valganciclovir and Adenoviridae-Infections

Little is known about adenovirus infections in adult organ transplant recipients. We prospectively assessed adenovirus infection in 263 transplant recipients using polymerase chain reaction (PCR) on plasma samples at regular intervals post-transplant. Adenovirus DNA was detected in 19 of 263 patients (7.2%). Viremia by transplant type was: liver (n = 10 of 121 [8.3%]), kidney (n = 6 of 92 [6.5%]) and heart (n = 3 of 45 [6.7%]). Time to viremia onset was within 10 days post-transplant (n = 4), on day 28 (n = 1), on day 100 (n = 7) and between months 6 and 12 (n = 7). At the time of viremia, 11 of 19 (58%) patients had no symptoms, 2 of 19 (10.5%) had gastrointestinal (GI) symptoms, 2 of 19 (10.5%) had respiratory symptoms and 4 patients (21%) had vague/non-specific symptoms. All patients recovered spontaneously. Only 1 of 19 (5%) patients had subsequent acute rejection. Adenovirus viremia is relatively common in adult liver, kidney and heart transplant recipients and most infections are asymptomatic, transient and self-limited. No serious clinical sequelae or effects on subsequent acute rejection were observed.

Topics: Adenoviridae; Adenoviridae Infections; Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; Cohort Studies; DNA Primers; DNA, Viral; Double-Blind Method; Female; Ganciclovir; Heart; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Liver; Liver Transplantation; Male; Middle Aged; Organ Transplantation; Polymerase Chain Reaction; Postoperative Complications; Prospective Studies; Time Factors; Valganciclovir

Adenovirus infections of immunocompromised patients can cause a severe multi-organ disease that often results in the patients' death. Presently, there are no drugs specifically approved to treat adenovirus infections, and clinicians resort to the off-label use of antivirals that are approved to treat other DNA virus infections, most frequently cidofovir (CDV). CDV, however, has considerable nephrotoxicity, thus it is recommended only for the most severe cases of adenovirus infections. To facilitate the development of effective, non-toxic antivirals against adenovirus, we have developed a permissive animal model based on the Syrian hamster that can be used to test the efficacy of antiviral compounds. Here, we show that in the hamster model, HAdV-C6 is a more useful challenge virus than the previously described HAdV-C5, because it is filtered out by tissue macrophages to a lesser extent. HAdV-C6 has a 10-fold lower LD50 in hamsters than HAdV-C5 and the pathology is caused by virus replication to a larger extent. We show that valganciclovir (VGCV), a drug that was shown to be active against intravenous HAdV-C5 infection previously, is efficacious against HAdV-C6 when administered either prophylactically or therapeutically. Further, we show for the first time that VGCV, and to a lesser extent CDV, can be used to treat respiratory adenovirus infections in the hamster model. These results extend the utility of the hamster model, and demonstrate the efficacy of two drugs available for clinicians to treat adenovirus infections.

Topics: A549 Cells; Adenoviridae Infections; Adenovirus Infections, Human; Adenoviruses, Human; Animals; Antiviral Agents; Cell Line; Cidofovir; Cricetinae; Cytosine; Disease Models, Animal; Ganciclovir; Humans; Immunosuppression Therapy; Liver; Male; Organophosphonates; Valganciclovir; Viral Load; Virus Replication

Adenovirus infections of immunocompetent adults are usually mild and resolve without serious sequelae. However, adenovirus infections of immunocompromised patients often develop into life-threatening multi-organ disease. Pediatric hematopoietic transplant patients are especially threatened, with high incidence of infection and high mortality rates. Presently, there is no drug specifically approved by the FDA to treat adenovirus infections; thus there is an urgent need to develop effective antivirals against the virus. Previously, we demonstrated that brincidofovir and valganciclovir were efficacious against lethal intravenous challenge with human type 5 adenovirus in the Syrian hamster model. Here, we tested the in vivo efficacy of the combination of these two drugs and showed that the combination of brincidofovir and valganciclovir is more efficacious than either drug alone, thus potentially allowing decreased patient exposure to the drugs while maintaining antiviral efficacy. As antiviral compounds often have toxic side effects, a decrease in dose or duration of therapy allowed by the combination could also improve tolerability.

Topics: Adenoviridae Infections; Adenoviruses, Human; Animals; Antiviral Agents; Cytosine; Disease Models, Animal; Drug Therapy, Combination; Ganciclovir; HEK293 Cells; Humans; Immunocompromised Host; Mesocricetus; Organophosphonates; Valganciclovir; Viral Load; Virus Replication

Adenovirus is commonly isolated from pediatric small bowel transplant recipients, but its clinical consequences remain poorly understood.. The medical records of pediatric small bowel transplant recipients transplanted between January 2003 and December 2007 were reviewed. Thymoglobulin and basiliximab induction and tacrolimus-based immunosuppression were the standard of care. Logistic regression analysis was performed to determine risk factors for infection, descriptive analysis to determine adenovirus incidence, and Kaplan-Meier curve analysis to determine the timing of events after transplantation.. Ninety-eight patients were included; 38 were positive for adenovirus (incidence 23.5%), 23 for viral shedding, 23 for infections. Nine infections developed in the first month after transplantation and 8 during the following 5 months. The small bowel was involved in 19 cases. Younger age at transplantation was a risk factor for adenovirus infection (odds ratio=0.81, 95% confidence interval, 0.663-0.994, P=0.04). Treatment of rejection did not increase the risk of adenovirus infection. Cytomegalovirus D+/R- sero-status was a protective factor (odds ratio=0.26, 95% confidence interval, 0.06-1.089, P=0.04).. Adenovirus infections affected 24% of recipients and developed mostly during the first 6 months after transplantation. Small bowel is the most frequently involved site. Younger age at transplantation is a risk factor for adenovirus infection; whereas cytomegalovirus D+/R- sero-status seems to be protective.

Topics: Adenoviridae Infections; Antibodies, Monoclonal; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Child; Ganciclovir; Humans; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Postoperative Complications; Recombinant Fusion Proteins; Reoperation; Retrospective Studies; Risk Factors; Tacrolimus; Valganciclovir; Virus Shedding