valganciclovir and Inflammation

The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository.

Topics: Administration, Oral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Inflammation; Infusions, Parenteral; Tissue Transplantation; Transplant Recipients; Treatment Outcome; Valganciclovir; Viral Load

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

Treatment failure or relapse is common in solid organ transplant recipients treated for cytomegalovirus (CMV) disease. Because CMV infections induce a vigorous inflammatory response, we investigated whether pretreatment levels of inflammatory markers were associated with virologic and clinical outcomes.. Solid organ transplant recipients enrolled in an international multicenter trial of CMV disease treatment (the VICTOR study) were studied (n=248). Plasma levels of markers of inflammation and endothelial cell activation were assessed at baseline and during follow-up by enzyme immunoassays.. Baseline values for the chemokine CXCL16 was an independent predictor of clinical outcome (P=0.003) and was a weak independent predictor of suppression of viral load below level of detection (LOD) (P=0.013) at day 21 after initiation of treatment. Baseline levels of the long pentraxin 3 (PTX3) was an independent predictor of suppression of viral load below LOD at day 21 (P=0.002), whereas baseline levels of von Willebrand factor (vWF) was an independent predictor of clinical outcome at day 21 (P=0.008), and vWF levels at day 21 was a weak independent inflammatory predictor of viral recurrence (P=0.018).. The present study shows that the plasma levels of CXCL16, PTX3 and vWF at the start of treatment are independently associated with virologic and clinical treatment failure during anti-CMV therapy in solid organ transplant recipients. These findings suggest a link between CMV infection and inflammation that also may influence the outcome of anti-CMV therapy.

Topics: Antiviral Agents; Biomarkers; C-Reactive Protein; Chemokine CXCL16; Chemokines, CXC; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Humans; Inflammation; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Outcome Assessment, Health Care; Postoperative Complications; Predictive Value of Tests; Receptors, Scavenger; Serum Amyloid P-Component; Transplantation; Treatment Outcome; Valganciclovir; von Willebrand Factor

Cytomegalovirus (CMV) is an immunomodulatory virus that indirectly increases the risk for bacterial, fungal, and viral infections. However, the pathogenesis of this phenomenon is poorly understood. We determined whether inflammatory responses to different Toll-like receptor (TLR) ligands are blunted during CMV infection in solid-organ transplant (SOT) patients. Peripheral blood mononuclear cells from 38 SOT patients with and without CMV were incubated in the presence of various viral, fungal, and bacterial TLR ligands. Cytokines were measured in the supernatant by multiplex enzyme-linked immunosorbent assay. Patients had blunted cytokine responses to bacterial, fungal, and viral ligands during CMV infection when compared to the absence of CMV infection. This was independent of viral load, clinical presentation of CMV infection or immunosuppression, supporting the clinical observation in SOT recipients that CMV infection increases susceptibility to bacterial, fungal, and other viral infections. Moreover, in the absence of CMV infection, patients with subsequent CMV infection had lower cytokines in response to TLR ligands compared to those without subsequent CMV infection, suggesting that inherent differences in patients not directly related to CMV also contribute to this increased susceptibility. In summary, these data provide novel ex vivo evidence to support indirect effects of CMV.

Topics: Adult; Antiviral Agents; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Humans; Immunosuppression Therapy; Inflammation; Leukocytes, Mononuclear; Ligands; Male; Middle Aged; Organ Transplantation; Pilot Projects; Postoperative Complications; Prospective Studies; Toll-Like Receptors; Transplant Recipients; Transplantation; Valganciclovir; Viral Load

Topics: Antibodies, Monoclonal; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Glomerulonephritis, IGA; HIV Seronegativity; Humans; Immunosuppression Therapy; Inflammation; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Renal Dialysis; Renal Insufficiency; Sinusitis; Tacrolimus; Valganciclovir

Colectomy with ileoanal pouch formation is usually contraindicated in patients with Crohn's disease (CD) due to the risk of recurrent disease and pouch failure. We report the case of a patient, initially thought to have ulcerative colitis (UC), who underwent such surgery but subsequently developed perianal CD. She presented with diarrhoea and weight loss. Inflammatory markers were raised. Pouchoscopy revealed deep ulcers within the pouch. The main differential diagnoses were idiopathic pouchitis and recurrent CD. However, immunohistochemical staining demonstrated positivity for cytomegalovirus (CMV). Stool frequency, C reactive protein and albumin normalised within 48 h of starting oral valgancyclovir. At 15 weeks, pouch appearances were improved, no histological evidence of CMV was found and baseline pouch function had returned. This case highlights that CD can present many years after surgery for apparent UC. Also, CMV pouchitis should be considered as a differential cause of pouchitis especially as it is treatable with antiviral therapy.

Topics: Adult; Anal Canal; Anastomosis, Surgical; Antiviral Agents; Chronic Disease; Colectomy; Colitis, Ulcerative; Colonic Pouches; Crohn Disease; Cytomegalovirus; Cytomegalovirus Infections; Diarrhea; Endoscopy; Female; Ganciclovir; Humans; Inflammation; Postoperative Complications; Pouchitis; Proctocolectomy, Restorative; Ulcer; Valganciclovir; Weight Loss

To report a case of cytomegalovirus (CMV) endotheliitis after insertion of an intravitreal fluocinolone acetonide (Retisert) implant.. Interventional case report.. Retrospective chart review.. A 40-year-old man received a Retisert implant in the left eye for recurrent Behçet uveitis. Although inflammation became quiescent within a month, corneal edema developed 4 months after insertion. Polymerase chain reaction analysis for aqueous humor detected 3.9 × 10(4) copies/mL of CMV DNA. After treatment with oral valganciclovir, CMV DNA nearly disappeared but visual outcome was poor due to corneal decompensation resulting from severe endothelial cell loss.. After Retisert implant, clinicians should be attentive to the potential risk of CMV endotheliitis.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents; Antiviral Agents; Behcet Syndrome; Corneal Edema; Cytomegalovirus Infections; Drug Implants; Endothelium, Corneal; Fluocinolone Acetonide; Ganciclovir; Humans; Inflammation; Male; Uveitis; Valganciclovir; Vision Disorders