Risk factors of low-level viremia in chronic hepatitis B patients receiving Entecavir monotherapy: a retrospective cohort study.

BACKGROUND AND AIM: Low-level viremia (LLV), a special case of poor response to antiviral therapy, has become a focus of liver disease research; however, most studies have focused on poor response to antiviral therapy, and little attention has been paid to LLV. Therefore, this study aimed to investigate the factors influencing LLV in patients with chronic hepatitis B (CHB) receiving entecavir (ETV) monotherapy. METHODS: Clinical data of CHB patients receiving ETV treatment for at least 1 year at the outpatient department of the Affiliated Hospital of Xuzhou Medical University from November 2018 to June 2020 were collected. Patients were divided into LLV (180 cases) and sustained virological response (SVR) groups (337 cases) according to the hepatitis B virus (HBV) DNA load at the end of the observation period. Demographic features and laboratory markers were also examined. Univariate and multivariate logistic regression analyses were performed to examine factors influencing LLV in patients receiving long-term ETV monotherapy. RESULTS: Significant differences were noted between the LLV and SVR groups in terms of age, sex, presence or absence of cirrhosis, HBeAg positivity rate, baseline HBV DNA load, and baseline HBsAg level before treatment. Multivariate logistic regression analysis showed that baseline HBeAg status, HBV DNA load, and HBsAg quantification were pretreatment risk factors for LLV in long-term ETV antiviral therapy. CONCLUSIONS: CHB patients with a high HBV DNA load, high HBsAg quantification, and positive HBeAg results tend to have a high risk of LLV despite long-term ETV antiviral treatment and should be dynamically monitored.

Chronic Hepatitis B: Treat all Who Are Viremic?

The main aim of antiviral therapy in patients with chronic hepatitis B (CHB) is to prevent disease progression and reduce the risk of hepatocellular carcinoma (HCC). In general, treatment is recommended for select patient groups viewed as being at higher risk of developing adverse outcomes from CHB. However, patients who do not meet treatment criteria under current international guidelines may still benefit from antiviral therapy to reduce CHB-related complications. Moreover, well-tolerated antiviral drugs that are highly effective at suppressing viral replication are now widely available, and withholding therapy from patients with viremia is increasingly controversial. In this article, we review traditional treatment paradigms and argue the merits of expanding treatment eligibility to patients with CHB who do not meet current treatment criteria.

Urine tenofovir-monitoring predicts HIV viremia in patients treated with high genetic-barrier regimens.

OBJECTIVE: Access to viral load measurements is constrained in resource-limited settings. A lateral flow urine tenofovir (TFV) rapid assay (UTRA) for patients whose regimens include TFV offers an affordable approach to frequent adherence monitoring. DESIGN: We conducted a cross-sectional study of patients to assess the utility of UTRA to predict virologic failure, defined as a viral load greater than 400 copies/ml. METHODS: We assessed urine TFV among 113 participants at increased risk of viral failure (who had previous viral failure on this regimen or had previously been ≥30 days out of care), comparing low genetic-barrier efavirenz (EFV) regimens (n = 60) to dolutegravir (DTG)-boosted or ritonavir-boosted protease inhibitor (PI/r)-based high genetic-barrier regimens (n = 53). Dried blood spots (DBS) for TFV-diphosphate and plasma for TFV concentrations were collected, with drug resistance assessed if viral failure present. RESULTS: Among 113 participants, 17 of 53 received DTG or PI/r had viral failure at the cross-sectional visit, with 11 (64.7%) demonstrating an undetectable urine TFV; the negative-predictive value (NPV) of undetectable UTRA for viral failure was 85% (34/40); none of the 16 sequenced had dual class drug resistance. In those treated with EFV regimens the sensitivity was lower, as only 1 (4.8%) of 21 with viral failure had an undetectable UTRA (P < 0.001). CONCLUSIONS: Urine tenofovir-testing had a high negative-predictive value for viral failure in patients treated with DTG or ritonavir-boosted protease inhibitor regimens, where viral failure was largely explained by poor drug adherence. Frequent monitoring with inexpensive lateral flow urine TFV testing should be investigated prospectively in between viral load visits to improve viral load suppression on DTG-based first-line therapy in resource-limited settings.

Hepatitis E Virus Infection in Cancer Patients.

Hepatitis E virus (HEV) infection in immunocompetent patients can lead to chronic hepatitis and liver failure. However, the burden of HEV infection in cancer patients is largely unknown. We studied the characteristics of HEV infection in patients at a tertiary care cancer center in the United States. This retrospective study included adult cancer patients with HEV infection diagnosed between September 2011 to September 2021. A total of 405 patients were tested for HEV, and 63 (16%) had detectable HEV IgG. Thirty-three patients (52%) were male, 43 were born in America (68%), 46 (73%) were screened for HEV because of pre-existing liver conditions, and 22 (35%) had hematological malignancies. Only 2 patients had detectable HEV RNA. The first patient had myelodysplastic syndrome and underwent allogeneic stem cell transplantation (HSCT). He developed elevated liver enzymes with HEV RNA 14,000 IU/mL (4.2 log IU/mL) 13 months after HSCT. After reducing immunosuppression, his HEV viremia resolved. The second patient had diffuse large B-cell lymphoma and underwent anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. She had elevated liver enzymes with HEV RNA 4,560,000 IU/mL (6.7 log IU/mL) 12 months after CAR T-cell therapy. She developed chronic HEV infection, and ribavirin treatment failed. Now she is being considered for salvage treatment with peginterferon alfa-2a and ribavirin. This study is the first report of chronic HEV infection in patients who received CAR T-cell therapy. HEV infection in cancer patients appears to be at least as common as in the general population. Cancer patients with hematologic malignancies may be at risk for HEV viremia and chronic infection refractory to antiviral treatment.

The Impact of Direct-Acting Antiviral Agents on Cytomegalovirus Reactivation in Chronic Hepatitis C Infection.

OBJECTIVE: The co-infection of HCV/CMV may accelerate the progression of liver diseases and worsen responsiveness to IFN treatment. The Direct-acting antiviral agents (DAAs), currently approved therapy for HCV, may cause a transient change in immune status, favoring the reactivation of other viruses. The current study aims to evaluate the impact of DAAs treatment on the reactivation of latent CMV in HCV patients. METHODS: The serological IgG, IgM Abs against CMV were detected by ELISA on192 HCV patients. The seronegative CMV IgM patients received (sofosbuvir/daclatasvir) regimen, then the CMV reactivation was examined by measuring the CMV IgM by ELISA and CMV DNA by real-time PCR. RESULTS: The serological data revealed that all patients were positive for CMV IgG (100%) while (64%) patients were positive for CMV IgM. The seronegative CMV IgM (36%) received the DAAs protocol. The sustained virological response was monitored by measuring the HCV RNA viremia in the patient sera. The serological data revealed that 28.6% of patients had a reactivation of CMV, while 18.5% of patients had detectable CMV DNA viremia. Moreover, there was a significant improvement in liver function as well as a decrease in FIB-4 and APRI scores at EOT. SVR was reached 97.4% among the total studied patients (N= 192). CONCLUSION: CMV co-infection has no impact on the response rate to DAAs. However, the CMV reactivation might have occurred after the complete eradication of HCV by DAAs.

Emerging COVID-19 Neurological Manifestations: Present Outlook and Potential Neurological Challenges in COVID-19 Pandemic.

The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic.

Comparative impact of methamphetamine and other drug use on viral suppression among sexual minority men on antiretroviral therapy.

BACKGROUND: Substance use decreases the likelihood of achieving undetectable HIV viremia; however, the comparative effects by drug have not been fully described. In this study, we compare the effects of methamphetamine use versus other drugs on viremia in sexual minority men on antiretroviral therapy (ART). METHODS: HIV-positive participants currently on ART (N = 230) were selected from an ongoing cohort of diverse young sexual minority men (mSTUDY) enrolled from August 2014 to May 2018. Substance use and sociodemographic factors associated with viremia outcomes were assessed using ordinal regression analysis with generalized estimating equations. Viremia outcomes were grouped as undetectable (<20 copies/mL), low level suppressed (21-200 copies/mL), or not suppressed (>200 copies/mL). RESULTS: The prevalence of drug use across 825 study visits was 73 %, with methamphetamine use most prevalent (50 %). After adjusting for unstable housing and ART adherence, methamphetamine use, either alone (adjusted OR = 1.87; 95 % CI 1.03-3.40) or with other drugs (adjusted OR = 1.82; 95 % CI 1.12-2.95), was associated with higher odds of increasing viremia compared to no drug use. Other drug use excluding methamphetamine did not show a similar association (adjusted OR = 1.29; 95 % CI 0.80-2.09). Among our study population, nearly half the instances of viremia could be reduced if methamphetamine was discontinued (attributable fraction = 46 %; 95 % CI 3-71 %). CONCLUSIONS: Methamphetamine use, either alone or in combination with other drugs, is associated with failure of viral suppression among sexual minority men on ART independent of adherence and sociodemographic factors. This accounts for nearly half of the observed instances of unsuppressed viremia in this study.

Case Report: Cytomegalovirus Reactivation and Pericarditis Following ChAdOx1 nCoV-19 Vaccination Against SARS-CoV-2.

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for vaccines to protect individuals at high risk for complications and to potentially control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge about adverse events of SARS-CoV-2 vaccines during post-marketing surveillance. Varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation has already been reported in COVID-19 patients. In addition, adverse events after SARS-CoV-2 mRNA vaccination have also been in the context of varicella zoster virus (VZV) reactivation and directly associated with the mRNA vaccine. We present the first case of CMV reactivation and pericarditis in temporal association with SARS-CoV-2 vaccination, particularly adenovirus-based DNA vector vaccine ChAdOx1 nCoV-19 against SARS-CoV-2. After initiation of antiviral therapy with oral valganciclovir, CMV viremia disappeared and clinical symptoms rapidly improved. Since huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must be in place to assess vaccine safety that is important for the detection of any events. In the context of the hundreds of millions of individuals to be vaccinated against SARS-CoV-2, a potential causal association with CMV reactivation may result in a considerable number of cases with potentially severe complications.

Clinical Characteristic and Outcomes of BK Virus Infection in Kidney Transplant Recipients Managed Using a Systematic Surveillance and Treatment Strategy.

BACKGROUND: BK virus (BKV)-associated nephropathy is a significant complication of kidney transplantation that progresses to graft dysfunction and graft loss. The aim of this study was to know the infection rate and progression of BKV according to our strategy. MATERIALS AND METHODS: This study included 302 patients who received kidney transplantation between August 2010 and October 2012. Patients were divided into 4 groups: no BK infection, BK viruria only, low BK viremia, and high BK viremia. RESULTS: In this study, 57 patients had BK viremia (18.9%), and 18 patients had BK nephropathy (5.9%) during a 2-year follow-up period. Age, sex, cytomegalovirus (CMV) viremia, existence of donor-specific antibodies, type of transplantation, and delayed graft function were not significantly different. Disappearance of BKV infection was better in the viruria and low viremia groups than in the high viremia group (P = .001), and duration of BK infection was longer in the high viremia group than the low viremia group (P = .002). CONCLUSION: All diagnosed cases of BKV nephropathy were in the high BK viremia group. For BK viruria and viremia, early detection of BK infection together with early intervention by reduced immunosuppressant is a useful strategy to maintain allograft function. Long-term follow up is required to identify the risk factors for BK infection and graft survival after kidney transplantation.

CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption.

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.

TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy.

Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist-induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques.

Rituximab May Cause Increased Hepatitis C Virus Viremia in Rheumatoid Arthritis Patients Through Declining Exosomal MicroRNA-155.

OBJECTIVE: Several studies have shown that rituximab may enhance hepatitis C virus (HCV) activity. MicroRNAs (miRNAs) have been implicated in modulating the host immune response in HCV infection; miRNAs can be packaged into the exosomes and then shuttled by the exosomes to aid biologic functions. However, the role of exosomal miRNAs (exo-miRNAs) in rituximab-related HCV activity enhancement remains unclear. METHODS: The association between rituximab and increased HCV activity was examined using an in vitro cell-based assay. Purified exosomes were confirmed using immunoblotting and flow cytometry and quantified using enzyme-linked immunosorbent assay. Exosomal miRNA-155 (exo-miR-155) levels were measured using quantitative reverse transcription-polymerase chain reaction. RESULTS: In vitro data showed that B cell-derived miR-155 could inhibit HCV replication in hepatocytes through exosome transmission. Rituximab could both induce B cell depletion and affect intracellular miR-155 production as well as exo-miR-155 transmission and then enhance HCV activity in hepatocytes (P < 0.005). Serum exosome levels were increased in rheumatoid arthritis (RA) patients with HCV infection compared with the levels in RA patients without HCV infection (P < 0.01). The exo-miR-155 levels were significantly increased in RA patients with HCV infection compared with those without infection (P < 0.01). A significantly greater decrement of exo-miR-155 expression was observed after rituximab therapy compared with those observed before therapy (P < 0.01), and hepatitis C viral loads increased simultaneously (P < 0.05). CONCLUSION: Circulating exo-miR-155 levels were negatively correlated with hepatitis C viral loads and subsequently associated with rituximab-related HCV activity enhancement in RA patients. Exo-miR-155 may become a potential diagnostic biomarker or therapeutic target.

Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.

OBJECTIVE: To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin. DESIGN: Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for 3 consecutive weeks. CD4 T cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. Plasma samples were collected 24 and 72 h after romidepsin infusions. METHODS: Single-genome sequencing of the env and p24-RT region was used to genetically characterize the virus from proviral DNA, the transcribed cell-associated RNA and the plasma RNA pool. RESULTS: In three of six participants with available plasma samples we identified plasma HIV-1 RNA sequences that were identical to DNA and/or cell-associated RNA sequences from peripheral blood CD4 T cells. In two participants, plasma RNA sequences contained expansions of identical sequences, corresponding to 62 and 100% of the total sequences, respectively. Plasma HIV-1 RNA had very low amounts of defective viruses compared to cell-associated RNA (odds ratio 20.85, P < 0.001) and to DNA (odds ratio 7.07, P = 0.011) during romidepsin therapy. CONCLUSIONS: Romidepsin induced transcription from proviruses in peripheral blood cells, which contributed to viremia in patients on suppressive therapy. The intermingling of these cell-associated HIV-1 RNA with DNA sequences indicates transcription from a diverse range of proviruses, but the expansions of identical viral plasma sequences with few defects indicate that the romidepsin-induced viremia arises from intact proviruses with highly similar or identical genetic backgrounds.

High-dose steroid therapy in BK viremia adversely affected the long-term graft function after kidney transplantation.

BACKGROUND: Although high-dose steroid therapy has been attempted for the management of clinically suspected allograft rejection, before testing for BK viral activity or acute cellular rejection accompanied by BK polyomavirus nephropathy, its long-term outcome remains unknown. We investigated the impact of high-dose steroids on BK viral activity and long-term graft outcomes in patients with BK viremia. METHODS: The study population comprised 144 kidney transplant recipients with BK viremia. They were divided into 2 groups based on the amount of steroids administered: low-dose group (<2 g, n=123) or high-dose group (≥2 g, n=21). RESULTS: The baseline serum BK viral loads were 5.4±1.1 log cp/mL in the low-dose group and 6.0±1.3 in the high-dose group (P=.054). These changed to 5.2±1.3 and 6.1±1.4, 1 month after steroid treatment (P=.03) and 4.9±1.3 and 5.9±1.4 at 2 months (P=.033), respectively. From 3 months to 1 year, the serum BK viral titers were not different between groups. Kaplan-Meier analyses demonstrated that the rates of the decline of graft function and graft failure were higher in the high-dose group (P=.02 and P=.04, respectively). High-dose steroids (P=.012, hazard ratio [HR] 5.04, 95% confidence interval [CI] 1.42-17.85) and log serum BK viral load at 2 months after steroid treatment (P=.042, HR 1.52, 95% CI 1.02-2.28) were independent risk factors for the decline of graft function. CONCLUSION: High-dose steroids induced BK viral activation and subsequently resulted in poor long-term graft function and early graft failure in patients with BK viremia.

Rectal application of a highly osmolar personal lubricant in a macaque model induces acute cytotoxicity but does not increase risk of SHIV infection.

BACKGROUND: Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15. METHODS: Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure. RESULTS: Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models). CONCLUSIONS: Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission.

Increased BK viremia and progression to BK-virus nephropathy following high-dose intravenous immunoglobulin for acute cellular rejection.

BK virus nephropathy and cellular rejection are common causes of allograft dysfunction in renal transplant recipients. The two can be difficult to distinguish on allograft biopsy and can be present simultaneously. Management of the patient with coexistent BK infection and rejection is complicated by the conflicting ideals of decreasing immunosuppression to treat the former and increasing immunosuppression to treat the latter. The authors present the case of a 57-year-old renal transplant recipient who underwent allograft biopsy 8 weeks post-transplant for evaluation of increased serum creatinine in the setting of BK viremia (BKV). Biopsy revealed Banff classification 1b acute cellular rejection, with insufficient evidence to diagnose BK virus-associated nephropathy. The patient was administered intravenous immune globulin (IVIG), with no other changes in immunosuppressive therapy. Plasma and urine BK increased exponentially following IVIG administration, and allograft function further deteriorated. Repeat biopsy showed overt BK viral nephropathy, and BKV and creatinine decreased only after reduction in immunosuppression and initiation of leflunomide. Although case series have suggested a potential role for IVIG in the setting of BK infection, further study is needed to define the safety and efficacy of this approach.

Pharmacodynamic disparities in tacrolimus-treated patients developing cytomegalus virus viremia.

BACKGROUND: The optimal balance between efficacy and toxicity of tacrolimus (Tac) treatment remains unsolved. The quantification of nuclear factor of activated T cell (NFAT)-regulated gene expression may provide a tool to monitor the individual susceptibility to Tac. METHODS: Expression of NFAT-regulated genes (interleukin-2, interferon-gamma, and granulocyte-macrophage colony stimulating factor) in peripheral blood from renal transplant patients (N = 73) was measured by quantitative real-time polymerase chain reaction (at C0, C1.5, and C4) and correlated to clinical endpoints in a 1-year observation period. In a subgroup (n = 10), NFAT expression was quantified over a 12-hour dose interval. RESULTS: Median daily Tac dose of 73 stable renal transplant patients [median age 47 years (range 19-69 years)] was 5 mg (1-13), Tac trough (C0), 1.5-hour (C1.5) and 4-hour (C4) concentrations were 8.5 mcg/L (3-20), 20 mcg/L (4.7-50.4), and 14.5 mcg/L (4.5-37.5), respectively. The mean residual expression of all 3 NFAT-regulated genes was 21% at C1.5 (1-84) and 35% at C4 (2-88). The relative reduction of gene transcripts was inversely correlated with the individual Tac blood concentrations. Seven patients had cytomegalus virus viremia during the observation period, and their residual NFAT-regulated gene expression at C1.5 was significantly lower [13% (1-21) versus 26% (1-84), P = 0.02] compared with those without viremia despite comparable Tac blood concentrations (6.3 versus 8.6 mcg/L). CONCLUSIONS: Monitoring of NFAT-regulated gene expression in Tac-treated transplant recipients provides a tool to assess the individual response to Tac, identify patients at the risk of developing cytomegalus virus viremia, and may, thus, help to select the optimal Tac dose with respect to safety and toxicity.

The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients.

Late-onset cytomegalovirus (CMV) disease is a significant problem with a standard 3-month prophylaxis regimen. This multicentre, double-blind, randomized controlled trial compared the efficacy and safety of 200 days' versus 100 days' valganciclovir prophylaxis (900 mg once daily) in 326 high-risk (D+/R-) kidney allograft recipients. Significantly fewer patients in the 200-day group versus the 100-day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200-day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy-proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild-to-moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days' prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.