Resistant Cytomegalovirus Infection Research Articles

Drug Resistant CMV Infection in Lung Transplantation Patients: Incidence, Characteristics and Clinical Outcomes

Purpose Cytomegalovirus (CMV) infection and development of CMV drug resistance can cause significant morbidity and mortality in lung transplantation (LTX) patients. We investigated the incidence of CMV drug resistance in adult LTX patients and characterized this patient group and its outcomes. Methods We analyzed a single center retrospective cohort of LTX patients who had undergone CMV UL97 and UL54 genotyping for clinically suspected drug resistance. Of the 852 patients who received LTX between January 2012 and May 2018, 27 patients were genotyped, and 11 were confirmed to have drug resistance. Case-matched controls (3 control patients for each resistant patient) were identified by matching for CMV serostatus, development of CMV disease or significant CMV viremia (over 3000 IU/ml), and transplantation date. Results The cumulative incidence of drug resistant CMV was 1.29% (11/852). Altogether 27 patients were tested for drug resistance and 40.7% (11/27) of strains were resistant, 29.6% (8/27) sensitive, and 29.6% (8/27) inconclusive. The median follow-up time was 630 days (range 100-1950 days). Most patients (7/10) who developed resistant CMV infection were seronegative recipients who received a lung from a CMV seropositive donor. Comparison of characteristics and clinical outcomes between resistant CMV patients and control patients is provided in Table 1. No differences in immunosuppression, acute rejection, or pre-transplant sensitization were seen between groups. The peak CMV viral load and duration of CMV viremia were significantly higher in the resistant group. The resistant group had a significantly increased overall mortality after onset of viremia compared to the controls. Conclusion We conclude that drug resistant CMV infection is rare but patients who develop it have decreased overall survival. Risk factors for developing resistant CMV infection were peak CMV viral load and duration of CMV viremia.

Clinical Validation of the Definitions of Resistant and Refractory Cytomegalovirus (CMV) Infection and Disease in Hematopoietic Cell Transplant (HCT) Recipients.

Introduction Resistant or refractory CMV infections are not well defined and are associated with high morbidity and mortality in HCT recipients. Ganciclovir (GCV), Foscarnet (FOS) and valganciclovir (VGC) are available for treatment of CMV infections with successful results, however, toxicities from these drugs are common and associated resistance have been reported. Definitions for “resistant and refractory CMV infections” were published recently for clinical trials use and to provide guidance for clinical practice (Chemaly RF et al, CID, 2018). Methods We performed a single center retrospective chart review (1/2010 to 9/2018) of HCT recipients who had CMV genotype performed for suspected antiviral resistance. Based on the published definitions, we categorized patients as either having refractory CMV (defined as CMV viremia that fails to decrease after at least 2 weeks of appropriately dosed and delivered antiviral therapy; and in the absence of known genetic mutations to the available antiviral agents) or resistant CMV infection (defined as refractory infection with identification of genetic mutations in the UL97 and/or UL54 genes correlating with in vitro antiviral resistance). Primary outcomes were CMV disease and non-relapse mortality (NRM). Results CMV genotype analysis was performed in 120 patients and 29 (24%) patients had UL 97 and/or UL54 mutations. When compared to refractory CMV infection, patients with resistant CMV infection were more likely to have AML (38% vs 76%), had cord blood transplant (8% vs 24%), were diagnosed with resistant infection later after HCT (59 d vs 120 d), had greater number of prior episodes of CMV infections, had more CMV diseases (34% vs 62%), and specifically more CMV GI diseases (22% vs 55%); (all, p Conclusion Our data showed that resistant CMV infections are associated with higher morbidity including CMV disease while refractory CMV infections are associated with higher NRM. Whether this high NRM in patients with refractory CMV infections is a reflection of the host immunosuppression with persistent CMV infection needs to be determined.

Resistant Cytomegalovirus Infection in Solid-organ Transplantation: Single-center Experience, Literature Review of Risk Factors, and Proposed Preventive Strategies

BackgroundCytomegalovirus (CMV) infection causes morbidity and mortality in solid-organ transplant recipients. Drug-resistant CMV is an emerging problem with poor survival outcomes and limited therapeutic options. In this study we comprehensively address the issue of drug resistance in CMV when compared with standard therapies, such as ganciclovir (GCV) and foscarnet. MethodsWe conducted a retrospective review of adult patients diagnosed with CMV after solid-organ transplant at our center between 2013 and 2017, and identified 7 resistant CMV cases. To study risk factors in the published literature, we performed an extensive database search. ResultsAll patients had documented UL97 mutations, and 3 patients harbored both UL97 and UL54 mutations. For cases with increasing viral load or failure to achieve clinical improvement despite optimal therapy, genetic resistance testing was carried out. Patients received GCV and foscarnet combination therapy. As an adjunct, CMV immunoglobulin, cidofovir, and leflunomide were added. Risk factors, including donor+/recipient− serostatus, persistent high viral replication, prolonged therapeutic GCV exposure (>2.5 months), and allograft rejection, were assessed. ConclusionPatients at risk, especially those with D+/R− serostatus, should be judiciously monitored for resistance. Prolonged intravenous GCV exposure increases the risk for development of drug resistance. Therefore, precise guidelines are required for prevention of long-term GCV/VGCV exposure. Investigation regarding interferon-gamma release assay and adoptive transfer of T cells in diagnosed CMV patients is warranted to improve future prophylactic and management strategies against CMV, with a potential to reduce the requirement for available toxic antiviral drugs.

Resistant Cytomegalovirus Infection After Renal Transplantation: Literature Review

BackgroundResistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene). MethodsWe describe our experience in management of R-CMV after renal transplant at our center (2012–2016). ResultsWe encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks). ConclusionsResistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.

Adjuvant and salvage therapy with leflunomide for recalcitrant cytomegalovirus infections in hematopoietic cell transplantation recipients: A case series

Cytomegalovirus (CMV) reactivation is a clinically significant complication in hematopoietic stem cell transplant (HCT) recipients. Alternative therapy for multidrug-resistant CMV is limited and often fails. Leflunomide has been used to treat resistant CMV infections, however, data on efficacy, safety, and guidance for therapeutic drug level monitoring are lacking. In this report, we describe 3 HCT recipients with multi-drug resistant CMV infections who received leflunomide as adjuvant and salvage therapy. The therapeutic effect of leflunomide as an anti-CMV agent based on virologic responses and therapeutic drug monitoring were evaluated.

Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: A single-center experience

BackgroundThe emergence of resistance to available antiviral drugs may cause higher Cytomegalovirus (CMV)-associated morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Few novel antiviral drugs are being developed with potential effect against refractory or resistant CMV infections. Brincidofovir, an oral nucleotide analog and prodrug of cidofovir, has shown in vitro activity against CMV. MethodsWe reviewed data of 4 cancer patients with resistant CMV or herpes simplex virus (HSV) infections and were treated with brincidofovir under emergency IND application. ResultsThree out of the 4 patients with resistant CMV or HSV infections responded to brincidofovir. Brincidofovir achieved virological response in 2 patients with confirmed UL97 mutation (ganciclovir-resistant CMV infection), but failed to control CMV when a specific UL54 mutation was present (conferring resistance to foscarnet and cidofovir), as seen with patient 3. Furthermore, brincidofovir was effective for treatment of acyclovir resistant HSV infection, as described in patient 4 which is in alignment with the high in vitro potency of brincidofovir (about 100-fold more than acyclovir) for inhibition of HSV replication. Only one patient had brincidofovir-related diarrhea without any evidence of concurrent gastrointestinal GVHD. ConclusionWithout the nephrotoxicity of cidofovir, brincidofovir could be an effective alternative for CMV-resistant and HSV-resistant infections. Combination therapy of brincidofovir with other antiviral agent, at a conventional or a lower dose, could be considered to potentiate efficacy and minimize side effects of the approved antiviral agents.

Resistant cytomegalovirus infection in related donor kidney allograft recipients

To clarify whether cytomegalovirus (CMV) infection can affect the results of living related donor kidney transplantation. A study group included 17 (7.27%) patients (10 men and 7 women; 8 children and 9 adults) aged 3 to 51 years who had developed resistant CMV infection. For comparative analysis, a control group was formed from 113 patients (61 men and 52 women; 40 children and 73 adults) aged 1 to 61 years, whose CMV polymerase chain reaction (PCR) had always been negative, i.e. CMV DNA was absent. The duration of CMV infection episodes was 44 to 232 days. The patients were given valganciclovir in a dose of 450 mg/day. CMV PCR was negative in all the patients at the end of therapy. None of the patients died; one graft was lost. In the control (negative CMV PCR) group, 6 grafts were lost in 113 patients lost and 4 patients died. Statistical analysis showed that the results of related donor kidney transplantation were virtually equal. Suppression of resistant CMV infection can be achieved with the longer use of valganciclovir or its higher dose. CMV infection fails to affect the results of related donor kidney transplantation.

Ganciclovir-Resistant Cytomegalovirus Infection in a Kidney Transplant Recipient Successfully Treated with Foscarnet and Everolimus.

Cytomegalovirus (CMV) infection remains a major cause of morbidity, graft failure, and death in kidney transplant recipients. We describe a case of a 53-year-old CMV-seronegative man who underwent renal transplant from a CMV-positive donor and who developed ganciclovir- (GCV-) resistant CMV infection. Foscarnet was started while immunosuppressive therapy was modified with the introduction of everolimus minimizing tacrolimus dosage. Only two weeks after the start of this treatment regimen was the patient's viral load negative. At two-year follow-up the patient has no clinical or laboratory signs of CMV infection and a good and stable renal function or graft survival. In our case, administration of an mTOR inhibitor combined with foscarnet led to rapid and persistent viral clearance without compromising short- and medium-term graft function. This combination therapy supports the need for the kidney transplant community to individualize a target therapy for each type of GCV-resistant CMV infection.

Resistant cytomegalovirus infection in renal transplant recipients

Resistant cytomegalovirus infection is a significant problem in the transplant population including renal transplant recipients. A combination of factors including receipt of potent immunosuppression, high viral loads and suboptimal levels of anti-cytomegalovirus antivirals leads to emergence of resistant strains. Reports of associated poor graft survival and mortality demonstrate the potential pathogenic nature of such strains. Genotypic and phenotypic resistance testing are available for laboratory diagnosis of resistant cytomegalovirus infection and may help guide therapy. Various agents, including novel and newly minted antivirals and treatment approaches have been employed, with variable success. Thus, in spite of major advances in both diagnostics and therapeutics, management of resistant cytomegalovirus infection in renal transplant recipients remains a challenging prospect.

The impact of drug-resistant cytomegalovirus in pediatric allogeneic hematopoietic cell transplant recipients: a prospective monitoring of UL97 and UL54 gene mutations.

Cytomegalovirus (CMV) infection is a major cause of morbidity in allogeneic hematopoietic cell transplant (alloHCT) recipients. Little is known about the epidemiology of antiviral resistance in the pediatric population. We performed the prospective study to assess the impact of drug-resistant CMV infections in pediatric alloHCT recipients. Pediatric alloHCT recipients who developed CMV infection were consecutively enrolled from May 2009 to April 2012. CMV polymerase chain reaction amplification and sequencing analysis for UL97 and UL54 genes were performed at enrollment and during follow-up. In total, 208 sequence data from viruses in 49 recipients were eligible for the final analysis. Resistant CMV infection caused by UL97 and UL54 mutations occurred in 4.1% (2/49) and 2.0% (1/49), respectively. Known UL97 mutations, M460V and C592G, were observed in each of 2 patients. One patient with the M460V UL97 mutation had an additional T700A UL54 mutation. Drug-resistant CMV attributable mortality was 2.0% (1/49). One or more known sequence variants (drug-sensitive) were observed in all 49 patients. Thirty-one (63.3%) and 28 patients (60.9%) already had known UL97 and UL54 sequence variants before antiviral therapy, respectively. This study provides comprehensive information on the epidemiology of both UL97 and UL54 variants and mutations in alloHCT recipients.

Leflunomide as part of the treatment for multidrug‐resistant cytomegalovirus disease after lung transplantation: case report and review of the literature

Treatment of cytomegalovirus (CMV) disease in transplant patients is challenging and, with antiviral resistance to first-line drugs, it remains uncertain which treatment algorithm to follow. Some data suggest that leflunomide, a pyrimidine synthesis inhibitor, can be used to treat resistant CMV infections. We report a 57-year-old CMV immunoglobulin-G (IgG)-seronegative woman, who received a bilateral lung transplant (LuTx) from a CMV IgG-positive donor with CMV primary disease. The CMV strain was genotypically resistant to ganciclovir, foscarnet, and cidofovir. After starting leflunomide as add-on therapy to a multidrug anti-CMV regimen, viral load declined substantially in 2 months without adverse events. This experience is discussed against the background of existing literature on the use of leflunomide as an anti-CMV agent in LuTx recipients.

High-Dose Intravenous Immunoglobulin (IVIG) Adjuvant Therapy for Cell-Mediated Pancreas Transplant Rejection

High-Dose Intravenous Immunoglobulin (IVIG) Adjuvant Therapy for Cell-Mediated Pancreas Transplant Rejection

Prevention of Resistant CMV Infection Using Persistent Valganciclovir Therapy through Leukopenia and Extending the Duration

Purpose Cytomegalovirus (CMV) infection increases morbidity and mortality in lung transplant recipients. Our center identified CMV-resistant (rCMV) disease resulting in the death of 3 out of 4 cases. We attributed rCMV to erratic dosing, inconsistent medication levels, and a shortened duration of valganciclovir (Val) prophylaxis. We describe the effect of changes in a prophylaxis protocol in order to prevent rCMV in at-risk patients. Methods and Materials The Pre-intervention cohort (Pre 3/08-4/11) received prophylaxis with Val for 3 (D+ and D-/R+) to 6 (D+/R-) months; Val was held for WBC 6 months and followed ≥12 months were included. Frequency of CMV events, time to first event (unadjusted and adjusted for changes in Val or IS), frequency of changes in Val dosing or IS (due to adverse effects) and frequency of rCMV were compared. Results 54 Pre and 23 Post patients were included. CMV event frequency (Pre 23/54 (43%) vs. Post 9/23 (39%) (p=0.77)), median time to events (Pre 54 days, Post 69 days) and time to event analysis was not different between groups (HR 1.087, 95% CI 0.50-2.35). Changes in IS or Val dosing were not more frequent Pre (11/54 (20%)) versus Post (6/23 (26%)) (p=0.57). Pre was associated with development of rCMV in 4/54 (7%) patients, but rCMV in Post has not yet been detected. Conclusions Our combination therapy was successful in preventing rCMV in at-risk patients even though the frequency of CMV events and the changes in IS or Val dosing were unchanged. Our findings suggest that a longer duration of prophylaxis with consistent dosing and perhaps the addition of CMV-IVIg leads to a reduction in rCMV.

Adoptive Immunotherapy with CMV Specific Cytotoxic T Lymphocytesfor Stem Cell Transplant Patients with Refractory CMV Infections,

Abstract 4033Adoptive immunotherapy with cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) is an effective strategy for preventing and treating viral reactivation following allogeneic stem cell transplantation (SCT). We have previously shown that CMV CTL can be generated in 1–2 weeks by stimulating donor lymphocytes with peptide mixes derived from full length pp65 and IE1. We conducted a multi-institutional study of CMV specific CTL for patients with persistent or anti-viral resistant CMV infections following allogeneic SCT, to determine the safety, feasibility, and immunologic effects of this approach. We were successful in stimulating CTL from 10/10 donors with pooled CMV overlapping peptide mixes. Five of the 7 subjects who met infusion criteria had new onset CMV specific CTL activity detected within 4–6 weeks post infusion. Of the two subjects who did not have immunologic responses post-infusion, one received CTL with a low viability post-thawing, and the other patient was receiving cyclosporine A and systemic corticosteroids at the time of the infusion, achieving only a low, transient increase (10%) in pp65 specific activity. There was no GVHD attributable to these infusions. These findings indicate that the infusion of CTL stimulated over 1–2 weeks with overlapping CMV peptides can result in virus specific immune reconstitution in SCT recipients, without exacerbations of GVHD. Disclosures:No relevant conflicts of interest to declare.

Leflunomide in renal transplantation

Leflunomide is a synthetic isoxazole-derivative drug that possesses both immunosuppressive and antiviral properties. Although its only US FDA-approved indication is for the treatment of rheumatoid arthritis, accumulating clinical experience in addition to animal study data makes it an appealing option for patients who are in need of reduction of immunosuppression in the setting of resistant cytomegalovirus infection or BK virus nephropathy, or in renal transplant recipients with chronic allograft dysfunction. While concern over adverse effects such as hepatotoxicity and hemolytic anemia cannot be ignored and there has yet to be a prospective randomized trial for its use in transplantation, its careful usage under close monitoring may provide the best chance for patients who risk allograft rejection during the time of immunosuppressive reduction as they attempt to eradicate BK virus or cytomegalovirus. At the present time, its use as a first-line agent in lieu of mycophenolate mofetil or sirolimus cannot be recommended.

237 Ganciclovir Resistant Cytomegalovirus in a Renal Transplant Recipient: A Medical Challenge

GANCICLOVIR RESISTANT CYTOMEGALOVIRUS IN A RENAL TRANSPLANT RECIPIENT: A MEDICAL CHALLENGE Aashish K Pandey, David B. Butcher Department of Nephrology and Hypertension St. John Hospital & Medical Center, Detroit, Michigan The PV 16000 study reported ganciclovir resistant cytomegalovirus (CMV) in 1.9% renal transplant recipients. The resistant strain may present amino acid deletions or substitutions in conserved regions of the UL97 protein, point mutation in the DNA polymerase (UL54) or both. We describe a case of a 54 year old African American female, who received a deceased donor renal allograft in August, 2009. CMV serology status was seronegative for the recipient and seropositive for donor. Patient had intermittent lapses in CMV prophylaxis due to missing medication followed by leucopenia. Her Immunosuppressant medications included Tacrolimus, Mycophenolate Mofetil and prednisone. One month post transplant, patient developed Acute AntibodyMediated rejection, and received treatment with Plasmapheresis, IV Immunoglobulin and Rituximab. A week later she developed CMV pneumonitis, and was started on Valganciclovir. A viral load of 381,000 was detected that progressively decreased to 44,800 over a period of 4 months. Patient continued to feel lethargic and was admitted again in the hospital. Her viral load had increased to 80,300. A genotypic testing for drug resistance was performed, and patient found to have a UL97 mutation with resistance at site L595S. Treatment was initiated on a combination synergistic regimen of one half dose of ganciclovir and one half dose of Foscarnet, which helped bring the viral load down to 17,300 in 3 weeks. Renal function remained stable with IV hydration. The intensity of immunosuppression, CMV seronegative status and intermittent CMV prophylactic treatment contributed to the development of ganciclovir resistant CMV infection in our renal transplant patient.

Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients

Despite advances in cytomegalovirus (CMV) prophylaxis and therapy, some transplant recipients still develop refractory CMV infections. Maribavir (MBV), an investigational benzimidazole antiviral agent, acts by a mechanism different from that of existing anti-CMV drugs. Previous Phase I and II studies have demonstrated a favorable safety profile for MBV, but its utility in treatment of complex CMV syndromes is unknown. Between June and December 2008, MBV was released for use under individual emergency investigational new drug applications requested by treating physicians and approved by the US Food and Drug Administration and local institutional review boards. Six patients (5 solid organ transplant recipients and 1 hematopoietic stem cell transplant recipient) who had failed to respond to other therapies and/or had known ganciclovir-resistant CMV were treated with MBV at a starting oral dose of 400 mg twice daily. Patients were treated for a median of 207 days (range, 15-376). Four of 6 patients had no detectable CMV DNAemia within 6 weeks of starting MBV therapy. One patient, who had an initial viral load of 1.8 million copies/mL, developed MBV resistance mutations. One patient, who had low serum levels of MBV, had persistent CMV DNAemia and viruria without developing genotypic or phenotypic resistance to MBV. One patient cleared CMV DNAemia, but died of pneumonia and multiorgan failure. No significant adverse effects attributable to MBV were observed. MBV deserves further systematic evaluation as treatment for CMV infection that is resistant and/or refractory to standard therapies, but its optimal dose, duration of therapy, and use in combinations versus as a single agent have yet to be determined.

Update in management of ganciclovir-resistant cytomegalovirus infection

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.

Viral monitoring and successful treatment of a ganciclovir‐resistant cytomegalovirus infection in a heart transplant recipient

We reported a ganciclovir (GCV)-resistant cytomegalovirus (CMV) infection in a heart transplant recipient. Genotypic and phenotypic susceptibility assays demonstrated an A594V mutation in the UL97 phosphotransferase gene and GCV IC(50)>96 microM. Low GCV concentration exposure, immunosuppressive treatment, donor-positive/recipient-negative CMV serostatus, viral reactivations within antiviral prophylaxis or treatment, contributed to GCV-resistant strain selection.

Use of high‐dose ganciclovir for a resistant cytomegalovirus infection due to UL97 mutation

Cytomegalovirus (CMV) infection is a major complication following solid organ transplantation resulting in significant morbidity and mortality. The guidelines published in 2004 have recommendations for therapy; however, the frequency of resistant CMV infection is increasing and therapy is not clearly defined. There are a few alternatives to ganciclovir such as foscarnet, cidofovir, and leflunomide; however, their use is limited by adverse effects. This report summarizes the successful use of high-dose ganciclovir for the treatment of a resistant CMV caused by UL97 mutation.