Cytomegalovirus Retinitis In AIDS Patients Research Articles

Monkeypox Virus: Transmission, Signs and Symptoms, Prevention, and Epidemiology

Monkeypox virus causes a zoonotic disease that is similar to smallpox-like illness. This review focuses on the overall epidemiology of monkeypox infection along with the transmission, signs and symptoms, treatment and prevention of the infection among humans. The early symptoms of the infection are flu-like and include fever, malaise, headache, papulopustular rash, sore throat and enlarged lymph nodes. Previously, it was reported in African countries only, with majority of the reported cases in Democratic Republic of Congo (DRC). Later in 2003, the first case of monkeypox infection was reported outside Africa in the U.S. with additional cases in the UK, Israel and Singapore. The transmission of monkeypox virus occurs primarily from animal to human and secondarily from human to human by contact with respiratory secretions or lesions of infected persons. Moreover, monkeypox virus can also be transmitted sexually from male to male and results in rashes and lesions around the genital or anal area of the infected person. Currently, there is no specific treatment for monkeypox infection. However, anti-viral treatment for smallpox, cytomegalovirus retinitis in AIDS patients, and the vaccine vaccinia virus intravenous immunoglobulins are the choice of therapeutics for treating the infection. This review focuses on the overall epidemiology of monkeypox infection along with the transmission, signs and symptoms, treatment and prevention of the infection among humans.

Development and Validation of a Deep Learning –Based  System for Detection of AIDS- Related  Cytomegalovirus Retinitis in Ultra-Wide-Field Fundus Images

Background: Ophthalmological screening for cytomegalovirus retinitis (CMVR) for HIV/AIDS patients is important. The application of a deep learning (DL) system to AIDS-related CMVR with ultra-wide-field (UWF) fundus images is promising, but the feasibility and efficiency of this method have not been studied. Methods: We independently developed and internally validated a DL system for identifying active CMVR, inactive CMVR and non-CMVR in 6960 UWF fundus images from 862 AIDS patients and validated the system in a prospective and an external validation data set using area under curve (AUC), accuracy, sensitivity, and specificity. A heat map identified the most important area (lesions) used by the DL system for differentiating CMVR. This trial is registered with ClinicalTrials.gov, number NCT04831333. Findings The DL system showed AUCs of 0·945 (95% confidence interval [CI]: 0·929, 0·962), 0·964 (95% CI: 0·870, 0·999) and 0·968 (95% CI: 0·860, 1·000) for detecting active CMVR from non-CMVR and 0·923 (95% CI: 0·908, 0·938), 0·902 (0·857, 0·948) and 0·884 (0·851, 0·917) for detecting active CMVR from non-CMVR in the internal cross-validation, external validation, and prospective validation, respectively. It also showed the ability to differentiate active CMVR from non-CMVR and inactive CMVR as well as to identify active CMVR and inactive CMVR from non-CMVR (all AUCs in the three independent data sets >0·900). The heat maps successfully highlighted lesion locations. Interpretation: Our system showed reliable performance for detecting AIDS-rated CMVR. DL technology is promising for screening and differentiating CMVR in AIDS patients. Clinical Trial: This trial is registered with ClinicalTrials.gov, number NCT04831333. Funding: Scientific Research Project of Beijing Youan Hospital, CCMU, 2018 (YNKTQN20180201); Capital Health Research and Development of Special (2020-1-2052); Science & Technology Project of Beijing Municipal Science & Technology Commission (Z181100001818003); Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20150201). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: This study was conducted in accordance with the Declaration of Helsinki. Both the Ethics Committee of Beijing YouAn Hospital (LL-2018-150-K) and the Ethics Committee of Beijing Tongren Hospital (TRECKY2018-056) approved the study. Written informed consent was obtained from each subject.

Spectral-domain optical coherence tomography finding in cytomegalovirus retinitis in AIDS patients.

To observe the findings of spectral domain optical coherence tomography (SD-OCT) scan in cytomegalovirus retinitis (CMVR). Forty-six eyes of 33 patients with acquired immunodeficiency syndrome and CMVR were enrolled in the study. Complete ophthalmologic examinations, color fundus photography, SD-OCT and fundus autofluorescence (FAF) were performed for all patients at the first visit and each follow-up visit. Retinal necrosis in CMVR was analyzed on SD-OCT and classified into two types, the typical type and the atypical type. Forty-one eyes of active CMVR and 4 eyes of recurrent CMVR were classified into typical type, and 4 eyes with graying retinal lesion without hemorrhage or only punctate hemorrhage were classified into atypical type. In active stage of CMVR, the retina in typical type was significant thickened with hyperreflective lesion and full-thickness disruption of retinal architecture with enlarged vessel; while in atypical type, the retina was also destroyed in all layers but without thickening or slightly thinned. The choroid, vitreous and retinal vessels were not significantly involved. In healed stage, the retina was thin with destroyed layers in both types. In typical type, FAF showed mottled hypofluorescence mixed with punctuate hyperfluorescence. In atypical type, the retina showed some "cavity" in outer nuclear layer, and FAF showed mild hyperfluorescence. SD-OCT show different changes in the retina in typical type and atypical type of CMVR, which should be useful in assisting diagnosis and follow-up management of the disease.

Cytomegalovirus Treatment

Opinion statementIn treating cytomegalovirus (CMV) infection, it is crucial to decide whether one is treating pre-emptively or if one is treating established disease. Disease may be further divided into viral syndrome and tissue-invasive disease. Generally, mild disease in immunosuppressed patients may be treated with oral valganciclovir. Treatment may also be started with valganciclovir for CMV retinitis in AIDS patients. In other tissue-invasive syndromes, starting with intravenous ganciclovir or foscarnet at full doses (adjusted for renal function) is preferred. Treatment at full doses should be continued until symptom resolution and until blood antigenemia (or DNAemia) is cleared. Patients receiving treatment must be closely monitored for side effects to the drugs, as well as for response. Drug-resistant CMV is a therapeutic challenge; combination therapy with both ganciclovir and foscarnet may be tried. In extreme cases, resorting to unconventional agents like leflunomide or maribavir may be necessary. Immune reconstitution, through reduction in immunosuppression, or the introduction of anti-retroviral therapy, should be attempted. CMX001 is a novel agent active against double-stranded viruses; thus far, resistance to CMX001 does not confer resistance to ganciclovir or foscarnet. Hence, prophylaxis or pre-emptive treatment with CMX001 may allow the use of ganciclovir or foscarnet for treatment.

Study of the ionic equilibriums in aqueous solutions and coordination properties of Adefovir and Cidofovir used as antiviral drugs

The dissociation constants of Adefovir ({[2-(6-amino-9H-purine-9-l)ethoxi]methyl}phosphoric acid) used in the treatment of hepatitis B and Cidofovir ({[2-(6-amino-9H-purine-9-l)ethoxi]methyl}phosphoric acid), used in the treatment of cytomegalovirus retinitis in AIDS patients, together with the stability constants of its Cu2+, Ni2+, Zn2+, Co2+, Ca2+, and Mg2+ complexes were studied by potentiometric titration. Adefovir and Cidofovir were abbreviated to PMEA and HPMPC. All measurements were obtained under two sets of conditions: at 298K and ionic strength (I) of 0.1moldm−3 (NaCl) and at 310K and I of 0.16moldm−3 (NaCl), corresponding to the conditions of human blood. Equilibrium constants in aqueous solution were calculated using the program SUPERQUAD. Also, solvent effects on the equilibrium constants of the ligands were examined. Moreover, all coordination studies were carried out with the ligand/metal molar ratios of 1:1. This ligand/metal stoichiometric ratio was spectrometrically determined using Job's method.

Utilité du cidofovir topique dans le traitement des molluscums contagiosums en contexte d’immunosuppression thérapeutique chez l’enfant

Molluscum contagiosum (MC) is common and often numerous and recalcitrant in immunocompromised children. The response to available treatments is frequently unsatisfactory. Cidofovir is a nucleoside analog of the deoxycytidine antiviral drug approved for the intravenous treatment of cytomegalovirus retinitis in AIDS patients. We report four cases of children, 5-8 years old, who developed extensive MC in the context of chemotherapy for acute lymphoid leukemia and who were treated with a cream containing cidofovir 1%. In all patients, the lesions began to regress within 2 to 4 months. For three patients, complete regression was observed in 7 to 9 months, and the children remained clear of recurrence. For one patient, partial regression was obtained after 17 months of treatment. No side effects have been observed. Treatment of MC in immunocompromised children is difficult because the usual treatments are inappropriate. Successful use of either topically or intralesionally administered cidofovir in several virally induced cutaneous diseases has been demonstrated and recently documented in the treatment of MC in immunocompromised adults. Conversely, its use in children is not documented. Although intravenous use of cidofovir may lead to severe adverse effects, one single case of a systemic side effect has been reported after topical use at a greater concentration, but no changes in laboratory data were observed. Topical cidofovir offers an effective and well-tolerated therapeutic alternative option for the treatment of MC in immunosuppressed children.

Prevalence and clinical management of cytomegalovirus retinitis in AIDS patients in shanghai, china

BackgroundCytomegalovirus retinitis is a common AIDS-associated illness, leading to blindness in up to 30% of patients. This study was to investigate the prevalence and clinical management of the cytomegalovirus retinitis associated with AIDS in a large municipality of China.MethodsClinical and laboratory data from 23 cytomegalovirus retinitis patients (35 eyes) out of 303 hospitalized AIDS individuals in a single medical center were analyzed retrospectively. Two of 23 patients were diagnosed cytomegalovirus retinitis just before hospitalization without anti-CMV therapy. Ganciclovir combined with the high active anti-retroviral therapy was installed for treatment of cytomegalovirus retinitis after diagnosis was confirmed. The data were analyzed by specialists and statistics was also applied.ResultsThe prevalence of cytomegalovirus retinitis in hospitalized AIDS patients was 7.6% in this study. The level of CD4+ T lymphocytes was correlated well with the occurrence of cytomegalovirus retinitis, showing 16.8% (19/113) (95% confidence interval: 10.4,25.0), 5.4% (3/56) (95% confidence interval: 1.1,14.9), and 1.4% (1/69) (95% confidence interval: 0.0,7.8) occurrence in the patients with CD4+ T lymphocyte counts < 50, 50~99, and 100~199 cells/μl, respectively. The mean CD4+ T lymphocyte counts was 31.7 ± 38.6 cells/μl in 23 AIDS patients with cytomegalovirus retinitis. Median CD4+ T lymphocyte count is 20 cells/μl with inter-quartile range as (5, 36). Seven patients died (11 eyes) and 16 patients (24 eyes) survived. The proportion of blindness and low vision in eyes infected with cytomegalovirus retinitis respectively was 20.8% (5/24) and 29.2% (7/24) when they were diagnosed in survivors. The ganciclovir therapy was effective in 16 patients (24 eyes). Clinical recovery of cytomegalovirus retinitis was 41.7% (10/24) and clinical improvement 58.3% (14/24). After anti-CMV treatment, the proportion of blindness or low vision was 16.7% (4/24).ConclusionsThe AIDS patients with CD4+ T lymphocyte < 50 cells/μl had increased susceptibility to cytomegalovirus associated retinitis. Cytomegalovirus retinitis is a serious disease causing blindness. The cytomegalovirus retinitis in the AIDS patients was response well to ganciclovir therapy. We should check their eyes routinely such as dilated fundus examination with an indirect ophthalmoscope in the AIDS patients with CD4+ T lymphocyte counts < 50 cells/μl.

Tumor necrosis factor region polymorphisms are associated with AIDS and with cytomegalovirus retinitis

The tumor necrosis factor (TNF) gene is located within the highly polymorphic major histocompatibility complex region, exhibiting the -308 GA promoter region polymorphism and six microsatellites (TNFa-f) spanning the region nearby the TNF locus. In the present study, we evaluated the frequency of -308 GA and TNFa-e polymorphisms and respective haplotypes (in chromosomal sequence: TNFd-TNFe-308GA-TNFc-TNFa-TNFb), in 222 patients with AIDS, 52 of whom exhibited cytomegalovirus retinitis, and in 202 healthy HIV-negative individuals. TNF microsatellite and single nucleotide polymorphism typings were performed by PCR followed by polyacrylamide gel electrophoresis. The TNF-308A allele and the 4-3-G-2-7-1 haplotype were associated with susceptibility to AIDS, whereas the TNFb4 allele and the 3-3-G-1-11-4 haplotype were associated with protection against AIDS development. The TNFc2 allele and the 4-1-G-2-2-1 haplotype, which contains the TNFc2 allele, were associated with cytomegalovirus retinitis. This study highlights that polymorphic sites spanning the region nearby the TNF locus are associated with AIDS per se and with cytomegalovirus retinitis in AIDS patients.

Efficacy of therapeutic intervention with an oral ether–lipid analogue of cidofovir (CMX001) in a lethal mousepox model

In the 21st century we are faced with the potential use of natural or recombinant VARV and MPXV as biological weapons, and the emergence of human MPXV. Such an occurrences would require therapeutic and prophylactic intervention with antivirals. Cidofovir, an antiviral approved for the treatment of cytomegalovirus retinitis in AIDS patients, has activity against poxviruses, but must be administered intravenously and is associated with nephrotoxicity. An ether–lipid analogue of CDV, CMX001 (HDP-CDV), has potent antiviral activity against a range of DNA viruses including poxviruses, excellent oral bioavailability and minimal nephrotoxicity. CMX001 and CDV are equally efficacious at protecting mice from mortality following high ectromelia virus doses (10,000 × LD 50) introduced by the intra-nasal route or small particle aerosol. Using CMX001 at a 10 mg/kg dose followed by 2.5 mg/kg doses every other-day for 14 days provided solid protection against mortality and weight loss following an intra-nasal challenge of (100–200) × LD 50 of ectromelia virus. Furthermore, complete protection against mortality was achieved when administration was delayed until as late as 5 days post-infection, which is 3–4 days prior to the death of the untreated controls. This therapeutic window would be equivalent to intervening during the rash stage of ordinary smallpox.

Withdrawal of maintenance therapy for cytomegalovirus retinitis in AIDS patients exhibiting immunological response to HAART

Before the introduction of highly active antiretroviral therapy (HAART), CMV retinitis was a common complication in patients with advanced HIV disease and the therapy was well established; it consisted of an induction phase to control the infection with ganciclovir, followed by a lifelong maintenance phase to avoid or delay relapses. To determine the safety of CMV maintenance therapy withdrawal in patients with immune recovery after HAART, 35 patients with treated CMV retinitis, on maintenance therapy, with CD4+ cell count greater than 100 cells/mm(3) for at least three months, but almost all patients presented these values for more than six months and viral load < 30000 copies/mL, were prospectively evaluated for the recurrence of CMV disease. Maintenance therapy was withdrawal at inclusion, and patients were monitored for at least 48 weeks by clinical and ophthalmologic evaluations, and by determination of CMV viremia markers (antigenemia-pp65), CD4+/CD8+ counts and plasma HIV RNA levels. Lymphoproliferative assays were performed on 26/35 patients. From 35 patients included, only one had confirmed reactivation of CMV retinitis, at day 120 of follow-up. No patient returned positive antigenemia tests. No correlation between lymphoproliferative assays and CD4+ counts was observed. CMV retinitis maintenance therapy discontinuation is safe for those patients with quantitative immune recovery after HAART.

Efficacy of Valganciclovir in the Treatment of Cytomegalovirus Disease in Kidney and Pancreas Transplant Recipients

Cytomegalovirus (CMV) disease is relatively common following solid organ transplant, particularly if a serologically negative recipient receives an organ from a serologically positive donor (D +/R −). Although valganciclovir is approved for the treatment of CMV retinitis in AIDS patients and is used for the prophylaxis against CMV infection in solid organ transplant patients, the current standard treatment for CMV disease in solid organ transplant recipients remains intravenous ganciclovir. We retrospectively reviewed our experience using valganciclovir as treatment for CMV disease in CMV D +/R − kidney and/or pancreas transplant recipients from March 2002 to June 2005. A total of 37 cases with primary CMV disease were diagnosed and treated with either intravenous ganciclovir as induction followed with valganciclovir or valganciclovir from the beginning. We compared clinical outcomes and viremia between the two groups. Our data suggest that valganciclovir is an effective treatment modality for primary CMV disease in kidney and/or pancreas transplant recipients. It led to the resolution of disease and undetectable viremia. Valganciclovir allowed for early initiation of treatment and for treatment to be given as an outpatient. These advantages of valganciclovir have both health and economic impact for patients with CMV disease.

Safety of Cidofovir in High-Risk Paediatric Patients.

Purpose: Cidofovir has efficacy in the treatment of adenovirus and cytomegalovirus (CMV) infection in immunocompromised individuals. It is licensed for the treatment of CMV retinitis in AIDS patients over the age of 12 years, and is nephrotoxic and contra-indicated with the use of other concomitant nephrotoxic agents. Its use has been further limited due to concerns regarding an individual's ability to tolerate the hydration regimens associated with cidofovir administration. Despite this it is a valuable anti-viral agent particularly in the setting of haemapoietic stem cell transplantation. This study assessed the safety of cidofovir in a high-risk paediatric population.Methods: A retrospective review of all episodes of cidofovir administration at the Oncology Unit at the Children's Hospital at Westmead from 2000–2005 was undertaken. The dose of cidofovir and renal function (measured by urea and creatinine) pre and post infusion were recorded, and the medical notes reviewed for adverse events and concomitant use of other nephrotoxic drugs.Results: A total of 233 cidofovir infusions in 23 patients were studied.Patients: Age range 5 months - 19 years (mean 6.6 years). Sex: male 17 (74%), female 6 (26%). Clinical setting: 16 (70%) were post allogeneic stem cell transplantation, 4 (17%) were post autologous stem cell transplation, 3 (13%) had other malignancies. Indications for cidofovir: In 20 (87%) for proven adenovirus identified in stool, urine, nasopharyngeal aspirate, CSF, or tissue biopsy; 2 (9%) for adenovirus prophylaxis as part of haplo-identical stem cell transplant conditioning, 1 (4%) for extended coverage in sepsis without an identified organism. Cidofovir doses: 111 (48%) were 1mg/kg, 75 (32%) were 3mg/kg, 47 (20%) were 5mg/kg. All episodes of cidofovir administration received the same standard recommended regimen of oral probenecid 40mg/kg at hour -3, 20ml/kg of intravenous 0.9% NaCl from hour −1 to 0, cidofovir infusion with 20ml/kg 0.9% NaCl from hour 0 to +1, maintenance intravenous fluids from hour +1 to +3, followed by oral probenecid 20mg/kg at hour +3 and +9. All patients received concomitant nephrotoxic agents: 4 (17%) received 1, 4 (17%) received 2, 5 (22%) received 3, and 10 (43%) received 4 or more agents. In 19 (83%) patients with normal renal function (defined by urea/creatinine within normal range for age), there was no evidence of nephrotoxicity (defined as >150% increase in urea/creatinine from baseline) following cidofovir therapy - mean change in urea/creatinine pre and post infusion −7.5%/+5.6%. There was no deterioration in renal function in 4 (17%) patients with pre-existing renal impairment (defined by urea/creatinine above the upper limit of normal) - mean change in urea/creatinine pre and post infusion −10.9%/+3.0%. Symptomatically cidofovir was tolerated by 20 (87%) patients without adverse events. Cidofovir therapy was associated with significant morbidity in 3 (17%) patients - 1 developed blindness and axonal degeneration of unknown aetiology, and in 2 patients, both with pre-existing pneumonitis post allogeneic stem cell transplantation, the fluid regimen precipitated a respiratory deterioration secondary to fluid overload.Conclusion: Cidofovir is a safe and well tolerated drug in a high-risk paediatric population, even with the use of concomitant nephrotoxic agents. An aggressive fluid regimen may not be necessary, with particular care required in patients with significant pulmonary disease in whom the fluid regimen may precipitate respiratory compromise.

Valganciclovir for cytomegalovirus prevention and treatment

Cytomegalovirus (CMV) continues to be an important cause of significant disease in various groups of immunocompromised hosts, including organ and hematopoietic stem cell transplant recipients and AIDS patients. Therapeutic and preventative strategies have been used in these patients to improve overall outcomes. Ganciclovir has traditionally been the first-line drug for the treatment and prevention of CMV. Valganciclovir is a prodrug of ganciclovir with enhanced oral bioavailability. Studies have shown that it is effective for the prevention of CMV disease in high-risk (donor seropositive/recipient seronegative) solid-organ transplant recipients. It is also as effective as intravenous ganciclovir for the treatment of CMV retinitis in AIDS patients. The side-effect profile is similar to ganciclovir. Treatment studies in solid-organ transplant recipients, evaluation in pediatric patients, and prevention studies in stem cell recipients are ongoing and will help define the full role of valganciclovir in immuno...

ANTIVIRAL POTENTIAL OF A NEW GENERATION OF ACYCLIC NUCLEOSIDE PHOSPHONATES, THE 6-[2-(PHOSPHONOMETHOXY)ALKOXY]-2,4-DIAMINOPYRIMIDINES

Three acyclic nucleoside phosphonates (ANPs) have been formally approved for clinical use in the treatment of 1) cytomegalovirus retinitis in AIDS patients (cidofovir, by the intravenous route), 2) chronic hepatitis B virus (HBV) infections (adefovir dipivoxil, by the oral route), and 3) human immunodeficiency virus (HIV) infections (tenofovir disoproxil fumarate, by the oral route). The activity spectrum of cidofovir {(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [(S)-HPMPC)]}, like that of (S)-HPMPA {(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine} and (S)-HPMPDAP {(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine}, encompasses a broad spectrum of DNA viruses, including polyoma-, papilloma-, adeno-, herpes-, and poxviruses. Adefovir {9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)} and tenofovir {(R)-9-[2-(phosphonomethoxy) propyl]adenine [(R)-PMPA)]} are particularly active against retroviruses (i.e., HIV) and hepadnaviruses (i.e., HBV); additionally, PMEA also shows activity against herpes- and poxviruses. We have recently identified a new class of ANPs, namely 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines, named, in analogy with their alkylpurine counterparts, HPMPO-DAPy, PMEO-DAPy, and (R)-PMPO-DAPy. These compounds exhibit an antiviral activity spectrum and potency that is similar to that of (S)-HPMPDAP, PMEA, and (R)-PMPA, respectively. Thus, PMEO-DAPy and (R)-PMPO-DAPy, akin to PMEA and (R)-PMPA, proved particularly active against HIV-1, HIV-2, and the murine retrovirus Moloney sarcoma virus (MSV). PMEO-DAPy and (R)-PMPO-DAPy also showed potent activity against both wild-type and lamivudine-resistant strains of HBV. HPMPO-DAPy was found to inhibit different poxviruses (i.e., vaccinia, cowpox, and orf) at a similar potency as cidofovir. HPMPO-DAPy also proved active against adenoviruses. In vivo, HPMPO-DAPy proved equipotent to cidofovir in suppressing vaccinia virus infection (tail lesion formation) in immunocompetent mice and promoting healing of disseminated vaccinia lesions in athymic-nude mice. The 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines offer substantial potential for the treatment of a broad range of retro-, hepadna-, herpes-, adeno-, and poxvirus infections.

Treatment of Cytomegalovirus Infection or Disease in Solid Organ Transplant Recipients With Valganciclovir

Valganciclovir (VGC) has proved efficacious and safe for the prophylaxis against cytomegalovirus (CMV) in high-risk transplant recipients and for the treatment of CMV retinitis in AIDS patients. We used VGC for the treatment of CMV infection (viremia without symptoms) or disease (CMV syndrome or tissue-invasive disease) in kidney, heart, and lung transplant recipients. Fourteen transplant recipients were treated: five for asymptomatic CMV infection and nine for CMV disease. VGC was administered in doses adjusted to renal function for 4 to 12 weeks (induction and maintenance therapy). Clinically, all nine patients with CMV disease responded to treatment. Microbiologically, treatment with VGC turned blood culture negative for CMV within 2 weeks in all patients and was associated with a ≥2 log decrease in blood CMV DNA within 3 weeks in 8 of 8 tested patients. With a follow-up of 6 months ( n = 12 patients), asymptomatic recurrent CMV viremia was noted in five cases, and CMV syndrome noted in one case (all cases in the first 2 months after the end of treatment). VGC was clinically well tolerated in all patients; however, laboratory abnormalities occurred in three cases (mild increase in transaminases, thrombocytopenia, and pancytopenia). This preliminary experience strongly suggests that therapy with VGC is effective against CMV in organ transplant recipients; however, the exact duration of therapy remains to be determined: a longer course may be necessary to prevent early recurrence.

Therapeutic potential of nucleoside/nucleotide analogues against poxvirus infections.

Several nucleoside and nucleotide analogues have been identified as potent antiviral agents with convincing activity against poxviruses (including variola, vaccinia, monkeypox, cowpox, molluscum contagiosum, orf). Among the nucleoside analogues, 8-methyladenosine and 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242), have been identified as promising anti-poxvirus agents. Among the nucleotide analogues, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC, cidofovir], (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP] and (S)-6-(3-hydroxy-2-phosphonylmethoxypropyl)oxy-2,4-diaminopyrimidine [(S)-HPMPO-DAPy] have been identified as promising anti-poxvirus agents. These nucleoside and nucleotide analogues have proved to be efficacious in various animal models for poxvirus infections. Only one compound, cidofovir, has also proved efficacious against poxvirus infections in humans, i.e. molluscum contagiosum and orf (sheep pox). Cidofovir is formally licensed for clinical use (intravenous administration for the treatment of cytomegalovirus retinitis in AIDS patients); however, it could also be formulated for topical administration, or for oral administration in prodrug form, i.e. as 1-O-hexadecyloxypropyl-cidofovir.

TREATMENT OF CMV INFECTION OR DISEASE IN SOLID ORGAN TRANSPLANT PATIENTS WITH VALGANCICLOVIR

P810 Background: Valganciclovir (VGC) is a valyl ester of ganciclovir with much improved oral biodisponibility. It has proved successful for the prophylaxis against Cytomegalovirus (CMV) in high risk transplant recipients (CMV serostatus D+/R-), and for the treatment of newly diagnosed CMV retinitis in AIDS patients. We have recently used VGC for the treatment of CMV infection (viremia without symptoms) or disease (CMV syndrome or tissue-invasive disease) in kidney and lung transplant recipients. Methods: In 2003, 10 transplant recipients (7 kidney and 3 lung) were treated between 6 to 26 weeks after transplantation. CMV serostatus was D+/R- (n=7), D+/R+ (n=2), and D-/R+ (n=1). Three patients had received valaciclovir and 5 patients VGC prophylaxis during the first 3 months after transplantation. Four patients were treated for CMV infection and 6 for CMV disease (hepatitis n=1, colitis n=2, pneumonia n=1, CMV syndrome n=2). VGC was administered for 2 to 3 weeks (900 – 1800 mg per day, according to the renal function), followed by 2 to 4 weeks of secondary prophylaxis (450 – 900 mg per day, according to the renal function). Results: Clinically, all 6 symptomatic patients were cured. Microbiologically, treatment with VGC turned blood culture negative for CMV within 2 weeks in 10/10 patients, and was associated with a 2 log decrease in blood CMV DNA within 2 weeks in 3/3 tested patients. With a follow-up of 6 months, asymptomatic recurrent CMV viremia was noted in 5 cases, and CMV syndrome in one case. VGC was well tolerated in all patients, however an increase in transaminases was observed after 4 weeks of therapy in one case. Conclusions: Our preliminary experience strongly suggests that VGC is safe and effective to treat CMV infection/disease in organ transplant recipients, however the exact duration of therapy remains to be determined.

Foscarnet used in salvage therapy of HIV-1 patients harbouring multiple nucleotide excision mutations.

We used foscarnet as induction therapy or as maintenance therapy in different dosing regimens in seven severely immunocompromised multidrug-resistant HIV-1 patients. During induction the median decrease in viral load was 1.8 log and increases in CD4 cell counts ranging from zero to 136 cells/mm 3 were observed during maintenance therapy, suggesting that foscarnet could be an option in salvage therapy in patients with no treatment options left.

Influence of the Response to Induction Therapy on the Rate of Progression of Cytomegalovirus Retinitis in AIDS Patients on Intravitreal Maintenance Therapy

In order to assess whether complete inactivation of retinitis at the end of induction therapy leads to delayed progression during maintenance therapy with weekly intravitreal ganciclovir, the time to the first progression to retinitis was evaluated in 27 AIDS patients (34 eyes) with stable cytomegalovirus retinitis. Data were censored before the introduction of protease inhibitors. Overall, retinitis progressed in 22 of 34 eyes in a median time of 12 weeks (mean +/- SD, 33 +/- 9 weeks). However, retinitis progressed in 15 of 19 eyes in which only partial inactivation was achieved following induction therapy (median time, 10 weeks; mean +/- SD, 17 +/- 4 weeks) but in only 7 of 15 eyes when complete inactivation was obtained (median time, 59 weeks; mean +/- SD, 56 +/- 19 weeks) (P= 0.02). There were no differences between the groups in CD4+ cell counts, drugs, route of induction treatment, or length of induction therapy. Induction therapy should be prolonged until complete inactivation of retinitis is obtained, since achieving only a partial response appears to be a factor in earlier progression when patients are switched to maintenance therapy with intravitreal ganciclovir.

Successful preemptive cidofovir treatment for CMV antigenemia after dose-reduced conditioning and allogeneic blood stem cell transplantation.

Cidofovir (CDV) is a nucleotide analogue with proven in vitro effects against cytomegalovirus (CMV) and adenovirus and has been successfully used in the treatment of CMV retinitis in AIDS patients. We performed a prospective study to evaluate the efficacy of CDV in 17 patients with hematological malignancies after allogeneic blood stem cell transplantation from related (n=3) and unrelated (n=14) donors. Dose-reduced conditioning (DRC) regimen consisted of busulfan (Bu)/fludarabine (Flu) (n=9) and idarubicin/cytosine arabinoside/Flu (n=1). Myeloablative conditioning (MC) was performed with Bu/cyclophosphamide (Cy)/etoposide (Eto) (n=4), Bu/Cy (n=2), and total body irradiation (TBI)/Cy/Eto (n=1). Antithymocyte globulin (ATG) was used in seven patients with DRC and in six patients with MC. In all patients, either the donor, host, or both were CMV IgG positive pretransplant. Indication for therapy was preemptive treatment of primary CMV antigenemia defined as two consecutive positive tests of pp65 antigenemia assay after transplant. In case of response with a decreasing number of pp65-positive leukocytes, CDV was scheduled in a dosage of 5 mg/kg body weight once a week for 2 weeks followed by maintenance therapy every 2 weeks in an outpatient setting. All patients received probenecid and prehydration as recommended. Patients were monitored using an immunostaining assay for pp65 antigen and a qualitative and quantitative CMV polymerase chain reaction (PCR). Success of treatment was defined as negativity for the pp65 antigen. After DRC, nine of ten patients (90%) showed a response with seven of nine revealing a complete clearance of the virus (pp65 negative, qualitative PCR negative). In the remaining two responders, treatment was changed to ganciclovir because of either renal impairment or slow clearance of antigenemia. Only one of seven patients in the MC group experienced a temporary clearance of pp65 antigen. After MC, two patients experienced CMV disease. Treatment-related toxicity rate was moderate with four patients developing reversible renal impairment (creatinine 133-180 micromol/L); one patient with proteinuria and three patients with complaints of nausea and vomiting. Our data suggest the feasibility of CDV administration in patients after allogeneic transplantation. In the recommended dose, it might be used successfully for low-risk patients, e.g., after DRC or organ transplantation, in an outpatient setting.