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Human papillomavirus (HPV) has become widely known as the causative agent of cervical cancer and some oropharyngeal cancers. The development of HPV vaccines has further piqued public interest. As a result, dentists will have increasing numbers of patients who will inquire about oral HPV infection and its prevention by means of vaccination. Dental professionals must be informed.This review provides an overview of HPV, its association with HIV and oropharyngeal cancer and information on HPVvaccinations.

Background: This study reviewed the outcomes of a screening protocol for BK viremia to determine if early diagnosis, followed by immunosuppression minimization, would prevent progression to nephropathy and graft loss., Methods: This review included 369 renal transplant recipients tested for BK virus at serial time points after transplantation. Management included immunosuppression minimization plus cidofovir treatment for BK nephropathy., Results: Recipients received tacrolimus-based immunosuppression, with 8% prednisone-free and 6% who received desensitization. With a mean follow-up of 22 ± 10 months, 16% (n = 57) of recipients became BK viremia positive. The median (range) time to diagnosis was 3 (1-17) months. Because renal biopsy was performed selectively, 59% of recipients underwent biopsy, with 47% showing BK nephropathy. Seventy-four percent of recipients cleared the virus at a median (range) time of 9 (3-33) months, with four grafts lost to BK nephropathy. Cidofovir-treated recipients displayed a higher viral load at diagnosis but showed equivalent renal function at last evaluation. In multivariate analysis, recipient age, Asian ethnicity, deceased donor, and prednisone use were factors independently associated with BK viremia. Actuarial survival of BK-positive grafts was worse than that of BK-negative grafts (P<0.01, log-rank test). At 9 and 12 months, the mean estimated glomerular filtration rate of the BK-positive group was lower than that of the BK-negative cohort (P = 0.02)., Conclusions: Despite using a screening protocol combined with immunosuppression minimization, BK-positive recipients had a greater risk of graft loss and impaired function than recipients free of infection. Future investigations should focus on practices to prevent BK viremia.

Background: Cidofovir is an antiviral agent which inhibits the DNA polymerase of different viruses. Its use has been described for papillomavirus infections., Methods: Descriptive retrospective study, including patients with difficult to treat anogenital warts who were treated with cidofovir cream., Results: Nine immunocompetent patients were treated, where 6 of them had a complete response and 3 of them a partial response., Conclusion: Cidofovir cream could be a useful therapeutic alternative, although further studies are required to establish the best dosage and its cost-effectiveness., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Cidofovir has shown antiproliferative effects against human papillomavirus (HPV)-positive cells and successfully suppressed the growth of HPV-positive xenografts in athymic nude mice. The present study evaluated the effect of cidofovir on several disease parameters in this animal model. Intratumoral administration of cidofovir resulted in a beneficial effect on body weight gain, a reduction in splenomegaly, a partial restoration of tryptophan catabolism, and diminished the inflammatory state induced by the xenografts. Administration of cidofovir to tumor-free animals did not have a direct effect on these parameters. Beyond suppressing tumor growth, intratumoral treatment with cidofovir ameliorated the pathology associated with HPV-tumor growth., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Recurrent respiratory papillomatosis (RRP) is a viral induced disease, associated with exophytic epithelial lesions affecting the upper airways. Problem of treatment is the high recurrence of papilloma growth after surgical removal; therefore adjuvant therapy schemes have been established. Cidofovir was one of the agents used off-label in adjuvant therapy in the last years. However, there is ongoing discussion about the effectiveness and possible side effects. Aim of our study was to share our experience in treatment of RRP with cidofovir during the last 11 years. We analyzed all the data of patients treated for RRP at the Department for Phoniatrics of the Medical University of Graz between 1999 and 2011. 25 out of the 34 treated patients are at the moment under complete remission, in six patients partial remission could be achieved and two patients showed poor response to therapy, therefore the treatment with cidofovir was stopped. 21 patients received one cycle of monthly cidofovir, 11 patients received two and one patient three cycles of therapy. Number of procedures reached from one to six during each cycle. Average cumulative dose of one cycle was 79.7 mg (15-277.5 mg), in one patient 435 mg were used. One patient developed temporary, borderline neutropenia without symptoms. Despite the retrospective approach of this study with the limitation of several incomplete records, our results show promising long-term effects of adjuvant use of cidofovir. During this period, we did not observe any relevant side effects.

The Holý Trinity was named after Dr Antonín Holý (the Holý Trinity being an Unesco recognized monument in Olomouc, Czech Republic), who together with Dr John C. Martin (Gilead Sciences) and myself pioneered a new class of antiviral agents, the acyclic nucleoside phosphonates. These compounds have revolutionized the antiviral drug field with several drugs that have been approved for the treatment of various DNA virus infections (cidofovir), hepatitis B (adefovir), and AIDS (HIV infection; tenofovir). The latter is also available as its oral prodrug, tenofovir disoproxil fumarate, for the treatment of hepatitis B and in combination with emtricitabine ((-)FTC) for the treatment and prophylaxis of HIV infections and in combination with (-)FTC and other HIV inhibitors, that is, efavirenz, rilpivirine, or elvitegravir (and a pharmacoenhancer thereof, cobicistat), for the treatment of AIDS., (© 2013 Elsevier Inc. All rights reserved.)

Warts are common and are a challenge to treat in some children, especially immunocompromised children and those who fail or cannot tolerate salicylic acid preparations and cryotherapy. Cidofovir, a nucleotide analogue with antiviral activity, has demonstrated promising results when compounded into a topical form to treat refractory warts. We present a retrospective institutional review of 12 children with refractory verrucae treated with 1% to 3% topical cidofovir compounded in an unscented moisturizing cream, applied every other day to daily. In our institutional series, only three patients (25%) demonstrated complete clearance of their verrucae. An additional four patients (33%) demonstrated partial clearance. Our experience using topical cidofovir has been less successful than previous institutional reviews, possibly because we used a lower concentration and less-frequent dosing. More studies are needed to better characterize the efficacy, safety, and dosing of topical cidofovir for the treatment of refractory warts., (© 2012 Wiley Periodicals, Inc.)

Background: This is an update of a Cochrane Review originally published in Issue 4, 2005 of The Cochrane Library and previously updated in 2010.Recurrent respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the upper airway. It can affect both adults and children causing airway obstruction and voice change. Treatment usually involves repeated surgical debulking of the papillomata. Several agents have been proposed as adjuvants to surgical debulking, including antivirals, administered systemically or injected into the lesions., Objectives: To assess the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children and adults., Search Methods: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 24 February 2012., Selection Criteria: Randomised controlled trials., Data Collection and Analysis: We identified 143 references from the searches. Forty-three were appropriate for retrieval and assessed for eligibility by the authors. One randomised controlled trial met the inclusion criteria, involving 19 participants. We contacted the authors to obtain additional data to facilitate the review., Main Results: The included study was a single-institution, randomised, double-blind, placebo-controlled trial of intralesional cidofovir administered at the time of surgical debulking. Adults (n = 15) and children (n = 4) were included. We judged the study to have a reasonably low risk of bias. After a 12-month trial period, no difference was found between the cidofovir and placebo groups. Both groups showed a significant reduction in disease extent (as assessed at the time of surgery using the Derkay Scoring System), but no significant change in health-related quality of life., Authors' Conclusions: There is insufficient evidence to support the efficacy of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children or adults. The included randomised controlled trial showed no advantage of intralesional cidofovir over placebo at 12 months. The study was limited by a small sample size and a change in the cidofovir concentration midway through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. An adequately powered randomised controlled trial of intra-lesional cidofovir, consistently using higher concentrations of cidofovir in comparison with injected placebo, would be required to determine effectiveness convincingly. Future studies must include health-related quality of life and symptom-based outcome measures.

Cidofovir is an antiviral agent used in the therapy of recurrent respiratory papillomatosis (RRP). In this study, we hypothesized that cidofovir is effective in decreasing the viral load of human papillomavirus (HPV). We established a type specific real-time PCR and measured HPV DNA loads. The course of viral load of HPV types 6 and 11 after repeated applications of cidofovir intralesionally was compared to the clinical outcome using a modified Derkay score. In 6 of the 8 (75 %) patients, we detected HPV 6. In 2 (25 %) patients, we detected HPV 11. In all of the patients, the viral load and the modified Derkay score decreased significantly during the treatment. We conclude that viral load of HPV can be monitored using the technique described here. Cidofovir in combination with surgical debulking reduces the viral load in patients with RRP. Relapses of the symptoms cannot be avoided but might be delayed.

There is a growing range of treatment options for anal intraepithelial neoplasia (AIN). In HIV-positive patients, sustained treatment is often required to achieve clearance. The treatments considered are topically applied fluorouracil, imiquimod, cidofovir and trichloroacetic acid, the potential treatments of topical lopinavir and photodynamic therapy with aminolevulenic acid, and the surgical methods of electrosurgery, infrared coagulation and laser. Destructive treatment methods, possibly including TCA, are more effective than self applied topical treatments. Combining or alternating different treatments should be considered.

Background: Cutaneous warts are often recalcitrant to conventional therapy in immunocompromised patients. Cidofovir is a potent antiviral agent shown to have a broad spectrum of action against DNA virus, including human papillomavirus., Objective: To determine the efficacy of intralesional cidofovir in the treatment of florid warts in an immunocompromised renal transplant patient., Method: The patient received seven injections of intralesional cidofovir at 4 week intervals in his numerous palmar warts., Conclusion: Based on our results, intralesional cidofovir is a promising therapeutic modality in the treatment of cutaneous warts in the renal transplant population.

Background: Adenoviral infections are endemic in the pediatric population. Most of these infections are mild and self-limited in immunocompetent individuals. Although in profoundly immunocompromised hosts after solid organ or stem cell transplantation, adenovirus may cause fulminant hepatitis or other life-threatening infections, this is a rare complication in patients receiving standard chemotherapy., Observation: We report a case of severe adenovirus hepatitis in a 7-month-old child receiving induction chemotherapy for hepatoblastoma who fully recovered after treatment with cidofovir., Conclusions: To our knowledge, this is the first report documenting recovering of severe adenoviral hepatitis in a nontransplanted immunocompromised host.

Cidofovir is a nucleoside analog of deoxycytidine with a strong activity against a broad spectrum of DNA viruses, including human papillomavirus. The first objective was to evaluate efficacy of cidofovir for the treatment of cutaneous viral warts, recalcitrant after conventional therapies or where the surgery approach is difficult for their location or extension. Second, the present authors propose to point out possible local and systemic side effects consequent to treatment. Two-hundred eighty patients affected by recalcitrant cutaneous viral warts, were treated with intralesional cidofovir 15 mg/mL once a month. The present authors stated that candidates were those who had made before at least two other treatments reported in the guideline for management of cutaneous viral warts. In 276 cases, warts completely cleared: 158 of those have a follow-up period longer than 12 months and 118 have a follow-up of 6 months. On the average, 3,2 injections were enough to solve the problem. Local side effects consisted of pain and burning sensation during the injections; itching, erythema, and post-inflammatory hyperpigmentation were observed. No cases of systemic side effects were noted. The treatment was well tolerated, and the warts were completely cleared without relapses. Intralesional cidofovir is emerging as an effective therapeutic alternative for warts that are unresponsive to conventional treatments., (© 2012 Wiley Periodicals, Inc.)

Cidofovir (CDF) and its cyclic analogue (cCDF) have shown potential in vitro and in vivo antiviral activity against cytomegalovirus (CMV) retinitis. However, hydrophilic nature of CDF may affect cell permeation across lipophilic epithelium and thus limit its effectiveness in the treatment of CMV retinitis. In the present study, we have tested a novel hypothesis, which involves chemical derivatization of cCDF into lipophilic transporter-targeted prodrug [via conjugation with different carbon chain length of lipid raft and targeting moiety (biotin) for sodium-dependent multivitamin transporter (SMVT)]. We have synthesized and characterized three derivatives of cCDF including biotin B-C2-cCDF, B-C6-cCDF, and B-C12-cCDF. Physicochemical properties such as solubility, partition coefficient (n-octanol/water and ocular tissue), bioreversion kinetics, and interaction with SMVT transporter have been determined. Among these novel conjugates, B-C12-cCDF has shown higher interaction to SMVT transporter with lowest half maximal inhibitory concentration value, higher cellular accumulation, and high tissue partitioning. Improvement in physicochemical properties, lipophilicity, and interaction with transporter was observed in the trend of increasing the lipid chain length, that is, B-C12-cCDF > B-C6-cCDF > B-C2-cCDF. These results indicate that transporter-targeted lipid analogue of cCDF exhibits improved cellular accumulation along with higher transporter affinity and hence could be a viable strategy for the treatment of CMV retinitis., (Copyright © 2012 Wiley Periodicals, Inc.)

We present a case of a 27-year-old man who received an unrelated donor umbilical cord blood transplant for chronic lymphocytic leukemia. His postsurgery course was complicated by acute kidney injury, hemorrhagic cystitis, and pancytopenia. Transjugular kidney biopsy showed interstitial nephritis. Viral inclusions were present in tubular epithelial cells, and in situ hybridization studies confirmed the presence of adenovirus. Kidney function improved after a short course of cidofovir. Adenovirus-induced interstitial nephritis should be considered in the differential diagnosis in all cases of interstitial nephritis occurring in immunocompromised patients., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Human papillomavirus is responsible for common condyloma acuminata and a number of premalignant and malignant anogenital lesions. The immunocompromised population is at particular risk because of a higher incidence of malignant transformation. Lesions in this population may prove refractory to standard treatment. This is part II of a two-part review that will discuss the treatment of condyloma acuminata and vaginal, vulvar, penile, and anal intraepithelial neoplasias. This article will provide an updated review of available treatments, with a focus on recent advances and the challenges faced in successfully treating human papillomavirus lesions in the immunocompromised host., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

This review summarizes the basic milestones of the research of 5-azacytosine nucleosides chronologically from their discovery and anticancer activity identification, through to subsequent unveiling of their mechanism of action based on DNA hypomethylation and tumor-suppressor gene reactivation, to the final US FDA approval of 5-azacytidine (Vidaza(®)) and 2'-deoxy-5-azacytidine (Dacogen(®)) for the treatment of myelodysplastic syndromes. 5,6-dihydro-2'-deoxy-5-azacytidine, a compound with anti-HIV activity through lethal mutagenesis, representing a unique mechanism of action among existing anti-retroviral drugs, is discussed together with quite recent discovery of its so far unexpected hypomethylation activity. Special attention is paid to 5-azacytosine acyclic nucleoside analogues and phosphonomethyl derivatives with the emphasis on the new potent anti-DNA virus agent (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine and its prodrug forms. Considering the potential pharmaceutical applications, 5-azacytosine and 5,6-dihydro-5-azacytosine appear to be so far the most effective cytosine mimics for the design of novel antiviral and anti-tumor drug candidates.

Introduction: Sapacitabine is an orally bioavailable nucleoside analog prodrug that is in clinical trials for hematologic malignancies and solid tumors. The active metabolite of sapacitabine, CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine), exhibits the unique mechanism of action of causing single-strand breaks (SSBs) after incorporation into DNA, which are converted into double-strand breaks (DSBs) when cells enter a second S-phase. CNDAC-induced DSBs are predominantly repaired through homologous recombination (HR). Cells deficient in HR components are greatly sensitized to CNDAC. Therefore, sapacitabine could be specifically effective against tumors that are deficient in this repair pathway., Areas Covered: This review summarizes results from supporting evidence for the mechanisms of action of sapacitabine, its preclinical activities and the current results of clinical trials in a variety of cancers. The novel action mechanism of sapacitabine is discussed, with a view to validate it as a chemotherapeutic drug targeting malignancies with defects in HR., Expert Opinion: Knowledge of CNDAC mechanism identifies tumors that may be sensitized to sapacitabine, thus enabling a personalized treatment strategy. It also creates the opportunity to overcome resistance to current front-line therapies and identify synergistic interactions with known anticancer drugs. The results of such investigations may provide rationales for the design of sapacitabine-based clinical trials.

Molluscum contagiosum virus (MCV) is a poxvirus that causes localized papules in healthy persons. We evaluated a woman with severe immunodeficiency and disseminated MCV. During treatment with CMX-001, an antiviral with activity against other poxviruses, MCV DNA was detected in 20% of plasma samples. When the patient was not receiving CMX-001, MCV DNA was detected in 50% of samples. We also noted improvement in warts on her fingers during CMX-001 therapy. Although MCV is caused by direct inoculation of virus into skin in healthy persons, in a severely immunocompromised person MCV DNA was present in blood and may spread by viremia.

We present a report of dendritic ulcerative keratitis in a 4-year old locally immunosuppressed dog suspected to result from acute primary canine herpesvirus-1 (CHV-1) infection. The dog was presented for evaluation of mild blepharospasm and conjunctival hyperemia in the right eye (OD) shortly after attending a public boarding facility. For approximately 3 months, the dog had been receiving topical prednisolone acetate 1.0% and tacrolimus 0.02% in both eyes (OU) q12h for treatment of follicular conjunctivitis. Ophthalmic examination revealed three regions of corneal fluorescein retention OD. The lesions had a dendritic pattern, were approximately 2-3 mm in length, and were located at the dorsomedial, lateral, and ventromedial aspects of the cornea. No additional abnormalities were noted on complete ophthalmic and physical examinations. CHV-1 was identified in conjunctival samples OD by polymerase chain reaction, and paired CHV-1 serum virus neutralization antibody titers were positive and consistent with acute infection. Topical prednisolone acetate and tacrolimus were discontinued. The dog was treated with cidofovir 0.5% OU q12h for a period of 4 weeks, with resolution of corneal disease noted within 1 week of treatment. In conjunction with previous studies, this case report supports a central role for alterations in host immune status in the pathogenesis and clinical manifestations of CHV-1 ocular disease in dogs., (© 2011 American College of Veterinary Ophthalmologists.)

HIV-infected patients may develop rare anogenital pseudotumoral herpes potentially mimicking epidermoid carcinoma. We assessed treatment in five new cases with a median follow-up of 3.3 years. Recurrence and clinical nucleoside analog resistance were observed in all patients. All drug treatments were only temporarily curative and clinical responses varied between patients and recurrences. Foscavir seemed to be the most appropriate second-line treatment and cidofovir or thalidomide should be considered as alternative treatments.

Background: Viral-associated trichodysplasia of immunosuppression is a rare cutaneous eruption that is characterized by follicularly based shiny papules and alopecia with characteristic histopathologic findings of abnormally anagen follicules with excessive inner root sheath differentiation. Prior reports have described the histopathologic characteristics on vertical sections; however, to our knowledge, immunohistochemical analysis of polyomavirus proteins has not been previously performed., Observations: We discuss the thorough diagnostic evaluation and therapy of an unusual case of viral-associated trichodysplasia due to a newly described human polyomavirus that occurred in a patient with posttreatment chronic lymphocytic leukemia and an abnormal white blood cell count. Unique to our study is the immunohistochemical staining for the polyomavirus middle T antigen, which demonstrated positive staining of cellular inclusions within keratinocytes that compose the inner root sheath. Further evaluation with scanning electron microscopy and polymerase chain reaction analysis of viral DNA confirmed the presence of the virus. Treatment with topical cidofovir resulted in dramatic clinical improvement and hair regrowth., Conclusions: Several tools, including immunohistochemical staining for the polyomavirus middle T antigen, can be used to identify the pathogenic virus associated with viral-associated trichodysplasia. This case highlights the utility of multiple diagnostic modalities and a robust response to a topical therapeutic agent, cidofovir.

Background: BK virus nephropathy (BKVAN) causes about 10% of late kidney graft loss. Cidofovir is widely used to treat BKVAN, but the magnitude of the health benefits and costs are largely unknown. We aimed to evaluate the incremental health benefits and costs of cidofovir and immunosuppression reduction compared with immunosuppression reduction alone in kidney transplant patients with BKVAN., Methods: A probabilistic decision analytic model was developed to simulate a cohort of kidney transplant recipients aged 45 years and above with BKVAN who received cidofovir treatment compared with those who received standard care. The duration of the cycle was 1 year, and the model terminated when all recipients were deceased., Results: Compared with immunosuppression reduction alone, in the base-case, the incremental health benefits of cidofovir were 0.0061 life-years saved (2.2 days), with savings of $20,756 over the lifetime of a transplant recipient. When varying the most influential variables (the probability of response to treatment and graft loss) between best and worst case scenarios, the incremental health outcomes ranged from -0.967 to 1.093 life-years saved, with incremental costs ranging from an extra $27,313 to saving $20,756., Conclusions: Compared with immunosuppression reduction alone, based on best available data, cidofovir treatment and immunosuppression reduction for BKVAN seem to be cost saving and improves health outcomes. However, because of weak clinical data, particularly around comparative effectiveness, there is still moderate uncertainty in the incremental cost effectiveness. Adequately powered trials are still needed to better define optimal treatment strategies for BKVAN before cidofovir can be recommended strongly as routine therapy.

In the nineteenth century, smallpox ravaged through the United States and Canada. At this time, a botanical preparation, derived from the carnivorous plant Sarracenia purpurea, was proclaimed as being a successful therapy for smallpox infections. The work described characterizes the antipoxvirus activity associated with this botanical extract against vaccinia virus, monkeypox virus and variola virus, the causative agent of smallpox. Our work demonstrates the in vitro characterization of Sarracenia purpurea as the first effective inhibitor of poxvirus replication at the level of early viral transcription. With the renewed threat of poxvirus-related infections, our results indicate Sarracenia purpurea may act as another defensive measure against Orthopoxvirus infections.

Background: Changes of HHV-8 antibody reactivity and intermittent detection of HHV-8 DNA have been observed in subjects with Kaposis's Sarcoma and/or HIV infection. Little is known about the longitudinal dynamics of HHV-8 DNA and antibody response in allografted stem cell transplant (SCT) patients without Kaposis's Sarcoma., Objectives: To report the natural history of a HHV-8 seropositive patient with chronic lymphocytic leukemia who developed an active HHV-8 infection after SCT., Study Design: HHV-8 antibodies were measured by IFA and ELISA assays. HHV-8 DNA was detected by real-time PCR quantitative assay in serum and peripheral blood leukocytes (PBL)., Results: Twenty-two out of 26 (85%) serum samples had detectable HHV-8 antibodies: 21/26 (80%) samples were positive by both IFA and ELISA assays, while 1 sample was ELISA positive-IFA negative. The remaining 4 samples (15%) were negative by both assays. Five out of 6 (83%) serum-PBL samples pairs had detectable HHV-8 DNA: a median of 934 genomes/ml (range 254-6316 genomes/ml) in the serum and a median of 10,000 genomes/10(5) (range 1472-93,460 gen/10(5)) in PBL. An active HHV-8 infection occurred early within the first 30 days after the transplant, extended up to day +180 and occurred without evidence of HHV-8-related neoplastic or non neoplastic diseases., Conclusions: This study provides evidence that a patient infected with HHV-8 before SCT can be either intermittently HHV-8 DNA-positive and/or seropositive for HHV-8 after SCT. A high and persistent HHV-8 replication may be ongoing even in the absence of overt HHV-8-associated diseases., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy for many viruses. However, the requirement for intracellular activation and side-effects caused by distribution to off-target sites of toxicity still limit the efficacy of the current generation of drugs. Kinase bypass strategies, where phosphorylated nucleosides are delivered directly into cells, thereby, removing the requirement for enzyme catalyzed phosphorylation steps, have already changed the face of antiviral therapy in the form of the acyclic nucleoside phosphonates, cidofovir, adefovir (given orally as its dipivoxil prodrug) and tenofovir (given orally as its disoproxil prodrug), currently used clinically. These strategies hold further promise to advance the field of antiviral therapy with at least 10 kinase bypass and tissue targeted prodrugs, representing seven distinct prodrug classes, currently in clinical trials. This article reviews the history of kinase bypass strategies applied to nucleoside antivirals and the evolution of different tissue targeted prodrug strategies, highlighting clinically relevant examples., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Human herpesvirus 6 (HHV-6) is a ubiquitous virus inducing a life-long latent infection of its human host. Acute infections (AIs) have been recognized as the cause of severe diseases. These AIs correspond to primary infections (PIs), mainly occurring in young children, endogenous reactivations (ENRs), observed at any age, and putative exogenous reinfections (EXRs). The diagnosis of AIs is now essentially based on the quantification of viral load in bodily fluids and organs by means of real time PCR. However, this diagnosis is currently bothered by the lack of well established viral load thresholds for the different levels of virus replication, the concomitant infection with the two variants HHV-6A and HHV-6B, and the existence, albeit at low frequency, of chromosomal integration of viral DNA. An additional challenge is the difficulty to establish the causality relationship between AI and disease. Although many AIs are asymptomatic or poorly symptomatic with a spontaneous favourable outcome, some have been credited with serious clinical manifestations affecting central nervous system, liver, gastrointestinal tract, lungs, and bone marrow. The main favouring factor for such serious diseases is cellular immune deficiency. These severe diseases can be exemplified by encephalitis cases either associated with PI in young children or with ENR, especially in haematopoietic stem cell transplant recipients. The antiviral drugs ganciclovir, foscarnet and cidofovir have proven to be efficient against AIs and related diseases but the indications and conditions of their use are not yet formally approved. This emphasizes the need for controlled studies addressing both the clinical impact and therapy of HHV-6 AIs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The BK virus, a DNA virus from the Polyomavirus group, represents an opportunistic infection of immunosuppressed transplant recipients. Though the virus was discovered approximately 40 years ago, the emergence of BK virus nephropathy since 1995 onwards, with associated high graft loss rates, has revolutionized renal transplantation medicine. Kidney transplant professionals realized that the consequences of over-immunosuppression were as severe as the consequences of under-immunosuppression and we entered the era of immunosuppressive minimization. Despite this recognition, the optimal testing type for BK virus infections and frequency of testing are hotly debated. Similarly, optimal treatment strategies remain sources of intense controversy. The authors review the current strategies of screening, diagnosis, and possible treatment, and also review the amount and quality of evidence in favor or against. Similarities and differences between cytomegalovirus, Epstein-Barr virus, and BV virus, the three major viral infections in kidney transplantation, are highlighted.

Hypomethylating agents such as 5-azacytidine or decitabine have been a major breakthrough in the treatment of patients with myelodysplastic syndromes (MDS). They have been shown to improve transfusion requirements and to change the natural history of the disease. However, with increasing cumulative clinical experience, it has become apparent that these agents are not curative and have their own shortcomings. There is a subgroup of patients who do not respond to frontline therapy and a large, growing cohort of patients that lose response or progress while on hypomethylating agent-based therapy. There are no standard treatment options in this arena and it is therefore a focus of significant research interest. Since the mechanisms of resistance to hypomethylating agents are not known, selection of therapy is largely empiric but must take into account the age, comorbidities, and performance status of the patient, as well as the characteristics of the disease at the time of treatment failure. Higher intensity approaches and allogeneic stem cell transplant can yield improved response rates and long-term disease control but should be limited to a selected cohort of patients who can tolerate the treatment-related morbidities. For the majority of patients who likely will be better candidates for lower intensity therapy, several novel, investigational approaches are becoming available. Among these are newer nucleoside analogues, inhibitors of protein tyrosine kinases, molecules that interact with redox signaling within the cell, immunotherapy approaches, and others. Patients with MDS whose disease has failed to respond to hypomethylating agent therapy should be referred for clinical trials when available. As we learn more about the patterns and mechanisms of failure, the next challenge will be to determine which therapies are suitable for each individual patient., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Although acyclovir (ACV) has proven to be of value in the therapy of certain herpes simplex virus (HSV) infections, there is a need for more effective therapies, particularly for serious infections in neonates and immunocompromised individuals, where resistance to this drug can be problematic. CMX001 is an orally bioavailable lipid conjugate of cidofovir that is substantially less nephrotoxic than the parent drug and has excellent antiviral activity against all the human herpesviruses. This compound retains full antiviral activity against ACV-resistant laboratory and clinical isolates. The combined efficacy of CMX001 and ACV was evaluated in a new real-time PCR combination assay, which demonstrated that the combination synergistically inhibited the replication of HSV in cell culture. This was also confirmed in murine models of HSV infection, where the combined therapy with these two drugs synergistically reduced mortality. These results suggest that CMX001 may be effective in the treatment of ACV-resistant HSV infections and as an adjunct therapy in individuals with suboptimal responses to ACV.

Purpose: We report a severe case of human papillomavirus-associated epithelial hyperplasia in a man infected with human immunodeficiency virus. These lesions were recalcitrant to treatment with surgical modalities and were eventually controlled with the daily application of a topical cidofovir gel., Patient and Methods: A single case is presented, along with a relevant review of the published data., Results: Before the initiation of cidofovir treatment, the patient had approximately 80% of his gingiva and buccal mucosa engrossed by confluent papillomatous lesions. At 2 weeks after cidofovir treatment, the lesions had markedly regressed, and by 4 weeks, they were almost fully resolved. No untoward adverse reactions occurred., Conclusions: Cidofovir formulated as a gel can be safe and effective for the treatment of epithelial hyperplasia in those with human immunodeficiency virus infection., (Published by Elsevier Inc.)

HHV type 6 has been reported with enhanced pathogenicity in immunocompromised patients. Herein, we report about a two-yr-old girl who experienced primary HHV 6 infection after liver transplantation. She clinically presented with graft rejection and necrotic hepatitis as well as high fever, pneumonitis with respiratory failure and a rash. Therapy with cidofovir of 5 mg/kg per wk did not show improvement, so that a full pharmacokinetic profile of cidofovir was performed. It demonstrated enhanced body weight normalized clearance of cidofovir and cidofovir dosage was augmented to 12 mg/kg per wk to reach adequate drug exposure. With additional reduction of immunosuppression, the patient dramatically improved and liver function stabilized., (© 2010 John Wiley & Sons A/S.)

Respiratory papillomatosis affects the larynx in most cases. It is a relatively rare disease, with potentially devastating consequences for the patient. Many studies have proven the viral etiology of the disease. Surgery is the most successful mode of treatment. Adjuvant therapy is used in cases of aggressive disease. The most successful adjuvant drugs are interferon, various virostatics (e.g., acyclovir, valacyclovir, and cidofovir) and indole-3-carbinol. Vaccination with a quadrivalent vaccine against HPV will probably decrease the incidence of respiratory papillomatosis or help in the treatment of the disease in the future. The results of adjuvant therapy of laryngeal papillomatosis at the University Department of ORL & HNS in Ljubljana are comparable to the results in other centers around the world.

A case of severe diarrhoea associated with synergistic human bocavirus type 1 (HBoV) and human herpes virus type 6 (HHV6) is reported. The case supports the hypotheses that HBoV infection under clinical conditions may depend on helper viruses, or that HBoV replicates by a mechanism that is atypical for parvoviruses, or that HBoV infection can be specifically treated with cidofovir.

Adenoviruses (AdV) are DNA viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal (GI) tract, or conjunctiva. Rare manifestations of AdV infections include hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, or encephalitis. Adenovirus infections are more common in young children, owing to lack of humoral immunity. Epidemics of AdV infections may occur in healthy children or adults in closed or crowded settings (particularly military recruits). The disease is more severe, and dissemination is more likely in patients with impaired immunity (eg, organ transplant recipients, human immunodeficiency virus infection, congenital immunodeficiency syndromes). Fatality rates for untreated severe AdV pneumonia or disseminated disease may exceed 50%. More than 50 serotypes of AdV have been identified. Different serotypes display different tissue trophisms and correlate with clinical manifestations of infection. The predominant serotypes differ among countries or regions and change over time. Transmission of novel strains between countries or across continents and replacement of dominant serotypes by new strains may occur. Treatment of AdV infections is controversial because prospective, randomized therapeutic trials have not been done. Cidofovir is considered the drug of choice for severe AdV infections, but not all patients require treatment. Vaccines have been shown to be highly efficacious in reducing the risk of respiratory AdV infection but are currently not available., (© Thieme Medical Publishers.)

The use of the acyclic nucleoside phosphonates, starting with (S)-HPMPA as the prototype, yielded three clinically approved antiviral drugs, cidofovir for the treatment of CMV retinitis in AIDS patients, adefovir dipivoxil for the treatment of chronic hepatitis B and tenofovir disoproxil fumarate for the treatment of HIV infections (AIDS) and HBV infections. This era has now grown to many more acyclic (and cyclic) nucleoside phosphonates (such as the "open ring" DAPy and Fd4A phosphonates) and alkoxyalkyl and phosphonoamidate prodrugs thereof, as well as new clinical applications, including new drug combination regimens for the treatment of AIDS, the chemoprophylaxis of HIV infections, and the anticancer potential against some malignant disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)