Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial.

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

A randomized, double-blind, pharmacokinetic study of oral maribavir with tacrolimus in stable renal transplant recipients.

Maribavir is being developed as a novel agent for the prevention or treatment of cytomegalovirus infections after stem cell and organ transplantation. This was a randomized, double-blind, placebo-controlled study designed to evaluate the potential pharmacokinetic interaction of concomitant administration of maribavir and tacrolimus. Twenty-five adult renal transplant recipients with stable renal function and stable dosing regimens of tacrolimus were randomized (20 maribavir 400 mg p.o. q12 h: 5 placebo). Tacrolimus whole blood concentration profiles were determined before and after 7 days of co-administration with maribavir. When co-administered with maribavir, tacrolimus mean C(max) increased 38%, tacrolimus trough concentrations (12 h post-dose) increased 57% and tacrolimus AUC((0-tau)) increased 51%. Apparent oral clearance of tacrolimus decreased 34% and T(max) was delayed by 0.5 h. There were no serious adverse events and no subject prematurely discontinued treatment. Because of the limited 7-day dosing course, the adverse event profile could not be adequately assessed. However, as seen with other maribavir studies, dysgeusia was common (90% of maribavir subjects and 20% of placebo subjects). In conclusion, co-administration of maribavir 400 mg twice daily increases exposure to tacrolimus. Routine therapeutic drug monitoring of tacrolimus blood concentrations should be included both at initiation and completion of maribavir treatment.

Enteroviral meningitis: natural history and outcome of pleconaril therapy.

Enteroviral meningitis causes appreciable morbidity in adults, including hospitalization, decreased activity, and headache. Limited data define the natural history of disease. No antiviral therapeutic agent has demonstrated improved outcome in controlled clinical trials. Pleconaril, an inhibitor of enterovirus replication, was tested in two placebo-controlled clinical trials. Of 607 randomized patients in a multicenter, double-blind placebo-controlled study of pleconaril (200 mg three times daily versus an identical-appearing placebo), 240 patients were confirmed to have enterovirus infection. The time to headache resolution was evaluated by using Kaplan-Meier survival methodology. A Cox regression model evaluated multivariate factors associated with disease resolution. Resolution of headache in patients with concomitant moderate to severe nausea at baseline occurred at a median of 9.5 days in the absence of therapy and was reduced to 7.0 days for pleconaril recipients (P = 0.009). For a headache score of > 5 alone, treated patients resolved headache significantly more rapidly (P = 0.005). Males resolved headache 50% faster than females. Regardless of randomization group, patients with a baseline headache score of 5 or greater resolved headache 50% more slowly than patients with a baseline headache score of 4. No differences in either clinical or laboratory adverse events were noted. Over 50% of untreated patients had a persistent headache that was greater than 1 week in duration. Pleconaril shortened the course of illness compared to placebo recipients, especially in the early disease course. However, the benefit was achieved only modestly in a subgroup analysis of patients with more severe disease after adjusting for confounding variables.

Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection.

The purpose of this investigation was to prospectively characterize acute hepatitis C virus (HCV) infections and to evaluate the hypothesis that the outcome is affected by identifiable clinical or viral factors. One hundred forty-two people with a history of illicit drug use who were HCV antibody-negative in 1988 were followed semiannually through 1996. HCV seroconversion (second generation enzyme immunoassay and recombinant immunoblot assay) was recognized in 43 (30%) of the participants, who were followed up for a median of 72 months. HCV RNA was detected and quantified by polymerase chain reaction in a median of 10 specimens per participant and showed two distinct patterns of viremia: viral clearance was noted in 6 (14%) of the participants, and viral persistence was observed in 37 (86%) of the participants. Subjects with viral clearance were more likely to be white (P =.004), have jaundice (P =.03), and have lower peak viral titer (P =.003). However, the outcome for a given person could not be predicted by clinical features, RNA level, or HCV subtype (as ascertained by analysis of core-E1 complementary DNA sequence). No acute infections were recognized by health care providers. At the time of seroconversion, HCV RNA was detectable in 81% of participants, and recombinant immunoblot assay (RIBA) was positive in 85% of participants. We conclude that approximately 85% of people with acute hepatitis C develop persistent viremia. However, acute infections are uncommonly recognized clinically, underscoring the importance of screening individuals at risk. Long-term follow-up, but no single laboratory test, is necessary to ascertain the outcome and in some cases make the diagnosis of acute HCV infection.

Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy.

We hypothesized that hepatitis C virus (HCV) persistence is related to the sequence variability of putative envelope genes. This hypothesis was tested by characterizing quasispecies in specimens collected every six months from a cohort of acutely HCV-infected subjects (mean duration of specimen collection, 72 months after seroconversion). We evaluated 5 individuals who spontaneously cleared viremia and 10 individuals with persistent viremia by cloning 33 1-kb amplicons that spanned E1 and the 5' half of E2, including hypervariable region 1 (HVR1). To assess the quasispecies complexity and to detect variants for sequencing, the first PCR-positive sample was examined by using a previously described method that combines heteroduplex analysis and analysis of single-stranded conformational polymorphisms. The ratio of nonsynonymous to synonymous substitutions (dN/dS) within each sample was evaluated as an indicator of relative selective pressure. Amino acid sequences were analyzed for signature patterns, glycosylation signals, and charge. Quasispecies complexity was higher and E1 dN/dS ratios (selective pressure) were lower in those with persistent viremia; the association with persistence was strengthened by the presence of a combination of both characteristics. In contrast, a trend toward higher HVR1 dN/dS ratios was detected among those with persistent viremia. We did not detect any such association for factors that may affect complexity such as serum HCV RNA concentration. HVR1 had a lower positive charge in subjects with persistent viremia, although no consistent motifs were detected. Our data suggest that HCV persistence is associated with a complex quasispecies and immune response to HVR1.

Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected mothers. Women and Infants Transmission Study.

Antepartum plasma hepatitis C virus (HCV) RNA was quantified in 155 mothers coinfected with HCV and human immunodeficiency virus type 1 (HIV-1), and HCV RNA was serially assessed in their infants. Of 155 singleton infants born to HCV antibody-positive mothers, 13 (8.4%) were HCV infected. The risk of HCV infection was 3.2-fold greater in HIV-1-infected infants compared with HIV-1-uninfected infants (17.1% of 41 vs. 5.4% of 112, P = .04). The median concentration of plasma HCV RNA was higher among the 13 mothers with HCV-infected infants (2.0 x 10(6) copies/mL) than among the 142 mothers with HCV-negative infants (3.5 x 10(5) copies/mL; P < .001), and there were no instances of HCV transmission from 40 mothers with HCV RNA concentrations of < 10(5) copies/mL. Women dually infected with HIV-1 and HCV but with little or no detectable HCV RNA should be reassured that the risk of perinatal transmission of HCV is exceedingly low.

Incidence and risk factors for hepatitis C among injection drug users in Baltimore, Maryland.

Between 1988 and 1996, the incidence of and risk factors for hepatitis C virus (HCV) infection were studied in a cohort of injection drug users in Baltimore, Maryland. By second-generation antibody testing of stored serum samples, 142 participants were found to be susceptible to HCV at the time they entered the study. After a median follow-up of 6.5 years, 43 participants (30.3%) developed antibodies to HCV (anti-HCV). The overall incidence was 6.4 cases per 100 person-years, but a substantial decline in the annual incidence rate was observed after the first 2 years (1988 to 1990, 13.4/100 person-years; 1991 to 1996, 2.3/100 person-years [P = 0.0001 for trend]). Participants who acknowledged active drug use, especially those who acknowledged frequent use and sharing of drug paraphernalia, were at increased risk of HCV infection. However, high-risk sexual practices were not associated with HCV seroconversion. Efforts to reduce HCV infection must be focused on curbing drug use and especially on the sharing of needles and drug paraphernalia.

Hepatitis A among homosexual men and injection drug users: more evidence for vaccination.

As agencies develop guidelines for administering the newly developed hepatitis A virus (HAV) vaccine, information is needed regarding the occurrence of HAV infection in groups putatively at risk for the infection. We tested serum samples from 300 injection drug users (IDUs), 300 homosexual males, and 300 blood donors for the presence of total antibody to HAV (anti-HAV). Anti-HAV was detected in 66% of IDUs, 32% of homosexual males, and 14% of blood donors. Anti-HAV was not significantly associated (P > .10) with high-risk drug-using behaviors but was more prevalent among IDUs with annual incomes of <$5,000 (P = .018). The occurrence of anti-HAV increased among homosexual males as the number of sexual partners increased (P < .001) but was similar to the age-adjusted prevalence (30.6%) estimated for the general United States population. IDUs are at increased risk for HAV infection; however, our data suggest that factors related to low socioeconomic status contribute more to the occurrence of HAV infection among IDUs than does injection drug use. IDUs and persons at risk for injection drug use should receive HAV vaccine.