valganciclovir and HIV-Infections

Viral infections in the fetus or newborn often involve the central nervous system (CNS) and can lead to significant morbidity and mortality. Substantial progress has been made in identifying interventions decreasing adverse neurodevelopmental outcomes in this population. This review highlights progress in treatment of important viruses affecting the CNS in these susceptible hosts, focusing on herpes simplex virus (HSV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and enteroviruses. The observation that high-dose acyclovir improves mortality in neonatal HSV disease culminated decades of antiviral research for this disease. More recently, prolonged oral acyclovir was found to improve neurologic morbidity after neonatal HSV encephalitis. Ganciclovir, and more recently its oral prodrug valganciclovir, is effective in improving hearing and neurodevelopment after congenital CMV infection. Increasing evidence suggests early control of perinatal HIV infection has implications for neurocognitive functioning into school age. Lastly, the antiviral pleconaril has been studied for nearly two decades for treating severe enteroviral infections, with newer data supporting a role for this drug in neonates. Identifying common mechanisms for pathogenesis of viral CNS disease during this critical period of brain development is an important research goal, highlighted by the recent emergence of Zika virus as a potential cause of fetal neurodevelopmental abnormalities.

Topics: Acyclovir; Antiviral Agents; Brain; Cognition; Cognition Disorders; Encephalitis, Herpes Simplex; Enterovirus Infections; Female; Ganciclovir; HIV Infections; Humans; Infant, Newborn; Nervous System Diseases; Oxadiazoles; Oxazoles; Pregnancy; Valganciclovir; Virus Diseases

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Topics: Acyclovir; Adenine; Amantadine; Antiviral Agents; Comorbidity; Drug Therapy, Combination; Foscarnet; Ganciclovir; Guanine; Hepatitis; Hepatitis B, Chronic; Hepatitis C; Herpesviridae Infections; HIV Infections; Humans; Influenza, Human; Interferons; Lamivudine; Nucleosides; Oligopeptides; Organophosphonates; Oseltamivir; Proline; Protease Inhibitors; Pyrimidinones; Ribavirin; Telbivudine; Thymidine; Valacyclovir; Valganciclovir; Valine; Virus Replication; Zanamivir

Cytomegalovirus (CMV) is a common pathogen affecting the gastrointestinal tract in patients with AIDS. We report a case of CMV-induced pseudotumor of the duodenum in a patient with AIDS and review other reported cases of CMV-induced pseudotumors in the gastrointestinal tract. CMV-induced pseudotumor in patients with AIDS is an exceptionally rare clinical entity, and to our knowledge no reports have previously summarized this clinical entity.. All previous cases included in our literature review were found using a PubMed search (1980-November 2008) of the English-language medical literature applying the terms 'CMV infection', 'inflammatory mass', 'pseudotumor', and 'gastrointestinal tract'. The references cited in these articles were examined to identify additional reports.. Although CMV-induced duodenitis has been described in patients with HIV infection, to our knowledge CMV-induced pseudotumor of the duodenum has not been previously reported in the literature. We describe the first case of an AIDS patient with CMV pseudotumor responding to oral treatment with valganciclovir with complete resolution of the CMV mass. Among reports of non-duodenal pseudotumor reported in the English literature, we found only 14 cases of CMV-induced gastrointestinal pseudotumors in HIV-positive patients. The clinical manifestations, pathologic findings of the CMV pseudotumors, as well as the treatment and outcome of these HIV patients are reviewed.. CMV pseudotumor should be included in the differential diagnosis of gastrointestinal mass lesions in AIDS patients and in other immunocompromised patients. The tumor often responds to antiviral therapy, but resolution of a CMV mass as a result of oral antiviral therapy has not been previously described. Since pseudotumors secondary to CMV often respond to medical treatment, it is important that the physicians treating severely immunocompromised patients are aware of this entity.

Topics: AIDS-Related Opportunistic Infections; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Duodenal Diseases; Ganciclovir; HIV; HIV Infections; Humans; Male; Middle Aged; Valganciclovir

In this review we will discuss the recent findings in HIV-associated multicentric Castleman disease. On the basis of current knowledge on pathophysiology, we will illustrate different therapeutic approaches and try to provide guidelines at least for the initial care of the disease.. On the basis of pathological and virological data, pathophysiology appears to conjugate both proliferation of human herpesvirus (HHV-8) infected plasmablasts and replication of HHV-8. Therefore, recent therapies have targeted the infected cells using chemotherapy or rituximab, an anti-CD20 monoclonal antibody or both, and the virus replication by using valganciclovir, a potent antiviral drug usually used against cytomegalovirus.. Etoposide is the most effective first-line therapy for active multicentric Castleman disease. Rituximab can be used after an initial control of the attack and provides a 1-yearremission rate above 70%. Exacerbation of Kaposi sarcoma lesions, observed in half of the patients with previous Kaposi sarcoma lesions, may represent a limitation.Valganciclovir effectively suppresses HHV-8 replication both in vitro and in vivo, and reduction in HHV-8 viremia associated with clinical improvement has been suggested in short series of patients with multicentric Castleman disease treated with valganciclovir.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Asparaginase; Castleman Disease; Clinical Trials as Topic; Cytarabine; Daunorubicin; Etoposide; Ganciclovir; Herpesviridae Infections; Herpesvirus 8, Human; HIV Infections; Humans; Lymph Nodes; Rituximab; Thioguanine; Valganciclovir; Virus Replication

The present review summarizes recent developments in pathogenesis, prevention, and management of ganciclovir-resistant cytomegalovirus infection.. Basic science advances include reports of new resistance mutations and multidrug resistance. Innovative studies of the host immune response have shed light on differential risk. New laboratory techniques include rapid assays for resistance and measurement of ganciclovir levels. Clinical developments include studies on ganciclovir-resistant cytomegalovirus infection in thoracic transplant recipients and aspects of cytomegalovirus infection prevention. Although no resistance was seen in the valganciclovir arm of a prophylaxis trial, resistance has been described after both prophylactic and preemptive valganciclovir therapy. In the HIV realm, the incidence of ganciclovir-resistant cytomegalovirus infection has fallen dramatically. Newer options for therapy include maribavir, leflunomide, high-dose ganciclovir, switching to a sirolimus-based regimen, and the antimalarial drug, artesunate.. Antiviral-resistant cytomegalovirus infection remains a feared complication of transplantation but is less frequently seen in AIDS patients in the current era. New research on resistance mutations and pathogenesis has enhanced clinical understanding of risk. Although preemptive strategies and valganciclovir prophylaxis are associated with less resistance than oral ganciclovir, resistant cytomegalovirus infection has not been eliminated. Several strategies and newer drugs hold promise for the future.

Topics: Antiviral Agents; Chemoprevention; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; HIV Infections; Humans; Transplantation; Valganciclovir

To review the pharmacology, pharmacokinetics, and preliminary clinical data for valganciclovir, a new oral agent for the therapy of cytomegalovirus (CMV) retinitis.. Relevant literature was extracted via MEDLINE/PUBMED and searchable abstracts from infectious diseases conferences covering the period from January 1990 to April 2002. Tertiary references provided background information.. Current standard treatment for CMV retinitis consists of intravenous therapy, intraocular implant, and intraocular injection. The low bioavailability of oral ganciclovir restricts its use to prophylaxis and maintenance treatment. Oral valganciclovir, recently approved for both induction and maintenance therapy of CMV retinitis, may fill a niche for this disease.. Although only 1 clinical study has been published for valganciclovir, its favorable pharmacokinetic profile, encouraging preliminary efficacy data, ease of administration, and lack of potential catheter-related complications make it a favorable option for the treatment of CMV retinitis in HIV-positive patients.

Topics: Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus Retinitis; Drug Interactions; Drug Labeling; Ganciclovir; HIV Infections; Humans; Valganciclovir

High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS.. Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia.. 40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission.. Although mortality attributable to KS was lower in the EG the difference was not statistically significant.

Topics: Anemia; Antiretroviral Therapy, Highly Active; Herpesvirus 8, Human; HIV Infections; Humans; Sarcoma, Kaposi; Valganciclovir

Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35-40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia.. This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM.. Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies.. ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.

Topics: Child; Clinical Trials, Phase II as Topic; Cytomegalovirus; Cytomegalovirus Infections; HIV Infections; Humans; Infant; Multicenter Studies as Topic; Pneumonia; Randomized Controlled Trials as Topic; Treatment Outcome; Tuberculosis; Valganciclovir

Immunodiscordant HIV-infected patients show viral suppression during antiretroviral therapy but fail to recover CD4 T cells. Immunodiscordance is characterized by partial CD4 T-cell immunodeficiency and increased inflammation, activation and immunosenescence in both CD4 and CD8 T cells.. A randomized, controlled, 48-week intensification study to assess the effect of raltegravir on immunological parameters in immunodiscordant patients (CD4 cell counts <350 cells/μl; viral load <50 copies/ml for >2 years). Patients were randomized (2 : 1) to intensify therapy with raltegravir (intensified arm, n = 30) or continue with the same therapy (control arm, n = 14).. Both groups showed similar immunological baseline characteristics. CD4 T-cell counts increased faster in the intensified arm (P = 0.01, week 12). However, no differences between groups were observed at week 48. Additionally, no changes in thymic output (CD45RA(+)CD31(+) cells), activation (HLA-DR(+)CD95(+) cells) or ex-vivo cell death were observed in CD4 T cells at any time point intergroups or intragroups. Conversely, intensified arm showed significant decreases in the expression of the CD8 T-cell activation marker CD38 at weeks 24-48, which were more evident in memory cells. Despite this, the levels of HLA-DR expression in CD8 T cells and plasma soluble CD14 remained stable in both arms overtime.. Long-term (48-week) raltegravir intensification failed to counterbalance CD4 T-cell deficiency and its associated features: hyperactivation and death of CD4 T cells. However, raltegravir induced a specific reduction of CD38 expression in CD8 T cells, suggesting a beneficial effect on CD8 T-cell hyperactivation, which has been linked with HIV-associated comorbidities.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Flow Cytometry; Ganciclovir; HIV Infections; Humans; Hydroxychloroquine; Inflammation; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Valganciclovir; Viral Load

Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.

Topics: Adult; Anti-HIV Agents; Castleman Disease; Drug Therapy, Combination; Female; Ganciclovir; Herpesviridae Infections; Herpesvirus 8, Human; HIV Infections; Humans; Male; Middle Aged; Pilot Projects; Prodrugs; Protein Kinase Inhibitors; Protein Kinases; Survival Analysis; Valganciclovir; Viral Load; Viral Proteins; Virus Activation; Zidovudine

Elevated immune activation persists during treated human immunodeficiency virus (HIV) infection and is associated with blunted CD4 recovery and premature mortality, but its causes remain incompletely characterized. We hypothesized that asymptomatic cytomegalovirus (CMV) replication might contribute to immune activation in this setting.. Thirty antiretroviral therapy-treated HIV-infected CMV-seropositive participants with CD4 counts <350 cells/mm(3) were randomized to receive valganciclovir 900 mg daily or placebo for 8 weeks, followed by an additional 4-week observation period. The primary outcome was the week 8 change in percentage of activated (CD38(+) HLA-DR(+)) CD8(+) T cells.. Fourteen participants were randomized to valganciclovir and 16 to placebo. Most participants (21 [70%] of 30) had plasma HIV RNA levels <75 copies/mL. The median CD4 count was 190 (IQR: 134-232) cells/mm(3), and 12 (40%) of 30 had detectable CMV DNA in saliva, plasma, or semen at baseline. CMV DNA continued to be detectable at weeks 4-12 in 7 (44%) of 16 placebo-treated participants, but in none of the valganciclovir-treated participants (P = .007). Valganciclovir-treated participants had significantly greater reductions in CD8 activation at weeks 8 (P = .03) and 12 (P = .02) than did placebo-treated participants. These trends were significant even among those with undetectable plasma HIV RNA levels.. CMV (and/or other herpesvirus) replication is a significant cause of immune activation in HIV-infected individuals with incomplete antiretroviral therapy-mediated CD4(+) T cell recovery.. NCT00264290.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Ganciclovir; HIV Infections; Humans; Lymphocyte Activation; Saliva; Semen; Valganciclovir; Virus Replication

Human herpesvirus-8 (HHV-8) replication is critical in the induction and maintenance of Kaposi sarcoma, primary effusion lymphoma, and some cases of Castleman disease. In vitro and observational studies suggest that ganciclovir inhibits HHV-8 replication, but no randomized clinical trials have been conducted.. A total of 26 men infected with HHV-8 were randomized to receive 8 weeks of valganciclovir administered orally (900 mg once per day) or 8 weeks of placebo administered orally. After a 2-week washout period, participants in each group received the study drug they had not yet taken (either valganciclovir or placebo), for 8 additional weeks. Oral swab samples were collected daily during the study, and HHV-8 and CMV DNA were quantified by real-time PCR.. A total of 16 human immunodeficiency virus (HIV)-positive men and 10 HIV-negative men enrolled in and completed the study. Of the 3,439 swab samples that participants had been expected to provide, 3029 (88%) were available for analysis. HHV-8 was detected on 44% of swabs collected from participants who were receiving placebo, compared with 23% of swabs collected from participants who were receiving valganciclovir (relative risk [RR], 0.54 [95% confidence interval {CI}, 0.33-0.90]; P = .02). Valganciclovir reduced oropharyngeal shedding of cytomegalovirus by 80% (RR, 0.20 [95% CI, 0.08-0.48]; P < .001). Shedding of HHV-8 and shedding of cytomegalovirus were independent. Hematologic, renal, or hepatic toxicities were no more common among participants who received the active drug, compared with those who received placebo, though participants who received valganciclovir reported more days of diarrhea.. Valganciclovir administered orally once per day is well tolerated and significantly reduces the frequency and quantity of HHV-8 replication.

Topics: Adult; Aged; Antiviral Agents; Cross-Over Studies; Double-Blind Method; Ganciclovir; Herpesvirus 8, Human; HIV Infections; Humans; Male; Middle Aged; Oropharynx; Patient Compliance; Sarcoma, Kaposi; Valganciclovir; Virus Replication; Virus Shedding

Valganciclovir, an oral prodrug of the anti-cytomegalovirus (CMV) agent ganciclovir, was evaluated in a single-arm open-label safety study. AIDS patients (median CD4 lymphocyte count of 140 cells/microL) with treated CMV retinitis (N = 212) received 900-mg once-daily valganciclovir maintenance therapy with courses of 900-mg twice-daily valganciclovir induction therapy as needed to treat progression. After a median treatment duration of 372 days, the adverse event profile was similar to that reported for intravenous (IV) and oral ganciclovir. Adverse event rates of note were diarrhea (35%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/microL) (10%), and anemia (hemoglobin <8.0 g/dL) (12%). Consistent with prior treatment studies of oral ganciclovir, IV catheter-related adverse events were uncommon (6%) and lower than previously reported for IV ganciclovir. The mortality rate was 0.072 deaths per patient-year. Progression of CMV retinitis occurred in 17% of patients during the study treatment period, usually in association with a low CD4 cell count. Other than a higher than expected frequency of oral candidiasis (17%), no clinical toxicities or laboratory abnormalities occurred during treatment with valganciclovir that have not been observed during treatment with ganciclovir.

Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Antiviral Agents; Candidiasis, Oral; CD4 Lymphocyte Count; Cytomegalovirus Retinitis; Drug Tolerance; Female; Ganciclovir; HIV Infections; Humans; Male; Middle Aged; Prodrugs; Safety; Valganciclovir

Valganciclovir is the oral prodrug of ganciclovir. The pharmacokinetics of valganciclovir in patients with renal impairment is not known. Furthermore, it is not known whether there are any pharmacokinetic differences between patients who are positive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) and healthy subjects.. A total of 44 patients were included-18 with mild, medium, or severe renal impairment; 6 with end-stage renal disease who were on long-term hemodialysis; 8 HIV/CMV-positive patients with normal renal function; and 12 healthy subjects serving as controls. Valganciclovir and ganciclovir serum concentrations were measured after oral administration of 900 mg of valganciclovir. Pharmacokinetic parameters were estimated by means of noncompartmental and compartmental methods.. After oral administration of the prodrug valganciclovir, ganciclovir bioavailability was 60% and ganciclovir concentrations were higher (maximum concentration [C(max)], 8.5 microg/mL versus 5.8 microg/mL) and appeared later (time to maximum concentration [T(max)], 4.3 versus 2.0 hours) in patients with severe renal impairment compared with healthy subjects. The elimination half-life (t(1/2)) of ganciclovir was longer in patients with renal failure (t(1/2) of 68.1 hours in patients with end-stage renal disease compared with 3.5 hours in healthy subjects). Ganciclovir clearance was correlated with creatinine clearance (r = 0.975). Hemodialysis removed 50% of ganciclovir. We observed no differences in pharmacokinetics between HIV/CMV-positive patients and healthy subjects. A 2-compartment model with zero-order input and first-order elimination proved to be the most appropriate model for ganciclovir after oral administration of valganciclovir.. The dosage of valganciclovir has to be adjusted to the degree of renal impairment. Dosage adjustment is not necessary for HIV/CMV-positive patients.

Topics: Administration, Oral; Adult; Aged; AIDS-Related Opportunistic Infections; Antiviral Agents; Biological Availability; Cytomegalovirus Infections; Drug Administration Schedule; Female; Ganciclovir; HIV Infections; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prodrugs; Renal Dialysis; Valganciclovir

We developed a mathematical simulation model to anticipate outcomes from an upcoming trial of targeted, preemptive cytomegalovirus (CMV) therapy in high-risk, human immunodeficiency virus (HIV)-infected patients identified by means of CMV polymerase chain reaction screening. We estimated the costs and consequences of CMV prophylaxis in patients with CD4(+) counts < or =100 cells/microL under various assumptions regarding disease progression, complication rates, drug effects, and costs. Without CMV preemptive therapy, lifetime costs average $44,600 with expected duration of survival of 19.16 quality-adjusted life-months and 213 CMV cases per 1000 patients. Targeted preemptive therapy with orally administered valganciclovir increases costs and duration of survival to $46,900 and 19.63 quality-adjusted life-months, respectively. CMV cases decrease to 174 per 1000 patients. The cost per quality-adjusted life-year gained is $59,000. This result compares favorably with other strategies in end-stage HIV disease but hinges on valganciclovir cost and efficacy assumptions and the absence of minimally effective salvage antiretroviral therapy for HIV. The upcoming trial should resolve the clinical uncertainty surrounding some of these assumptions.

Topics: AIDS-Related Opportunistic Infections; Antiviral Agents; Chemoprevention; Cost-Benefit Analysis; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; HIV Infections; Humans; Models, Biological; Polymerase Chain Reaction; Predictive Value of Tests; Quality-Adjusted Life Years; Sensitivity and Specificity; Valganciclovir

To study clinical efficacy of valganciclovir in cytomegalovirus retinitis (CMVR) in human immunodeficiency virus (HIV)-positive-positive patients in a tertiary care clinic in a developing nation.. In a retrospective study, systemic and ocular records of HIV patients suffering from CMVR and treated with valganciclovir, were analyzed. Primary outcome measures were involvement of the other eye, incidence of retinal detachment, systemic involvement, and mortality encountered. Secondary outcome measures included change in BCVA.. Out of nine patients who were included, two patients developed CMVR in the other eye and only one patient (11.11%) developed retinal detachment during the course of the study. No patient developed any systemic manifestations or had mortality during the course of the study. The change in BCVA was not statistically significant.. Use of oral valganciclovir showed good outcome and was found to be a better alternative compared to the use of intravitreal ganciclovir in the literature. Introduction of valganciclovir at an affordable price in developing nations can decrease disease burden.

Topics: Antiviral Agents; Cytomegalovirus Retinitis; HIV; HIV Infections; HIV Seropositivity; Humans; India; Retinal Detachment; Retrospective Studies; Tertiary Care Centers; Valganciclovir

Topics: Castleman Disease; HIV Infections; Humans; Lymph Nodes; Valganciclovir

Topics: Adult; Anti-HIV Agents; Antibodies, Monoclonal, Humanized; Castleman Disease; Female; Herpesviridae Infections; Herpesvirus 8, Human; HIV Infections; Humans; Interleukin-10; Interleukin-1beta; Male; Middle Aged; Sarcoma, Kaposi; Treatment Outcome; Valganciclovir; Viral Load; Zidovudine

Topics: Castleman Disease; Herpesvirus 8, Human; HIV Infections; Humans; Sarcoma, Kaposi; Valganciclovir

We present the case of a 28-year-old man with recently-diagnosed human immunodeficiency virus and hepatitis C virus infection. He developed obstructive cholangiopathy secondary to cytomegalovirus and Kaposi sarcoma, both diagnosed by endoscopic retrograde cholangiopancreatography and biopsies. He received antiretroviral therapy, chemotherapy and valganciclovir with full recovery.

Topics: Abdominal Pain; Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Bile Duct Diseases; Biopsy; Cholangiopancreatography, Endoscopic Retrograde; Cytomegalovirus; Diarrhea; Fever; Hepatitis C; HIV Infections; Humans; Male; Sarcoma, Kaposi; Valganciclovir; Weight Loss

Topics: Acitretin; Antiviral Agents; Ganciclovir; HIV Infections; Humans; Keratolytic Agents; Male; Middle Aged; Polyomavirus; Polyomavirus Infections; Skin Diseases, Papulosquamous; Treatment Outcome; Valganciclovir

Human herpesvirus-8 (HHV-8)-positive, HIV-negative multicentric Castleman's disease is a rare lymphoproliferative disorder with no standardized treatment. Concurrent Kaposi's sarcoma, another HHV-8-related disease, is uncommon in HIV-negative patients. The role of antiviral therapy and rituximab in HIV-negative patients is not well established.. We report a case of a 5-year, durable remission of HHV-8-positive, HIV-negative comorbid multicentric Castleman's disease and Kaposi's sarcoma treated with long-term valganciclovir, following initial rituximab and liposomal doxorubicin.. Currently, there is no defined role for antiviral therapy in the treatment of HIV-negative HHV-8-positive multicentric Castleman's disease and Kaposi's sarcoma. Ganciclovir followed by indefinite, continuous valganciclovir is thought to have contributed significantly to the durable response in this case.

Topics: Antineoplastic Agents; Antiviral Agents; Castleman Disease; Doxorubicin; Ganciclovir; Herpesviridae Infections; HIV Infections; Humans; Male; Middle Aged; Polyethylene Glycols; Rituximab; Sarcoma, Kaposi; Valganciclovir

Topics: Adult; Antiviral Agents; Blood; Brain; CD4 Lymphocyte Count; Encephalitis, Viral; Ganciclovir; Herpesvirus 6, Human; HIV Infections; HIV-1; Humans; Magnetic Resonance Imaging; Male; Radiography; Roseolovirus Infections; Treatment Outcome; Valganciclovir; Viral Load

To evaluate clinical features and long-term visual outcome of cytomegalovirus (CMV) retinitis in patients without human immunodeficiency virus (HIV) infection, and to determine factors that predict visual outcome.. Retrospective cohort study.. Consecutive patients with CMV retinitis without HIV infection were reviewed. Main outcome measures included clinical features, proportion of eyes with 6-month and final visual acuity (VA) <20/70 and <20/400, and odds ratios of factors associated with poor visual outcome.. A total of 20 eyes from 13 patients were included with a median follow-up time of 17 months. All had at least 6 months of follow-up except 1 patient who died from sepsis at 1 month. At presentation, 50% of eyes had VA <20/70 and 25% had VA <20/400. Zone 1 involvement occurred in 55% and vitreous haze ≥grade 2+ occurred in 25%. Recurrence occurred in 33.3% at a mean time of 6.4 ± 3.3 weeks after discontinuation of anti-CMV therapy. The retinal detachment rate was 21.7% per eye-year and mortality rate was 11.7% per person-year. At final visit, 60% had VA <20/70 and 35% had VA <20/400. Macular involvement was significantly associated with poor final VA <20/400 (odds ratio = 25.00, P = .016).. CMV retinitis without HIV infection was often aggressive at presentation. Significant intraocular inflammation was not uncommon. The long-term visual outcome was poor, especially in those with macular involvement.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Cohort Studies; Cytomegalovirus Retinitis; Female; Follow-Up Studies; Ganciclovir; HIV Infections; Humans; Immunocompromised Host; Male; Middle Aged; Prognosis; Recurrence; Retinal Detachment; Retrospective Studies; Valganciclovir; Vision Disorders; Visual Acuity

A number of studies have demonstrated that cytomegalovirus (CMV) viraemia is a strong predictor for CMV end-organ disease (EOD) and death in HIV-infected patients. We assess the efficacy and safety of pre-emptive anti-CMV therapy (PACT) for preventing these events. We performed a retrospective study of all HIV-infected patients seen in our institution who had detectable CMV viraemia in 2007. Seventy-one patients with advanced HIV disease (median CD4 cell count = 61 cells/mm(3)) were studied. Sixteen patients received PACT (mainly valganciclovir). Patients who received PACT had lower CD4 cell counts and higher blood CMV DNA levels. The cumulative incidence of CMV EOD and death at one year was 44% and 21% in patients with and without PACT, respectively (p = 0.013). Both PACT and high blood CMV DNA levels were significantly associated with CMV EOD and death in unadjusted analysis. In adjusted analyses, only blood CMV DNA levels remained significantly associated with the risk of CMV EOD and death, whereas PACT was associated with a non-significant trend towards reduced CMV EOD or death (hazard ratio: 0.25, p = 0.13). Five patients with PACT experienced severe drug-related adverse events. In conclusion, the use of PACT in HIV-infected patients with CMV viraemia could improve outcome but is associated with significant toxicity.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Ganciclovir; HIV Infections; Humans; Immunocompromised Host; Incidence; Male; Middle Aged; Polymerase Chain Reaction; Retrospective Studies; Treatment Outcome; Valganciclovir; Viral Load; Viremia

A 54-year-old man presented with a 6-week history of chronic diarrhea and weight loss of 11 kg after returning from a holiday in Thailand. The patient had a 9-year history of an untreated HIV infection. Despite treatment of a culture-proven Shigella enteritis and strongyloidiasis the symptoms persisted. Finally, cytomegalovirus (CMV) colitis was diagnosed by colonoscopy. The patient recovered completely after starting antiretroviral and valganciclovir treatment. An additional opportunistic infection with multiresistant pulmonary tuberculosis was diagnosed.

Topics: Anti-Retroviral Agents; Chronic Disease; Colitis; Cytomegalovirus Infections; Diarrhea; Ganciclovir; HIV Infections; Humans; Male; Middle Aged; Thinness; Treatment Outcome; Valganciclovir; Weight Loss

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anus Diseases; Biopsy; Cytomegalovirus Infections; Ganciclovir; HIV Infections; Humans; Immunocompromised Host; Male; Middle Aged; Treatment Outcome; Ulcer; Valganciclovir

The HIV RNA viral load (VL) in vaginal secretions and semen is an independent predictor of HIV transmission. Blood VL is associated with semen VL, and local mucosal factors, such as semen cytomegalovirus (CMV) reactivation, may play an important role.. Twenty-one HIV-CMV-coinfected, antiretroviral-naive men received 900 mg of oral valganciclovir once daily for 2 weeks in an open-label study. Blood and semen were collected at baseline, after 2 weeks of valganciclovir, and 2 months after therapy completion. The primary end point was change in semen HIV levels at 2 weeks, and the secondary end points were change in semen HIV VL at 2 months and change in semen CMV levels.. The HIV VLs fell significantly at 2 weeks in semen (median 3.44-3.02 log10 copies/mL, P = 0.02) and blood (median 3.61-3.10 log10 copies/mL, P < 0.01) and returned to baseline after therapy completion (median 3.24 and 3.71 log10 copies/mL in semen and blood, respectively). Semen CMV levels also fell on treatment (median 2.13-1.62 log10 copies/mL, P < 0.01) and continued to fall after therapy completion (median 0.91 log10 copies/mL at week 8, P < 0.001 vs. baseline). The reduced semen CMV VL was associated with decreased semen T-cell activation and enhanced CMV-specific T-cell responses in blood; changes in the semen HIV VL were not associated with immune parameters.. Although valganciclovir therapy was associated with reduced HIV and semen CMV levels, these results suggest that the reduced HIV VL was a direct drug effect rather than a CMV antiviral effect or CMV-associated immune alterations.

Topics: Administration, Oral; Adult; Antiviral Agents; Blood; Coinfection; Cytomegalovirus Infections; Ganciclovir; HIV Infections; Humans; Male; Middle Aged; Semen; Valganciclovir; Viral Load; Young Adult

Epstein-Barr virus (EBV) is a common infection which usually produces mild or no symptoms in immunocompetent individuals. In human immunodeficiency virus (HIV) associated immunosuppression it is most commonly associated with malignancy which usually occurs at very low CD4+ cell counts. We describe a newly diagnosed HIV-positive patient who presented with headaches and cerebellar signs. She was incorrectly diagnosed with cerebral tuberculosis (TB) infection based on the histology report from a cerebellar biopsy specimen. After extensive investigation including cerebrospinal fluid sampling and reanalysis of the brain biopsy specimens she was found to have EBV-associated cerebral vasculitis and encephalitis and was successfully treated with valganciclovir and steroids. Whilst there are a few reports of EBV-associated encephalitis, cerebral vasculitis secondary to EBV in the context of HIV infection has not previously been described in the literature.

Topics: Adult; Anti-Inflammatory Agents; Antiviral Agents; Encephalitis, Viral; Epstein-Barr Virus Infections; Female; Ganciclovir; HIV Infections; Humans; Steroids; Treatment Outcome; Valganciclovir; Vasculitis, Central Nervous System

Our case illustrates the difficulties involved in diagnosing multicentric Castleman's disease (MCD) in a human immunodeficiency virus-infected man with febrile episodes and malaise. In the absence of well-established treatment protocols, we have chosen a new treatment algorithm with rituximab, etoposide, and valganciclovir, which led to the remission of clinical symptoms. Yet, we advocate focused exploration for MCD in immunosuppressed patients with unclear febrile episodes, as recent advances in treatment are promising.

Topics: Algorithms; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Phytogenic; Antiviral Agents; Castleman Disease; Drug Therapy, Combination; Etoposide; Ganciclovir; HIV Infections; Humans; Immunologic Factors; Male; Middle Aged; Rituximab; Seizures, Febrile; Treatment Outcome; Valganciclovir

To describe a case of significant CD4+ cell decline despite complete viral suppression in an HIV-positive patient receiving didanosine and valganciclovir.. A 68-year-old woman diagnosed with HIV and cytomegalovirus (CMV) enteritis (CD4+ cell count 22 cells/mm(3), viral load 88,898 [4.95 log] copies/mL) was treated with valganciclovir and began lamivudine, didanosine, and lopinavir/ritonavir. Three months later, her viral load was less than 50 copies/mL and CD4+ cell count was 317 cells/mm(3). Over the next 9 months, her viral load remained suppressed, but the CD4+ cell count declined to 83 cells/mm(3) and she experienced ongoing symptoms of didanosine toxicity. Didanosine was replaced with abacavir, leading to a complete CD4+ cell recovery and resolution of symptoms.. Paradoxical declines in CD4+ cell counts have been reported in HIV-infected patients virally suppressed on tenofovir/didanosine regimens, presumably via inhibition of purine nucleoside phosphorylase (PNP) by tenofovir and enhancement of didanosine toxicity. Ganciclovir and its prodrug valganciclovir also inhibit PNP and increase didanosine concentrations; thus, a similar immunological effect with this combination is possible. This hypothesis is consistent with observations from a historic multicenter CMV retinitis study, where a negative CD4+ cell response was observed in patients receiving ganciclovir, while those treated with foscarnet experienced a CD4+ cell increase and a mortality advantage. Of the subjects who received any type of nucleoside therapy during this study, didanosine use was proportionally higher in the ganciclovir arm versus the foscarnet arm. According to the Naranjo probability scale, our patient experienced a probable adverse reaction associated with the combination of didanosine and valganciclovir.. Patients receiving didanosine-containing highly active antiretroviral therapy and ganciclovir or valganciclovir for treatment of CMV infection should be monitored for didanosine toxicity and unexpected CD4+ cell loss or failure of CD4+ cell recovery. Reduction of didanosine dosage or substitution with an alternative antiretroviral may be necessary.

Topics: Aged; Antiviral Agents; CD4 Lymphocyte Count; Cytomegalovirus Infections; Didanosine; Drug Interactions; Female; Ganciclovir; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Valganciclovir

Topics: Administration, Oral; Antiviral Agents; Castleman Disease; Ganciclovir; Herpesviridae Infections; Herpesvirus 8, Human; HIV Infections; Humans; Male; Middle Aged; Valganciclovir

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Enfuvirtide; Ganciclovir; Hepatitis B; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Organophosphorus Compounds; Peptide Fragments; Tenofovir; Valganciclovir

Topics: Antiviral Agents; Cytomegalovirus Retinitis; Drug Costs; Drug Interactions; Ganciclovir; HIV Infections; Humans; Valganciclovir