Acquisition of carbapenemase-producing Enterobacteriaceae by healthy travellers to India, France, February 2012 to March 2013.

Healthy travellers to countries where carbapenemases-producing Enterobacteriaceae (CPE) are endemic might be at risk for their acquisition, even without contact with the local healthcare system. Here, we report the acquisition of CPE (two OXA-181, one New Delhi metallo-beta-lactamase 1 (NDM-1)) in three healthy travellers returning from India. The duration of CPE intestinal carriage was less than one month. The results indicate that healthy travellers recently returning from India might be considered as at risk for CPE carriage.

Late dihydroartemisinin-piperaquine treatment failure of P. falciparum malaria attack related to insufficient dosing in an obese patient.

We report the case of an obese patient who experienced late failure on day28 of a well-conducted treatment with artesunate, followed by dihydroartemisinin-piperaquine (DHA-PPQ) for a severe P. falciparum malaria attack. The same P. falciparum strain was evidenced at day0 and day28. Genotypic and phenotypic resistance tests could not explain this treatment failure. The low plasma piperaquine concentration at failure may explain the poor elimination of residual parasites.

Imported malaria in metropolitan France, from recommendations to clinical practice - proposal for improvement.

BACKGROUND: Approximately 5000 cases of imported malaria are observed each year in metropolitan France. Guidelines for the prevention and management of imported malaria were published by the French infectious disease society (French acronym SPILF) in 2017. OBJECTIVE: Study objective was to describe in a retrospective analysis (2015-2016) imported malaria cases recorded in a Parisian hospital, to analyze the congruence to previous guidelines (2014), deviation in respect to post hoc published guidelines and potential areas for improvement. RESULTS: Two hundred and one cases were analyzed using medical charts. There was a majority of men (sex ratio 2/1), with a mean age of 43 years at diagnosis. The main area of infection acquisition was sub-Saharan Africa (97%). The average time since return from the endemic area was 20 days. Patients consulted the emergency department for flu-like syndrome (32%), fever or chills (28%), and gastrointestinal symptoms (22%). Blood smears mainly identified Plasmodium falciparum (n=180, 90%). There were 52 (26%) severe malaria episodes. CONCLUSION: The analysis of national guideline adequacy highlighted difficulties in obtaining a complete biological workup at baseline, managing patients with vomiting, and in the post-treatment follow-up.

Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1.

BACKGROUND: Management of pregnant women with human immunodeficiency virus (HIV) type 2 infection remains unclear because of its low prevalence and important differences from HIV-1. METHODS: Pregnant women monoinfected with HIV-2 or HIV-1 and their infants enrolled in the prospective, national, multicenter French Perinatal Cohort between 1986 and 2007. RESULTS: Overall, 2.6% (223/8660) of mothers were infected with HIV-2, and they accounted for 3.1% (367/ 11841) of the total births. Most were born in sub-Saharan Africa. A higher proportion of HIV-2-infected mothers than HIV-1-infected mothers had no symptoms, had received no antiretroviral therapy at conception (85.9% vs 66.7%), and had received no antiretroviral therapy during pregnancy (42.8% vs 19.9%), particularly highly active antiretroviral therapy (HAART) (79.7% vs 46.1%), and they had higher CD4 cell counts near delivery (median, 574 vs 452 cells/mm3; P < .01). If antiretroviral therapy was used, it was started at a later gestational age for HIV- 2-infected mothers (median, 28 vs 25 weeks; P < .01). HIV-2-infected mothers were more likely to deliver vaginally (67.9% vs 49.3%) and to breastfeed (3.6% vs 0.6%; P < .01), and their infants less frequently received postexposure prophylaxis. In the period 2000-2007, the proportion with viral load <100 copies/mL at delivery was 90.5% of HIV-2-infected mothers, compared with 76.2% of HIV-1-infected mothers (P=.1). There were 2 cases of transmission: 1 case in 1993 occurred following maternal primary infection, and the other case occurred postnatally in 2002 and involved a mother with severe immune deficiency. The mother-to-child transmission rate for HIV-2 was 0.6% (95% confidence interval, 0.07%-2.2%). CONCLUSIONS: Care for HIV-2-infected pregnant women rests on expert opinion. The mother-to-child transmission residual rate (0.07%-2.2%) argues for systematic treatment: protease inhibitor-based HAART for women requiring antiretrov

Management of oral antiretroviral administration in patients with swallowing disorders or with an enteral feeding tube.

HIV infection has evolved into a chronic disease with comorbidities since the combination antiretroviral therapy era. Complications still occur and patients may need to be admitted to an intensive care unit. Acute respiratory failure is the first cause of these admissions, questioning the administration of solid oral dosage formulations. This issue is also observed in geriatric units where the prevalence of dysphagia is high and underestimated. The problem of antiretroviral administration is critical: altered solid oral dosage formulations and/or administration via enteral feeding tubes are sometimes the only option. The aim is to help manage antiretroviral treatment in unconscious or intubated patients and those with swallowing disorders who are hospitalized in intensive care units or geriatric units. This review provides information on the main antiretroviral regimens and on practical and legal aspects of manipulating solid oral dosage formulations and administration via enteral feeding tubes. Alternatives to the solid formulation are available for most of the 27 oral antiretrovirals available, or manufacturers provide recommendations for patients who are unable to swallow. Manipulation of solid oral dosage formulations such as crushing tablets or opening capsules and administration via feeding tubes are frequently reported but should be the last option for safety and liability issues. Before any off-label administration of a drug, physicians should consider alternatives to the solid oral dosage formulation and check whether the drug can be altered. Therapeutic monitoring is important in this particular setting as the pharmacokinetic profile of drugs is difficult to predict.

HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro.

OBJECTIVES: We investigated the in vitro phenotypic susceptibility of HIV-2 isolates from integrase inhibitor (INI)-naive patients to INIs and its relation to HIV-2 integrase gene polymorphism. METHODS: We determined the phenotypic susceptibility to raltegravir and elvitegravir of co-cultured isolates obtained from the HIV-2 ROD reference strain and from 14 clinical isolates. IC(50) values were compared with those for HIV-1 reference strains. HIV-2 integrase gene polymorphism was assessed in isolates from 52 INI-naive patients enrolled in the French HIV-2 cohort. RESULTS: Median raltegravir and elvitegravir IC(50) values for the 14 clinical HIV-2 isolates were 2.4 and 0.7 nM, respectively, and were similar to those observed for HIV-2 ROD and HIV-1 reference strains. Overall, 38% of HIV-2 integrase amino acids were polymorphic. The catalytic triad DDE and the HHCC and RKK motifs were fully conserved, at the same genomic positions as described in HIV-1. In subtype B isolates, the total length of the integrase gene varied, owing to the presence of stop codons at positions 288, 294, 297 and 302. Fourteen of the positions associated with substitutions conferring INI resistance in HIV-1 were polymorphic in HIV-2. CONCLUSIONS: Despite 40% heterogeneity between the HIV-1 and HIV-2 integrase genes, the phenotypic susceptibility of clinical HIV-2 isolates to INIs was similar to that of HIV-1. This new class of antiretroviral drugs thus represents a novel therapeutic possibility for HIV-2-infected patients who otherwise have few treatment options.

[Tolerance and efficacy of atovaquone-proguanil for the treatment of paediatric imported Plasmodium falciparum malaria in France: clinical practice in a university hospital in Paris]. / Tolérance et efficacité de l'atovaquone-proguanil dans le traitement du paludisme d'importation àPlasmodium falciparum de l'enfant en France métropolitaine: expérience d'un centre hospitalier parisien.

UNLABELLED: Only few drugs for uncomplicated Plasmodium falciparum malaria are available in children. Atovaquone-proguanil is a recent antimalarial drug licensed in France for the uncomplicated P. falciparum malaria in adults. Few paediatric studies have evaluated atovaquone-proguanil in children for uncomplicated malaria in endemic area, but no study have evaluated this treatment for imported malaria. OBJECTIVE: To evaluate treatment by atovaquone-proguanil for uncomplicated and imported P. falciparum malaria in children. METHODS: We retrospectively evaluated the tolerance and the efficacy of atovaquone-proguanil in the children admitted in Robert-Debré Hospital (Paris) for a P. falciparum malaria. From January 2004 to December 2005, 48 children with a median age of 7,5 years (IQR 4-11) were treated with atovaquone-proguanil for a uncomplicated P. falciparum malaria, except for 5 children who had an isolated hyperparasitemia greater or equal to 5%. RESULTS: Atovaquone-proguanil was stopped for 3/48 children because of vomiting. Fever resolved in all the children between Day 3 and 7, following the beginning of the treatment. One child, with a favourable outcome, had a positive parasitemia at Day 4 equal to the initial parasitemia (0,1%). No late therapeutic failure was observed among the 24 children evaluated up to one month after starting treatment. CONCLUSION: Atovaquone-proguanil is an efficient and well-tolerated antimalarial treatment for uncomplicated P. falciparum malaria in children. The risk of vomiting should lead to a systematic initial hospitalisation of children treated with atovaquone-proguanil.

[Mode of delivery of HIV-infected women: a retrospective study of 358 pregnancies followed in the same hospital between 2000 and 2004]. / Accouchement des patientes enceintes infectées par le VIH: étude rétrospective de 358 grossesses suivies entre 2000 et 2004.

OBJECTIVE: Evaluate the mode of delivery of HIV-infected women and the risk of mother-to-child transmission. PATIENTS AND METHODS: A retrospective study conducted on HIV-infected women who delivered at the maternity ward of Bichat Hospital in Paris between 1st January 2000 and 31(st) December 2004. Pregnancy care, antiretroviral therapy, decision of the mode of delivery and neonate treatment were conformable to the French recommendations. RESULTS: The analysis was performed on 332 cases out of 358 pregnancies followed during this period. 75% received a Highly Active Anti Retroviral Therapy (HAART), 24% an AZT monotherapy and 1% did not receive any antiretroviral treatment. Plasmatic HIV viral load was under the level of detectability (50 copies/ml) for 64,6% of women under HAART and 28,7% of women under AZT monotherapy. Only 31,7% of women under HAART delivered vaginally. 44,7% of women under HAART with undetectable viral load at the moment of delivery delivered vaginally. 59,5% of women who were allowed to deliver vaginally had finally a vaginal delivery. 332 women gave birth to 341 babies with 9 twin pregnancies and one still-birth at 22 WA. Out of these 340 babies, 3 babies whose mother received HAART were HIV infected (2 in utero and 1 per-partum). DISCUSSION AND CONCLUSION: The reasons why only one third of HIV-infected women could deliver vaginally in this study are primarily the persistence of a detectable HIV viral load under HAART. Women's choice of the mode of delivery comes next, which depends on the quality of the counselling about the benefits and risks of the cesarean section in the context of HIV infection. The third reason is obstetrical contra indications to vaginal delivery in the context of HIV infection. In the future, it is possible to reduce the incidence of cesarean section in HIV-infected women by elevating the level of HIV plasmatic viral load which allowed vaginal delivery (1000 copies/ml), by improving the observance to antiretroviral treatment, by adaptating antiretroviral medications posology using determination of serum protease inhibitors concentration and by modifying obstetrical management with less restrictive contra indications to vaginal delivery. However the impact of prophylactic cesarean section when plasmatic HIV viral load is undetectable must still be evaluated.

[Zika virus infection during pregnancy]. / Infection par le virus Zika chez la femme enceinte.

A Zika virus epidemic is currently ongoing in the Americas. This virus is linked to congenital infections with potential severe neurodevelopmental dysfunction. However, incidence of fetal infection and whether this virus is responsible of other fetal complications are still unknown. National and international public health authorities recommend caution and several prevention measures. Declaration of Zika virus infection is now mandatory in France. Given the available knowledge on Zika virus, we suggest here a review of the current recommendations for management of pregnancy in case of suspicious or infection by Zika virus in a pregnant woman.

Abacavir compared to protease inhibitors as part of HAART regimens for treatment of HIV infection: patient satisfaction and implications for adherence.

The purpose of this study was to compare treatment satisfaction with triple nucleoside reverse transcriptase inhibitor (NRTI) highly active antiretroviral treatment (HAART) regimens including abacavir (ABC) to HAART regimens that include protease inhibitors (PIs) and to estimate the relationship between patient satisfaction and adherence to HAART. Three open-label clinical trials comparing ABC-including HAART regimens with PI-including HAART regimens were completed, two with patients previously untreated with antiretroviral therapy and one with patients successfully treated with PI-including HAART regimens. The HIV Treatment Satisfaction Questionnaire (HIVTSQ) was completed at several time points during each trial. Levels of patient satisfaction with the ABC and PI regimens were compared for all three trials. The correlation between adherence and patient satisfaction scores was measured using data from an adherence questionnaire in one of the studies. In all three clinical trials, patient satisfaction scores were significantly higher with an ABC-including triple NRTI HAART regimen than with a PI-including HAART regimen. The difference was apparent by week 4 of the trial and was maintained throughout the trial time period. Inspection of the item responses in the patient satisfaction questionnaire indicated that treatment convenience, flexibility, impact on lifestyle, and side effects were key factors in the difference in satisfaction between the treatment groups. In addition, patient satisfaction was shown to be significantly correlated with adherence defined as taking 95% or more of prescribed doses. Greater satisfaction was reported by patients given an ABC-including HAART regimen than those given a PI-including HAART regimen. Patient satisfaction may be an indicator for better treatment adherence.

Pentamidine-induced derangements of glucose homeostasis. Determinant roles of renal failure and drug accumulation. A study of 128 patients.

OBJECTIVE: To assess the prevalence, presentation, and risk factors of pentamidine-induced dysglycemia. RESEARCH DESIGN AND METHODS: Blood glucose values were screened in 244 consecutive immunocompromised patients with Pneumocystis carinii pneumonia: 116 being treated with cotrimoxazole and 128 others with pentamidine. RESULTS: Two cotrimoxazole patients developed diabetes as a result of necrotizing pancreatitis (1.7%); the others remained euglycemic. Forty-eight pentamidine-treated patients (38.5%) developed severe glucose homeostasis disorders: hypoglycemia in 7, hypoglycemia and then diabetes in 18, and diabetes alone in 23 (P < 0.001 vs. the cotrimoxazole group). Hypoglycemia was early, sudden, often recurrent, and life-threatening, associated with inappropriately high insulin levels in plasma; the B-cell response to stimuli was poor. Of the 41 diabetic patients, 26 required insulin therapy; their plasma C-peptide levels were lower than normal, and the B-cell secretory responses to stimuli were poor. Islet cell antibodies, insulin antibodies, and insulitis were not detected. The pentamidine-treated dysglycemic patients differed from their euglycemic counterparts by higher pentamidine doses (P < 0.001), higher plasma creatinine levels (P < 0.001), and more severe anoxia (P < 0.05) and shock (P < 0.001). Most of them had received pentamidine mesylate parenterally (n = 36; 75%); six others received the isethionate salt and six exclusively pentamidine aerosols. CONCLUSIONS: Pentamidine-induced dysglycemic accidents are primarily due to inappropriate insulin release and toxicity to the islet B-cells. Drug accumulation due to excessive doses, iterative courses, and/or renal impairment is the determining risk factor.

Cytomegalovirus retinitis in AIDS patients: a comparative study of intravenous and oral ganciclovir as maintenance therapy.

OBJECTIVES: To compare the safety and efficacy or oral ganciclovir with intravenous ganciclovir for the maintenance therapy of cytomegalovirus (CMV) retinitis in AIDS patients. DESIGN: Multicenter, randomized, open-label study, with both masked and unmasked ophthalmic assessments. METHODS: Patients with AIDS and stable CMV retinitis were randomized after an induction course of intravenous ganciclovir (5 mg/kg twice daily) to receive maintenance therapy with oral ganciclovir (500 mg six times daily) or intravenous ganciclovir (5 mg/kg once daily). MAIN OUTCOME MEASURE: The primary endpoint of the study was time to progression of CMV retinitis from the start of maintenance therapy. RESULTS: The mean time to progression, evaluated by funduscopy was 109 days for the intravenous group, and 86 days for the oral group (P = 0.02). The masked photographic assessment revealed shorter time to progression for both oral and intravenous groups, as compared with funduscopy data, and showed no significant difference between the two treatment groups: 62 days for intravenous ganciclovir and 51 days for oral ganciclovir (P = 0.15). Diarrhea and neutropenia were the most frequent reported events in both groups, with the incidence of sepsis more than double in the intravenous compared with the oral ganciclovir group (3 versus 8.5%). CONCLUSIONS: Oral ganciclovir offers a reasonable alternative to intravenous ganciclovir for the maintenance therapy of CMV retinitis in AIDS patients.

Comparison of plasma cytokine levels in African patients with HIV-1 and HIV-2 infection.

OBJECTIVE: To determine plasma cytokine levels [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6] in African patients infected with HIV-2 relative to values in HIV-1-infected patients, and their relation to immunologic and clinical status. DESIGN: Questions about the observed differences in the pathogenesis of HIV-2 and HIV-1 remain unanswered. Cytokines, especially TNF-alpha, are involved in the regulation of HIV-1 replication, and can be found in the plasma of HIV-1-infected individuals. Therefore, we evaluated TNF-alpha, IL-1 beta and IL-6 levels in the plasma of African patients with different stages of HIV-2 disease. This was a 3-year prospective follow-up study. METHODS: Cytokine plasma levels were assayed in 40 HIV-2- and 51 HIV-1-infected patients from Africa. Nineteen of the 40 HIV-2-infected-patients underwent serial assays every 4 months for 3 years. Data were analysed in relation to the number of CD4+ and CD8+ cells, viral load and clinical status. RESULTS: Plasma levels of TNF-alpha and IL-1 beta were significantly higher in all the HIV-1- and HIV-2-infected patients than in healthy controls; IL-6 levels were around the detection limit for all patients. TNF-alpha levels were lower in the HIV-2-infected than in the HIV-1-infected patients at all Centers for Disease Control and Prevention (CDC) disease stages, including the asymptomatic phase. The CD4+ cell count was always higher in the HIV-2-infected patients, regardless of CDC stage. The prospective follow-up showed that TNF-alpha levels remained stable during the course of HIV-2 disease, as did the CD4+ cell count and virus load. CONCLUSION: Lower and stable plasma TNF-alpha levels in African patients infected with HIV-2, associated with lower viral load and higher CD4+ cell count, suggests the existence of a more appropriate and efficient immune response to HIV-2 than to HIV-1.

AIDS-associated Kaposi's sarcoma in female patients.

Kaposi's sarcoma (KS) is very unusual in Caucasian women with AIDS. We conducted a retrospective survey of 12 female AIDS patients with KS, including 11 Caucasian women. HIV infection was thought to have been acquired after sexual contact, intravenous drug use (nine cases) or blood transfusion (three cases). In these patients KS was often the first manifestation of AIDS and showed an aggressive course. The disease was associated with a severe immunodeficiency (CD4 T lymphocyte count less than 100 x 10(6)/l in 50% of cases) and a poor prognosis. In four patients, lesions first developed on areas of sexual contact, supporting the hypothesis that KS is a sexually transmitted disease.

Pulmonary function tests in HIV-infected patients.

OBJECTIVE: To evaluate alterations in lung function during the course of HIV infection. DESIGN: Total lung capacity (TLC), the ratio of forced expiratory volume in one second to vital capacity (FEV1/VC), the carbon monoxide transfer factor (TLCO) and the alveolar-arterial oxygen gradient [delta (A-a)O2] were determined in this retrospective study. PATIENTS: Pulmonary function tests (PFT) were performed on 331 patients at various stages of HIV infection. Patients with a history of intravenous drug use or Kaposi's sarcoma were excluded. RESULTS: No significant differences were observed between the results for asymptomatic patients and those with AIDS-related complex (ARC). TLC, delta (A-a)O2 and TLCO were greatly altered in patients with acute Pneumocystis carinii pneumonia (PCP). No significant differences were observed in the TLC, delta(A-a)O2 or TLCO results between AIDS patients with no history of PCP and those with a history of a single episode of PCP. TLCO was significantly lower (P < 0.001) in AIDS patients with one previous episode of PCP than in the patients with ARC. Interestingly, both TLC and TLCO were significantly lower in the AIDS patients with no history of PCP than in the patients with ARC. Follow-up of 28 patients at different stages of HIV infection confirmed the alteration of PFT results in the late stages. CONCLUSIONS: The reasons for alterations in PFT results in PCP-free AIDS patients remain to be determined. Our findings suggest that PFT can provide valuable information throughout the course of HIV infection, particularly with regard to the indication for bronchoalveolar lavage.

Cellular and plasma viral load in patients infected with HIV-2.

OBJECTIVE: To determine circulating viral load in HIV-2-infected individuals. METHODS: Viral load was determined in 40 HIV-2-infected adults using standardized quantitative cell and qualitative plasma viraemia assays. We also tested for proviral HIV-2 DNA using single and nested polymerase chain reaction (PCR) in fresh lymphocytes from 27 subjects. The results were compared, on the basis of the CD4+ lymphocyte count, with our published data for HIV-1 infection. RESULTS: HIV-2 was isolated from peripheral blood mononuclear cells (PBMC) from 19 individuals and plasma from four patients. The rate of cell and plasma viraemia positivity correlated with the CD4+ cell count and HIV-2 virus load increased as the CD4+ cell count fell. The cellular HIV-2 load in the patients with a CD4+ count < 200 x 10(6)/l was similar to reported values for HIV-1, but the HIV-2 isolation rate from the plasma of these individuals was significantly lower than for HIV-1. When the CD4+ count was between 200 and 500 x 10(6)/l, the rate of HIV-2 isolation from plasma and the cellular virus load were both significantly lower than for HIV-1. When the CD4+ count was > 500 x 10(6)/l, HIV-1 and HIV-2 were undetectable in plasma and HIV-1 was isolated from PBMC in significantly more cases than HIV-2. By single PCR, amplification were positive in 14 out of 27 subjects and there was a correlation between positivity and CD4+ cell count. By nested PCR, only four of the 27 subjects, all with a high CD4+ count, remained negative. CONCLUSIONS: Differences in viral load between individuals infected with HIV-2 and those infected with HIV-1 could partly account for reported differences in the pathogenicity of the two viruses.

HIV-1 detection in cervicovaginal secretions during pregnancy.

OBJECTIVE: To assess the reproducibility of and factors associated with HIV detection in cervicovaginal secretions (CVS). DESIGN: Longitudinal study of 43 HIV-1-infected pregnant women in Paris. METHODS: HIV DNA was detected in peripheral blood mononuclear cells (PBMC) by Amplicor and gag nested polymerase chain reaction (PCR) assays. The HIV genotype was determined by heteroduplex mobility assay. Amplicor and gag nested PCR assays were performed on serial CVS samples for HIV DNA detection, and the HIV Monitor test was used for HIV RNA detection in plasma and CVS. RESULTS: A total of 144 CVS samples were collected from the women included in the study. HIV-1 DNA was detected in 36 (25%) of the 144 samples, from 16 (37.2%) of the 43 women. Results of HIV-1 DNA detection were concordant in the first two samples in 27 (84.4%) of the 32 women with at least two CVS samples. The last CVS sample collected in each woman was HIV-1 DNA-positive in 13 (30.2%) of the 43 women. Three factors were found to be independently associated with HIV-1 DNA detection in CVS: HIV-1 subtype B, absence of zidovudine therapy, and microbial cervicovaginal infection. HIV RNA was detected in CVS from 10 (23.3%) out of 43 women and correlated with DNA detection in the same sample and HIV RNA detection in plasma. CONCLUSIONS: DNA and RNA PCR can be used to detect HIV in cells and supernatants of CVS. These techniques may be useful in cohort studies to investigate HIV transmission and to evaluate the efficacy of antiretroviral drugs to reduce HIV excretion.

Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients.

OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients. DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]. CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.

Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy.

OBJECTIVE: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART). SETTING: Prospective multicentre cohort in 15 university hospitals in France. METHODS: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction). RESULTS: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l. CONCLUSION: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.