate was approximately 60% within the initial 6 months, increasing to 80–90% within the initial 12 months and, in many cases, leading to allograft loss and death or retransplantation. These recurrent infections were often more severe and more rapidly progressing than the initial infection, probably due to high-dose immunosuppressive regimens. The poor prognosis before introduction of HBIG made hepatitis B liver disease an absolute contraindication for liver transplantation, leaving these patients with very limited treatment options. This changed in the late 1980s with the introduction of HBIG, which reduced the incidence of hepatitis B in the transplanted liver to approximately 15–50%, with concomitant improvement in graft and overall survival. The prognosis was further improved by a combination of long-term HBIG and antiviral therapy, in particular lamivudine, which reduced the reinfection rate, in most cases to between 0 and 5%. Owing to the cost and relative inconvenience of HBIG, some transplant centers have experimented with early discontinuation of HBIG and replacement with antiviral monotherapy. A number of studies, however, have found significantly higher recurrence rates associated with lamivudine monotherapy (40–50%) compared with combination therapy and, hence, lamivudine monotherapy is not recommended.

HALT-C in the final analysis: A molehill out of a mountain

Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL, HALT-C Trial Investigators. Background In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain. Methods We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90μg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. Results We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly ( P P =0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group ( P =0.07). Conclusions Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NC6164.) 2008 Massachusetts Medical Society. [Abstract reproduced by permission of N Engl J Med 2008;359:2429–2441].

Long-term antiviral therapy for recurrent hepatitis C after liver transplantation in nonresponders: Biochemical, virological, and histological impact

More than 50% of patients with a recurrent posttransplant hepatitis C virus infection fail to respond to antiviral treatment. The aim of this study was to evaluate the interest of a long-term antiviral treatment maintained for more than 48 weeks. Seventy treated patients, with a histological follow-up > 1 year, were enrolled in this observational, retrospective study. The duration of antiviral treatment, tolerance, and occurrence of virological, biochemical, and histological responses were recorded. Thirty-two patients were nonresponders after 48 weeks of treatment. Combined antiviral therapy was maintained for >12 months in 26 and for >18 months in 21. Twelve patients had to discontinue their treatment. At 48 weeks, the rates of virological response and sustained virological response were 37% and 24.3%, respectively; at the end of the follow-up, they were 48.5% and 35.7%. Virological response was significantly associated with a higher incidence of biochemical and histological response, regardless of its time of occurrence (before or after 6 months). Even in the absence of virological response, the rate of progression of fibrosis was significantly slowed in patients treated for more than 6 months. Our results show the feasibility, safety, and efficacy of long-term antiviral therapy in nonresponder patients with a recurrent posttransplant hepatitis C virus infection.