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Herpes simplex esophagitis (HSE) has rarely been reported in immunocompetent individuals. In a search of Medline until October 2012, we found only one case of HSE in a pregnant female. We present the first case of HSE in a healthy 36-year-old female at 27 weeks gestation who recovered without antiviral therapy. [ABSTRACT FROM AUTHOR]

Objectives The aims of the study were to assess in patients with advanced HIV disease receiving antiretroviral therapy (ART) intensification with enfuvirtide (i) resistance at virological failure (VF), (ii) impact of baseline tropism on immunovirological response, and (iii) HIV-1 DNA tropism evolution during ART. Methods The ANRS 130 APOLLO randomized trial evaluated in naive patients the immunovirological impact of standard ART without (control arm) or with enfuvirtide. Tropism was determined on RNA and DNA by V3-loop sequencing interpreted using the Geno2Pheno algorithm. Results At baseline the median CD4 cell count was 30 cells/mm3. Among the 170 patients assessable in this virological substudy, HIV-1 RNA tropism was as follows: 60% of viruses were R5 and 40% were R5X4/X4. HIV-1 DNA tropism was as follows: 54% were R5 and 46% were R5X4/X4. At week 24, 39% and 49% of patients experienced VF in the enfuvirtide and control arms, respectively. In the enfuvirtide arm, only resistance-associated mutations to enfuvirtide were detected. In the control arm, two patients displayed drug-resistant viruses at the time of VF. No impact of baseline tropism was observed on immunovirological response, regardless of the study arm. Among the 25 patients experiencing DNA tropism switch between baseline and week 24, 16 (64%) switched from R5 to R5X4/X4. These latter were mostly successfully suppressed patients receiving enfuvirtide and exhibiting poorer immunological response. Conclusions Baseline RNA tropism had no impact on the immunovirological response. Drug resistance mutations were only detected for the fusion inhibitor. Finally, the mechanism of replenishment of the viral cellular reservoir with X4 viruses observed needs to be further analysed. [ABSTRACT FROM PUBLISHER]

Background: In countries with concentrated HIV epidemics, optimizing screening to reach individuals with undiagnosed infection is essential. The DICI-VIH study, a cluster-randomized crossover trial conducted in eight French emergency departments (EDs), found that a strategy combining nurse-driven targeted HIV screening with routine diagnostic testing was effective., Aim: The aim was to investigate factors associated with the implementation of HIV screening targeting key populations in EDs., Methods: A self-administered questionnaire was distributed at registration to patients aged 18-64 years and able to give consent during the DICI-VIH intervention. Based on their responses, those belonging to key populations were offered a rapid test by triage nurses. Two key stages of the process were evaluated: questionnaire distribution by providers and test acceptance by patients. Patient information, daily workload, and ED characteristics were collected. The associations between these variables and (a) the proportion of questionnaires distributed and (b) the proportion of tests accepted were evaluated using multilevel modeling in order to examine differences in screening implementation between EDs., Results: Questionnaire distribution proportions varied from 23% to 48% across EDs. They were higher on weekdays than weekends (odds ratio, OR: 3.77; 95% CI: 3.57-3.99) and when research staff participated (OR: 1.31; 95% CI: 1.26-1.37). They decreased over time (OR: 0.76; 95% CI: 0.71-0.82; 4th [Q3] vs. 1st quartile [Q0] of intervention days) and with increased patient flow (OR: 0.61; 95% CI: 0.56-0.67; Q3 vs. Q0 of eligible patients). Test acceptance varied from 64% to 77% across EDs, increased with research staff participation (OR 1.20; 95% CI: 1.03-1.40), and decreased over time (OR: 0.75; 95% CI: 0.60-0.92; Q3 vs. Q0). Patients who accepted were more likely to be younger (OR: 0.76; 95% CI: 0.61-0.96; 50-64-year-old vs. 30-39-year-old patients)., Linking Evidence to Action: Patient flow, intervention duration, weekdays, and research staff participation were important determinants of targeted screening implementation. These findings could help guide future implementation in similar settings., (© 2019 Sigma Theta Tau International.)

Objectives Long-term results at week 96 are needed to evaluate the capacity of the darunavir/ritonavir monotherapy strategy to maintain a sustained control of the HIV-1 viral load. Methods MONOI is a prospective, open-label, non-inferiority, randomized, 96 week trial comparing darunavir/ritonavir monotherapy versus a darunavir/ritonavir triple-therapy strategy to maintain HIV-1 viral load suppression in HIV-1-infected patients. Clinical trial registration: NCT00412551. Results From 225 randomized patients, 219 patients reached the 48 week follow-up and 211 reached the 96 week follow-up (106 patients in the darunavir monotherapy arm and 105 in the darunavir triple-therapy arm). Baseline characteristics were well balanced between the two treatment groups. At week 96, in intent-to-treat analysis, 91/103 patients (88%, 95% CI 81–94) allocated to the darunavir/ritonavir monotherapy arm and 87/104 patients (84%, 95% CI 75–90) allocated to the darunavir triple-therapy arm achieved an HIV-1 viral load <50 copies/mL, with no statistical difference between the two groups. Throughout the 96 week follow-up, 66/112 patients (59%, 95% CI 49–68) and 79/113 patients (70%, 95% CI 61–78) consistently had HIV-1 RNA <50 copies/mL with darunavir/ritonavir monotherapy and darunavir/ritonavir triple therapy, respectively. Conclusions The MONOI study establishes darunavir/ritonavir monotherapy as durable and efficacious for maintaining virological suppression in HIV-1 patients. Darunavir/ritonavir monotherapy should be considered as a (tailored) treatment option for standard triple-therapy patients who have had a substantial period of viral suppression. [ABSTRACT FROM PUBLISHER]

Objectives: The HEPAIG study was conducted to better understand Hepatitis C virus (HCV) transmission among human immuno-deficiency (HIV)-infected men who have sex with men (MSM) and assess incidence of HCV infection among this population in France. Methods and Results: Acute HCV infection defined by anti-HCV or HCV ribonucleic acid (RNA) positivity within one year of documented anti-HCV negativity was notified among HIV-infected MSM followed up in HIV/AIDS clinics from a nationwide sampling frame. HIV and HCV infection characteristics, HCV potential exposures and sexual behaviour were collected by the physicians and via self-administered questionnaires. Phylogenetic analysis of the HCV-NS5B region was conducted. HCV incidence was 48/10 000 [95% Confidence Interval (CI):43-54] and 36/10 000 [95% CI: 30-42] in 2006 and 2007, respectively. Among the 80 men enrolled (median age: 40 years), 55% were HIV-diagnosed before 2000, 56% had at least one sexually transmitted infection in the year before HCV diagnosis; 55% were HCV-infected with genotype 4 (15 men in one 4d-cluster), 32.5% with genotype 1 (three 1a-clusters); five men were HCV re-infected; in the six-month preceding HCV diagnosis, 92% reported having casual sexual partners sought online (75.5%) and at sex venues (79%), unprotected anal sex (90%) and fisting (65%); using recreational drugs (62%) and bleeding during sex (55%). Conclusions: This study emphasizes the role of multiple unprotected sexual practices and recreational drugs use during sex in the HCV emergence in HIV-infected MSM. It becomes essential to adapt prevention strategies and inform HIV-infected MSM with recent acute HCV infection on risk of re-infection and on risk-reduction strategies. [ABSTRACT FROM AUTHOR]

Purpose: Several researchers have found that plasma citrulline could be a marker of reduced enterocyte mass. The aim of this study was to assess the relationship between plasma citrulline and bowel inflammation and/or disease location in pediatric and adolescent Crohn's disease (CD) patients. Methods: Between January 2008 and January 2010, 31 CD patients and 44 controls were included in our study, and 15 out of the 31 CD patients continued a prospective survey. We evaluated the differences between groups, at baseline, in plasma citrulline and glutamine and between their baseline and final values during the prospective survey, and correlation between baseline values of citrulline and duration of disease, C-reactive protein, and fecal calprotectin. Results: Mean citrulline value was 33.0 ± 7.5 μmol/L in controls and 23.5 ± 8.4 μmol/L in CD patients ( P < 0.0001). Plasma citrulline was significantly lower in patients with small bowel (SB) location than in patient with only ileo-colon disease (14.2 ± 5.5 and 24.7 ± 8.0, respectively; P = 0.0037). Citrulline ≤22 μmol/L reached sensitivity of 100% (95% confidence interval (CI) 54-100) and specificity of 98% (CI 89-99) in differentiating control subjects from CD with SB location. Conclusions: CD patients have reduced concentration of plasma citrulline than controls. Intestinal damage rather than inflammation seems to be responsible for the reduced biosynthesis of citrulline, which decreases particularly in CD patients with SB location. This finding suggests the potential role of citrulline as marker of disease location, but future works will be needed to confirm this suggestion. [ABSTRACT FROM AUTHOR]

Background: There are few large published studies of HIV controllers with long-term undetectable viral load (VL). We describe the characteristics and outcomes of 81 French HIV controllers. Methods and Results: HIV controllers were defined as asymptomatic, antiretroviral-naïve persons infected $10 years previously, with HIV-RNA ,400 copies/mL in .90% of plasma samples. All available CD4 and VL values were collected at enrolment. Mixed-effect linear models were used to analyze CD4 cell count slopes since diagnosis. HIV controllers represented 0.31% of all patients managed in French hospitals. Patients infected through intravenous drug use were overrepresented (31%) and homosexual men were underrepresented (26% of men) relative to the ANRS SEROCO cohort of subjects diagnosed during the same period. HIV controllers whose VL values were always below the detection limit of the assays were compared with those who had rare ''blips'' (,50% of VL values above the detection limit) or frequent blips (.50% of VL values above the detection limit). Estimated CD4 cell counts at HIV diagnosis were similar in the three groups. CD4 cell counts remained stable after HIV diagnosis in the ''no blip'' group, while they fell significantly in the two other groups (20.26!CD4 and 20.28!CD4/mm³/year in the rare and frequent blip groups, respectively). No clinical, immunological or virological progression was observed in the no blip group, while 3 immunological and/or virological events and 4 cancers were observed in the blip subgroups. Conclusions: Viral blips in HIV controllers are associated with a significant decline in CD4 T cells and may be associated with an increased risk of pathological events, possibly owing to chronic inflammation/immune activation. [ABSTRACT FROM AUTHOR]

Aims Natural history and prognosis of acute coronary syndrome (ACS) in HIV-infected patients remain to be determined. We sought to compare coronary risk factors, angiographic features, acute results of percutaneous coronary intervention, in-hospital outcomes, and pre-specified 1 year prognosis of HIV-infected and HIV-uninfected patients with ACS. Methods and results HIV-infected and HIV-uninfected patients with a first episode of ACS were matched for age (±5 years), sex, and type of ACS. The primary endpoint was the rate of major adverse cardiac and cerebral events (MACCE), comprising cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke. Overall, 103 HIV-infected and 195 HIV-uninfected patients were enrolled (mean age 49.0 ± 9.4 years, 94% men). Coronary risk factors were well balanced, but HIV-infected patients more frequently used illicit drugs (23 vs. 6%, P = 0.001) and had higher triglyceride concentrations (246 ± 189 vs. 170 ± 139 mg/dL, P = 0.002) compared with HIV-uninfected patients. Angiographic features of coronary artery disease were similar (multivessel disease 41 vs. 39%, P = 0.96; ACC/AHA type culprit lesion ≥B2, both 77%, P = 0.83). At 1 year, the rate of occurrence of first MACCE did not differ between groups [hazard ratio (HR) 1.4, 95% CI 0.6–3.0]. Recurrent ACS was more frequent in HIV-infected patients (HR 6.5, 95% CI 1.7–23.9) with no difference in the rate of clinical restenosis. Conclusions These results suggest that the acute management of ACS in HIV-infected patients can routinely be the same as that of HIV-uninfected patients, but that specific secondary prevention measures are needed to alleviate the increased risk of recurrent ACS. [ABSTRACT FROM PUBLISHER]

Objectives We evaluated a monotherapy maintenance regimen with lopinavir/ritonavir versus continuing current combined antiretroviral treatment (cART) in HIV patients with suppressed plasma HIV-1 RNA. Patients and methods This was an open-label, non-inferiority, multicentre trial in 23 sites in France. Adults were randomized if they had no history of virological failure while receiving a protease inhibitor, maintained HIV-1 RNA <50 copies/mL for at least 6 months and did not change cART during the last 3 months. The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 (non-inferiority margin set at −12%) with missing data and treatment modification considered as failure. The trial has been registered in ClinicalTrials.gov under the identifier NCT00140751. Results At Week 48, 84% (73/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group [difference, −4.0%, lower limit of 90% two-sided confidence interval (CI) for difference, −12.4%]. In secondary analysis with success defined as plasma HIV-1 RNA <400 copies/mL, 87% (76/87) of patients in the lopinavir/ritonavir monotherapy group were virologically suppressed compared with 88% (87/99) in the cART group (difference, −0.5%, lower limit of 90% two-sided CI for difference, −8.5%). If antiretroviral treatment intensification was taken into account, 91% (79/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group (difference, +2.9%, lower limit of 90% two-sided CI for difference, −4.5%). Failures of lopinavir/ritonavir monotherapy did not show acquired resistance mutations in the protease gene. Conclusions Lopinavir/ritonavir monotherapy did not achieve non-inferiority versus cART for maintaining plasma HIV-1 RNA <50 copies/mL. Nevertheless, the incidence of virological failure was low (mostly with HIV-1 RNA <400 copies/mL) and easily managed by treatment intensification. [ABSTRACT FROM PUBLISHER]

Objectives: We investigated why, despite its beneficial effect on the CD4 cell count, IL-2 therapy had no clinical benefit as shown in the ESPRIT and SILCAAT trials. We focused on subgroups of patients defined according to CD4 cell counts at baseline and over time to assess the threshold above which IL-2 therapy was no longer beneficial in a large cohort of HIV-1 infected patients. [ABSTRACT FROM PUBLISHER]

Background. The association between cancer-related fatigue and pathological processes in the body is largely unknown. This study was designed to investigate a possible linkage between fatigue and intestinal injury during pelvic radiotherapy. Methods. Twenty-nine women undergoing pelvic radiotherapy for anal or uterine cancer were prospectively followed. Fatigue and diarrhea were assessed using patient self-reported questionnaires. Plasma citrulline concentration, as a sign of intestinal injury, and C-reactive protein, orosomucoid, albumin, α1-antitrypsin, and haptoglobin, as signs of systemic inflammation, were analyzed. Results. Fatigue increased significantly (p<.001) and citrulline decreased significantly (p < .001) during treatment. A significant negative correlation (r = 0.40; p < .05) was found between fatigue and epithelial atrophy in the intestine (as assessed by plasma citrulline) after 3 weeks of treatment and a significant positive correlation (r = 0.75; p < .001) was found between fatigue and diarrhea. Signs of systemic inflammation were evident, with significant increases in serum orosomucoid, serum haptoglobin (p < .05) and serum α1-antitrypsin (p < .001) and a significant decrease in serum albumin (p < .001). Conclusion. The present study indicates a link between fatigue and intestinal injury during pelvic radiotherapy. This observation should be considered as a preliminary finding because of the small sample size but may serve as a rationale for therapeutic interventions aimed at alleviating both fatigue and gastrointestinal symptoms during pelvic radiotherapy. [ABSTRACT FROM AUTHOR]

Background Little is known about the causes of death in human immunodeficiency virus (HIV)-infected women in the era of combination antiretroviral therapy (ART). [ABSTRACT FROM PUBLISHER]

Many infections favor or are directly implicated with lipid metabolism perturbations and/or increased risk of coronary heart disease (CHD). HIV itself has been shown to increase lipogenesis in the liver and to alter the lipid profile, while the presence of unsafe habits, addiction, comorbidities, and AIDS-related diseases increases substantially the risk of cardiovascular disease (CVD) in the HIV-infected population. Antiretroviral therapy reduces such stimuli but many drugs have intrinsic toxicity profiles impacting on metabolism or potential direct cardiotoxicity. In a moment when the main guidelines of HIV therapy are predating the point when to start treating, we mean to highlight the contribution of HIV-1 to lipid alteration and inflammation, the impact of antiretroviral therapy, the decisions on what drugs to use to reduce the probability of having a cardiovascular event, the increasing use of statins and fibrates in HIV-1 infected subjects, and finally the switch strategies, that balance effectiveness and toxicity to move the decision to change HIV drugs. Early treatment might reduce the negative effect of HIV on overall cardiovascular risk but may also evidence the impact of drugs, and the final balance (reduction or increase in CHD and lipid abnormalities) is not known up to date. [ABSTRACT FROM AUTHOR]

Background. The introduction of 2 or 3 fully active drugs in human immunodeficiency virus (HIV)-infected patients receiving failing antiretroviral therapy is a key determinant of subsequent treatment efficacy. The aim of this study was to assess the safety and efficacy of a regimen containing raltegravir, etravirine, and darunavir/ ritonavir for treatment-experienced patients infected with multidrug-resistant HIV. Methods. Patients enrolled in this phase II, noncomparative, multicenter trial were naive to the investigational drugs and had plasma HIV RNA levels 11000 copies/mL, a history of virologic failure while receiving nonnucleoside reverse-transcriptase inhibitors (NNRTI), ⩾3 primary protease inhibitor and nucleoside reverse transcriptase inhibitor (NRTI) mutations, and ⩽3 darunavir and NNRTI mutations. The primary end point was the proportion of patients with plasma HIV RNA levels <50 copies/mL at 24 weeks. Results. A total of 103 patients enrolled in the study. At baseline, genotypic resistance profiles showed a median of 4 primary protease inhibitor mutations, 1 NNRTI mutation, and 6 NRTI mutations. In addition to the investigational drugs, 90 patients (87%) received optimized background therapy that included NRTIs (86 patients) or enfuvirtide (12 patients). At week 24, 90% of patients (95% confidence interval, 85%-96%) had an HIV RNA level <50 copies/mL. At week 48, 86% (95% confidence interval, 80%-93%) had an HIV RNA level <50 copies/ mL. The median CD4 cell count increase was 108 cells/mm3. Grade 3 or 4 clinical adverse events were reported in 15 patients (14.6%). Only 1 patient discontinued the investigational antiretroviral regimen, because of an adverse event. Conclusion. In patients infected with multidrug-resistant virus who have few remaining treatment options, the combination of raltegravir, etravirine, and darunavir/ritonavir is well tolerated and is associated with a rate of virologic suppression similar to that expected in treatment-naive patients. [ABSTRACT FROM AUTHOR]

Background More than 10 years after the introduction of combination antiretroviral therapy (cART), we examined the trend in the proportion of deaths caused by end-stage liver disease (ESLD) in HIV-infected adults in France between 1995 and 2005. Design and methods In 2005, 34 departments prospectively recorded all deaths in HIV-infected patients who were followed in those departments (around 24 000). Results were compared with those of four previous cross-sectional surveys conducted since 1995 using the same methodology. Results Among 287 reported deaths in 2005, 100 (35%) were related to AIDS, and 48 (17%) to ESLD. Three out of four patients who died from ESLD-related causes had chronic hepatitis C. Excessive alcohol consumption was reported in approximately half of the patients (48%). At death, 62% of patients had undetectable HIV viral load and the median CD4 count was 237 cells/μL. From 1995 to 2005, the proportion of deaths caused by ESLD increased from 2 to 17% ( P<0.001). The proportion of deaths caused by hepatocellular carcinoma increased from 5% in 1995 to 25% in 2005 ( P=0.0337). Conclusions Over the 10 years from 1995 to 2005, the proportion of deaths caused by hepatitis C virus-related ESLD has increased in HIV-infected patients. ESLD is currently a leading cause of death in this population, with hepatocellular carcinoma representing a quarter of liver-related deaths. Recommendations for the detection of hepatocellular carcinoma should be strictly applied in these patients. [ABSTRACT FROM AUTHOR]

Background. The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. Methods. We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category. Results. During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]). Conclusions. In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management. [ABSTRACT FROM AUTHOR]

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Objective We aimed to retrieve the vital status of patients lost to follow-up (LFU), with no further visits for at least 12 months, for the 34 835 patients in the Agence Nationale de Recherche sur le SIDA CO4 French Hospital Database on HIV (ANRS CO4 FHDH) seen in 1999 and to examine how loss to follow-up might influence estimates of survival and the impact of delayed access to care (DAC) on survival. Methods The status of LFU patients was established by using the mid-2006 update of the FHDH in which their status 12 months after loss to follow-up was added when available and by matching with the Mortalité 2000-Epidemiological Centre for Medical Causes of Death (CépiDc) database, which included HIV-infected patients dying in 2000. We compared Kaplan–Meier and hazard ratio (HR) estimates before and after correction for the status of LFU patients. Results In the mid-2006 updated FHDH, of the patients seen in 1999, 7.5% were LFU: of these, 2.1% later returned for follow-up, with a median time without follow-up in an FHDH centre of 3.5 years, and 5.4% had no further FHDH visits whatsoever, of whom 29.8% died according to Mortalité 2000-CépiDc. After correction, the estimated 1-year survival rates following enrolment in 1999 differed between the original and updated analyses (97.1 vs. 95.9%, respectively; P=0.017); the estimates of mortality HRs associated with DAC did not differ during the first 6 months, but did differ for the 6–18-month period. Conclusions Among LFU patients, 28.1% returned to follow-up after several years and at least 21.4% died, which led to a slight overestimation of both survival and the impact of DAC on survival. [ABSTRACT FROM AUTHOR]

Background. The goal of the current study was to describe the distribution and characteristics of malignancy-related deaths among human immunodeficiency virus (HIV)--infected patients with use of data obtained from a national survey conducted in France in 2005 and to compare with results obtained from a similar survey conducted in 2000. Method. The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards and networks that were involved in the treatment of HIV-infected patients. Results. Among the 1042 deaths reported in 2005 (964 were reported in 2000), 344 were cancer related (34%), which represented a significant increase from 2000 (29% of deaths were cancer related) (P=.02); 134 of the cancer-related deaths were AIDS related and 210 were not AIDS related. Among the cancer-related causes of death, the proportion of hepatitis-related cancers (6% in 2000 vs. 11% in 2005) and non-AIDS/hepatitis-related cancers (38% in 2000 vs 50% in 2005) significantly increased from 2000 to 2005 (P=.03 and P=.01, respectively), compared with the proportion of cancer that was AIDS related and adjusting for age and sex. Among cases involving AIDS, the proportion of non-Hodgkin lymphoma--associated deaths did not change statistically significantly between 2000 and 2005 (11% and 10% of deaths, respectively). Conclusions. In this study, an increasing proportion of lethal non--AIDS-related cancers was demonstrated from 2000 to 2005; meanwhile, the proportion of lethal AIDS-related cancers remained stable among HIV-infected patients. Thus, cancer prophylaxis, early diagnosis, and improved management should be included in the routine long-term follow-up of HIV-infected patients. [ABSTRACT FROM AUTHOR]

Highly active antiretroviral therapy (HAART)-associated metabolic complications include lipoatrophy (loss of subcutaneous adipose tissue (SAT)) and insulin resistance. Thiazolidinediones are insulin-sensitizing antidiabetic agents which--as an untoward side effect in obese diabetic patients--increase SAT. Furthermore, troglitazone has improved lipoatrophy and glycemic control in non-HIV patients with various forms of lipodystrophy. These data have led to 14 clinical trials to examine whether thiazolidinediones could be useful in the treatment of HAART-associated metabolic complications. The results of these studies indicate very modest, if any, effect on lipoatrophic SAT, probably due to ongoing HAART negating the beneficial effect. The benefit might be more prominent in patients not taking thymidine analoges. Despite the poor effect on lipoatrophy, thiazolidin-ediones improved insulin sensitivity. However, especially rosiglitazone induced harmful effects on blood lipids. Current data do not provide evidence for the use of thiazolidinediones in the treatment of HAART-associated lipoatrophy, but treatment of lipoatrophy-associated diabetes may be warranted. The role of thiazolidinediones for novel indications, such as hepatosteatosis, should be studied in these patients. [ABSTRACT FROM AUTHOR]

The objective of the present study was to determine mortality because of end-stage liver disease (ESLD) in a nationwide population of HIV-infected patients, 7 years following the introduction of highly active antiretroviral therapy (HAART). All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV-infected patients during 2003. Fifty-nine departments, following a total of 20 940 HIV-infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995, 1997 and 2001. Among 215 deaths observed during 2003, 101 (46.9%) were related to AIDS, 27 (12.6%) to ESLD and 87 (40.5%) to other causes. Mortality because of ESLD represented 23.7% of non-AIDS-related deaths. Patients dying from ESLD had chronic hepatitis because of hepatitis C virus (HCV) in 92.6% of cases and moderate (30–60 g) or high (>60 g) alcohol consumption (43.5% and 26.0%, respectively). In this population, deaths because of ESLD were 1.5% in 1995, 6.6% in 1997, 14.3% in 2001 and 12.6% in 2003. The prevalence of hepatocellular carcinoma as a cause of death remained high in 2003 but stable when compared with 2001 (25% vs 14.8%). Treatment of hepatitis C in patients who died from ESLD was more frequent in 2003 (44.4%) than in 2001 (26.3%). Seven years after the introduction of HAART, ESLD associated with HCV infections is a leading cause of mortality in HIV-infected patients, which did not increase between the years 2001 and 2003. [ABSTRACT FROM AUTHOR]

Objective To determine the incidence of Isospora belli infection in HIV-infected patients in France, and to study risk factors. Methods The French Hospital Database on HIV (FHDH) is a prospective cohort study that collects demographic, clinical and therapeutic data on patients managed in 62 hospitals. We reviewed all cases of I. belli infection recorded between 1992 and 2003. We compared the incidence in 1992–1994 [before the use of dual therapy and combination antiretroviral therapy (cART)] and in 1997–2003 (when use of cART was widespread), after stratification for CD4 cell count (< 50, 50–99, 100–199 and > 200 cells/μL). Results A total of 164 patients had I. belli infection either at enrolment ( n=71) or during follow up ( n=93). During the study period, I. belli infection tended to occur less frequently during follow up, and to be diagnosed mainly at database enrolment. The incidence of I. belli infection during follow up fell by 79% [relative hazard (RH) 0.21; 95% confidence interval (CI) 0.13–0.33] in the cART period compared with the pre-cART period; no such change was noted among patients with CD4 cell counts below 50 cells/μL. In multivariable analysis, the risk of I. belli infection was significantly higher among patients from sub-Saharan Africa (RH 4.3; 95% CI 2.6–7.3). After adjustment for CD4 cell count, patients receiving cotrimoxazole prophylaxis were found to be at a lower risk of I. belli infection (RH 0.3; 95% CI 0.2–0.6). Conclusions In France, I. belli infection among HIV-infected patients is now mainly seen in patients from sub-Saharan Africa, who present at an advanced stage. [ABSTRACT FROM AUTHOR]

Background The literature contains conflicting findings on the influence of gender and HIV transmission group on the initial prescription of highly active antiretroviral therapy (HAART) and its biological and clinical efficacy. Methods We conducted a cohort study involving 62 French hospitals. We used Cox proportional hazards models to examine whether gender and HIV transmission group influenced the timing of elective HAART initiation, and the clinical and biological response to treatment. Results We studied 5735 patients enrolled between January 1997 and December 2001 who did not start HAART or develop a stage C HIV-related event during the first 3 months after inclusion. In multivariate analysis, no gender differences were found in the interval between enrolment in the database and HAART initiation, but this interval was shorter in homosexual patients than in other transmission groups; CD4 cell counts at treatment initiation were also higher in the homosexual group. The immunovirological response to treatment did not differ according to gender, but was better in homosexual patients than in patients in other categories. Injecting drug users had the weakest immunovirological responses. Clinical outcome was not related to gender or to HIV transmission group. Conclusions The interval between diagnosis of HIV-1 infection and elective HAART initiation was not influenced by gender. However, homosexual patients had higher CD4 cell counts than other patients at treatment initiation, and also had better immunovirological responses. [ABSTRACT FROM AUTHOR]

Background. We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. Methods. We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS-free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. Results. During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.9 1-3.06), and those with a higher CD4+ count at the time of HAART initiation (relative rate per log2 cells/μL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4+ count (relative rate per log2 cells/μL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/μL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 copies/mL (relative rate, 2.21; 95% CI, 1.3 3-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. Conclusion. The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV- infected population. [ABSTRACT FROM AUTHOR]

The article discusses effectiveness of antiretroviral agents. Despite the growing number of antiretroviral agents available, therapeutic options for HIV-1 infected patients experiencing failure of antiretroviral therapy remain limited. Indeed, treatment failure is frequently associated with the emergence of drug-resistance. Nucleoside reverse transcriptase inhibitors (NRTIs), which were the first antiretroviral agents available, are still the most frequently used class of drugs. Resistance to NRTIs has been associated with NRTI-associated mutations, which can be detected in plasma by use of genotypic resistance tests that sequence the reverse transcriptase gene. In HIV-1 infected patients experiencing failure of antiretroviral therapy, didanosine retains short term antiviral activity.

Context Treatment of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients is a growing concern. Most data on the virologic efficacy and safety of the combination of peginterferon alfa-2b and ribavirin in coinfected patients come from uncontrolled studies. Objective To study the safety and efficacy of peginterferon alfa-2b plus ribavirin vs standard interferon alfa-2b plus ribavirin in HIV-HCV coinfected patients. Design and Settings A multicenter, randomized, parallel-group, open-label trial. Patients were enrolled from February 2000 to February 2002 and followed up for 72 weeks. Patients Four hundred twelve HIV-HCV coinfected patients with detectable serum HCV-RNA, abnormal liver histology, a CD4 cell count of at least 200 × 106/L, and stable plasma HIV-RNA. Intervention Treatment with ribavirin 400 mg twice a day, orally, plus either peginterferon alfa-2b (1.5 µg/kg subcutaneous injection once a week) or standard interferon alfa-2b (3 million units of subcutaneous injection 3 times a week) for 48 weeks. Main Outcome Measures Sustained virologic response, defined by undetectable serum HCV-RNA at week 72. Results More patients had sustained virologic responses in the peginterferon group than in the standard interferon group (27% vs 20%, P = .047). This difference between the treatments was found in patients with HCV genotype 1 or 4 infection (17% for peginterferon vs 6% for standard interferon, P = .006) but was not found in patients with HCV genotype 2, 3, or 5 (44% for peginterferon vs 43% for standard interferon, P = .88). Together, a decline in HCV-RNA of less than 2 log10 from baseline and detectable serum HCV-RNA at week 12 predicted 99% of treatment failures. Histologic activity diminished and fibrosis stabilized in virologic responders. The 2 regimens showed similar tolerability although dose modifications for clinical and biological events were more frequent with peginterferon... [ABSTRACT FROM AUTHOR]

To describe the management of primary HIV infection (PHI), focusing on changes in the design of therapies and time to initiation of antiretroviral treatment, the clinical outcome, and the immuno-virological response over time to highly active antiretroviral therapy (HAART) and its tolerance.In the French PRIMO multicentre cohort, 291 patients presenting with PHI were enrolled between 1996 and 2001. Data were analysed to describe treatment prescription habits over a period of 5 years, and response to and tolerance of treatment.The proportion of patients who initiated treatment during PHI decreased from 92% in 1996 to 56% in 2001. At 6 months, whatever the initiated treatment, 74% of treated patients achieved a plasma viral load<400 HIV-1 RNA copies/mL and 53% achieved a viral load of<50 copies/mL. Prescription of protease inhibitor (PI)-sparing regimens has become more frequent since 1999. Despite a similar virological response, patients in the PI-containing group tended to experience a greater 1-year increase in CD4 cell count than those in the non-nucleoside reverse transcriptase (NNRTI)-containing group (218 cells/μL versus 157 cells/μL, respectively). An adverse event was recorded in 51% of treated patients. The most frequent events were gastrointestinal disorders (71%), lipodystrophy (27%) and mood disorders (19%). The main reason for modifying or stopping therapy was the occurrence of an adverse event.Limitations of therapy and poor tolerance to antiretroviral regimens have changed physician attitudes in PHI. This suggests the need for evaluation of better-tolerated regimens and new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Patients who use nucleoside reverse-transcriptase inhibitors (NRTIs) before highly active antiretroviral therapy (HAART) have an increased rate of virus rebound. Study of rebound according to specific NRTIs used might inform which NRTIs retain activity once others have failed. We focused on 2280 patients who had received zidovudine and either didanosine or lamivudine before starting HAART, started HAART that included zidovudine with didanosine or lamivudine or stavudine with didanosine or lamivudine, and had virus loads < 500 copies/mL within 24 weeks. In a Cox model, the relative hazard (RH) of virus rebound for having switched from zidovudine to stavudine (vs. retaining zidovudine) was 0.94 (95% confidence interval [CI], 0.77-1.15), which suggests little or no benefit in terms of reduced rebound rate. Having switched from didanosine to lamivudine, or vice versa, was associated with a reduced rebound rate (RH, 0.59 [95% CI, 0.48- 0.73]), which suggests that these drugs retain appreciable activity after use of the other and of zidovudine. [ABSTRACT FROM AUTHOR]

Recent advances in the development of three different types of antiviral drugs, the nucleotide and non-nucleotide analogues acting as reverse transcriptase inhibitors (NRTIs) and the nonpeptidic viral protease inhibitors (PI), and their introduction in the management of patients with AIDS, either alone or in combination, have dramatically improved the clinical course of the disease and prolonged life expectancy in patients with AIDS. The increase in life expectancy in association with the long-term use of the above antiviral agents, however, have generated novel morbidities and complications. Central among them is the quite common AIDS-related insulin resistance and lipodystrophy syndrome, which is characterized by a striking phenotype and marked metabolic disturbances. To look for the pathologic causes of this particular syndrome, we focused on one of the HIV-1 accessory proteins, Vpr, which has multiple functions, such as virion incorporation, nuclear translocation of the HIV- 1 preintegration complex, nucleo-cytoplasmic shuttling, transcriptional activation, and induction of apoptosis. Vpr may also act like a hormone, which is secreted into the extracellular space and affects the function of distant organs. Vpr functions as a coactivator of the glucocorticoid receptor and potentiates the action of glucocorticoid hormones, thereby inducing tissue glucocorticoid hypersensitivity. Vpr also arrests host cells at the G2/M phase of the cell cycle by interacting with novel 14-3-3 proteins. Vpr facilitates the interaction of 14- 3-3 and its partner protein Cdc25C, which is critical for the transition of G2/ M checkpoint in the cell cycle, and suppresses its activity by segregating it into the cytoplasm. The same Vpr protein also suppresses the association of 14-3-3 with other partner molecules, the Foxo transcription factors. Since the Foxo proteins function as negative transcription factors for insulin, Vpr may cause resistance of tissues to insulin. Through these two newly identified functions of Vpr, namely, coactivation of glucocorticoid receptor activity and inhibition of insulin effects on Foxo proteins, Vpr may participate in the development of AIDS-related insulin resistance/lipodystrophy syndrome. [ABSTRACT FROM AUTHOR]

To evaluate factors associated with durable viral suppression (DVS), low viral rebound (virus load of 500–5000 copies/mL), and high viral rebound (virus load above 5000 copies/mL), we studied 3736 patients who achieved an undetectable virus load (i.e., <500 copies/mL) while receiving an initial highly active antiretroviral therapy regimen containing a protease inhibitor (PI). A total of 2636 patients (71%) had DVS, 387 (10%) had low viral rebound, and 713 (19%) had high viral rebound. Factors associated with DVS were antiretroviral-naive status, choice of PI (indinavir or boosted PI), lower virus load and higher CD4[sup+] cell count, shorter duration of therapy (<6 months), and larger CD4[sup+] cell increment until an undetectable virus load was attained. These factors (except for receipt of indinavir) were also associated with low versus high viral rebound. Compared with patients with DVS, patients with high viral rebound were more likely to experience clinical failure (adjusted hazard ratio [aHR], 1.71; 95% confidence interval [CI], 0.97–3.02) and immunologic failure (aHR, 1.57; 95% CI, 1.34–1.83), and patients with low viral rebound were as likely to experience these types of failure (aHR for clinical failure, 1.18 [95% CI, 0.48–2.92]; aHR for immunologic failure, 1.07 [95% CI, 0.87–1.32]), suggesting that a low viral rebound while receiving HAART that contains a PI has no significant consequence on midterm clinical outcome. [ABSTRACT FROM AUTHOR]

Background: Thirteen clustered cases of American histoplasmosis, a deep mycosis caused by Histoplasma capsulatum and acquired through inhalation of airborne spores was reported. Twenty-five persons traveled in Martinique, French West Indies. Thirteen underwent trekking and passed through a mountain tunnel full of bats (tunnel group). The 12 others performed canyoning and did not go through the tunnel (control group). Fifteen days after exposure, 1 patient of the tunnel group developed fever, chills, and cough. Methods: The index case was diagnosed in the hospital, but 12 cases where initially diagnosed as prolonged influenza. All individuals were contacted and submitted to a phone questionnaire. They were asked about eventual occurrence of influenza-like symptoms, about activities practiced, and the notion of contact with bats. All were invited to have clinical examinations, chest x-ray films, and blood samplings. Serologic testing for histoplasmosis was performed by immunodiffusion. Clinical evidence of infection with H. capsulatum was obtained in all the remaining patients of the tunnel group and in none in the control group. Symptoms occurred with an acute onset in 11 to 23 days: fever and chills, severe asthenia, headaches, digestive tract involvement, and then cough, dyspnea, hepatic involvement. Pulmonary micro- or macronodules and mediastinal adenopathies were seen on radiograph and/or computed tomography scan. Results: H. capsulatum serologic tests were positive in all 13 cases with presence of specific M and or H precipitins, 5 to 13 weeks after exposure, and were negative in control group. All patients were treated with itraconazole 200 mg per day during at least 2 months. Treatment was well tolerated; patients progressively recovered. Clinical and serologic follo-up was obtained for some patients at 1 and 4 years. The present study reports the first large outbreak of histoplasmosis acquired in Martinique. Conclusion: Histoplasmosis still occurs and is po [ABSTRACT FROM AUTHOR]

We compared use of a 3-class regimen (nevirapine [Nvp], stavudine [d4T], and indinavir [Idv; 1000 mg 3 times daily]) with use of a 2-class regimen (lamivudine [3TC], d4T, and Idv [800 mg 3 times daily]) for 145 patients infected with human immunodeficiency virus type 1 (HIV-1). At week 72, the plasma HIV-1 RNA level was undetectable in 52% of Nvp recipients versus 79% of 3TC recipients (P< .001). Idv trough levels were 81 ng/ mL in the Nvp group and 99 ng/mL in the 3TC group (P = .012). In the Nvp group, 42.5% of patients discontinued the study regimen; in the 3TC group, 22.5% of patients discontinued therapy (P = .013). The rate of resistance to nonnucleoside analogue reverse-transcriptase inhibitors among patients in the Nvp group with virological failure was not different from the rate of resistance to 3TC among patients in the 3TC group with virological failure. These results do not support the use of a 3-class regimen that includes Nvp for patients with no or limited exposure to nucleoside analogues. [ABSTRACT FROM AUTHOR]

The incidence of human immunodeficiency virus (HIV)-Leishmania coinfections in France was estimated on the basis of the French Hospital Database on HIV, and risk factors for the occurrence of visceral leishmaniasis (VL) were analyzed by a multivariate Cox model. VL was diagnosed in 165 of 55,626 HIV-infected patients followed since 1992. The incidence of VL decreased from 11.6 ± 1.2 per 10,000 persons-years before 1996 to 6.3 ± 0.7 per 10,000 persons-years after 1996, the year when highly active antiretroviral therapy (HAART) was initiated in France. The relative hazard (RH) for development ofVL was higher in (1) intravenous drug users versus other transmission groups (RH = 1.56; 95% CI, 1.13-2.15), (2) patients living in southern France versus those living in northern France (RH = 3.36; 95% CI, 2.44 -4.61), and (3) patients who had a CD4 cell count of &les;50/mm[SUP3] during their follow-up versus those who did not (RH = 6.45; 95% CI, 4.27-9.75) but was lower in (4) patients who received antiretroviral therapy including &ges;3 drugs versus those who did not (RH = 0.41; 95% CI, 0.26-0.65). We found a significant decrease in the incidence of HIV-Leishmania coinfections after 1996, associated with the introduction of HAART in France. [ABSTRACT FROM AUTHOR]

Abstract Background We have previously shown that lipid alterations in HIV-1-associated lipodystrophy (LD) are correlated with decreased serum dehydroepiandosterone (DHEA) and increased cortisol:DHEA ratio and IFN-α levels. Objective To evaluate in a longitudinal study whether steroid and cytokine modifications are associated with the evolution of physical changes and lipid alterations associated with LD. Methods Thirty-four HIV-1-positive men were followed during 32·5 ± 4·0 months and tested at four time-points. The patients were subdivided into five groups according to physical changes and anthropometric measurements: LD-negative, initially LD-negative becoming LD-positive, LD-positive unchanged, aggravated or improved. Serum lipids, apolipoproteins, adrenal steroids and cytokines were measured and compared with baseline values. Results (1) LD aggravation is associated with persistent elevated lipids, a decrease in serum DHEA, an increase in cortisol:DHEA ratio and persistent high levels of IFN-α. (2) LD improvement is associated with normalization of serum lipids, an increase in serum DHEA leading to normalization in cortisol:DHEA ratio, and normalization of IFN-α levels. (3) In LD-positive men evolution of VLDL cholesterol is negatively correlated with DHEA (r = -0·56, P < 0·01) and positively with cortisol:DHEA ratio (r = 0·62, P < 0·004) and with IFN-α (r = 0·57, P < 0·01). (4) The switch to LD is associated with a decrease in serum DHEA. (5) Patients who remained LD-negative maintained normal lipids, elevated cortisol and DHEA, and normal cortisol:DHEA ratio and normal levels of IFN-α. Conclusions This study indicates that cortisol:DHEA ratio and serum IFN-α levels are closely associated with clinical evolution and atherogenic lipid alterations in LD. [ABSTRACT FROM AUTHOR]

JC virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating central nervous system infection that mainly affects patients with acquired immunodeficiency syndrome. The diagnostic value of the detection of JCV DNA in cerebrospinal fluid (CSF) has been proved. A correlation between the JCV burden in CSF and the PML prognosis has been proposed. To our knowledge, the present study is the first to examine JCV burden in CSF in relation to the magnitude of neurological damage. An in-house quantitative polymerase chain reaction assay was used for measurement of the JCV burden in CSF samples from 12 patients with PML. A wide variation in JCV load (6.4 log) was found among the patient CSF samples, a finding that makes JCV load measurements worthwhile. Virus load values of >4.68 log were associated with shorter patient survival time. No correlation was found between the virus load values and the global volume of brain tissue damaged. Our data suggest that factors other than the volume of neurological lesions influence the shedding of JCV in the CST. [ABSTRACT FROM AUTHOR]

Abstract Background A syndrome of lipodystrophy (LD) associated with peripheral lipoatrophy and central/visceral adiposity has been reported in HIV-1-infected patients treated by combined antiretroviral therapy (ART). Lipid metabolism is partly regulated by both steroid hormones and cytokines and we have previously reported that dyslipidaemia in LD-positive men is correlated to an increase in cortisol : DHEA ratio (Christeff et al. , AIDS 1999;13:2251). In this study we questioned whether it is also related to cytokine perturbations. Materials and Methods A cross-sectional study was performed on 42 HIV-1-positive men on ART, 27 of whom had symptoms of LD, defined by computed tomography scan. Serum cytokines (IFN-α, TNF-α, sTNF-RI, sTNF-RII, IL-6, IL-1β and IL-2) and lipids [cholesterol, triglycerides (TG) and their subclasses], and apolipoproteins (Apo), were determined. Results Serum IFN-α was markedly increased in LD-positive compared with LD-negative men and controls. IL-6 and TNF-α concentrations were also significantly elevated in HIV-positive men compared to controls but the levels of these cytokines did not differ between the two groups of patients. A significant positive correlation was found between accumulation of IFN-α and increased levels of cholesterol, TG, VLDL cholesterol, VLDL TG, ApoB and ApoB–ApoA1 ratio. A multivariate forward-performed analysis revealed that IFN-α is the best marker for lipid perturbations associated to LD, followed by insulin and cortisol: DHEA ratio. Conclusions This study demonstrates an association between serum IFN-α and lipid alterations in LD-positive men. The concomittant action of IFN-α and cortisol : DHEA ratio is probably one of the mechanisms responsible for hyperlipidaemia in LD syndrome. [ABSTRACT FROM AUTHOR]

Presents abstracts of posters on clinical pharmacology as of July 8, 2001. Predictions of midozalam concentrations using a population pharmacokinetic software in intensive care patients; Decrease in the activity of hepatic cytochrome P450 by serum.