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In high-income countries, causes of death in people living with HIV (PLHIV) have changed. Three French national surveys from 2000 to 2010 showed a decrease in AIDS-related and an increase in non-AIDS-related deaths. Deaths notified in PLHIV followed between January 1, 2011 and December 31, 2015 in 1 of 13 participating hospitals northeast of Paris area were described. Risk factors for death were assessed, using a multivariable logistic regression model. Of 14,403 individuals, 295 died. Median age at death was 52 years (interquartile range = 47-60) and 77% were men. Sixty-seven individuals (23%) died from non-AIDS-defining nonviral hepatitis-related (NaNH) malignancy, 40 (14%) from AIDS, 34 (12%) from cardiovascular disease (CVD), 33 (11%) from non-AIDS infection, 21 (7%) from liver disease, and 12 (4%) from suicide. Men and women born in sub-Saharan Africa had a lower adjusted odds ratio (aOR) of dying than men having sex with men (MSM) born in France (0.70, 95% confidence interval = 0.45-1.09; and 0.45, 0.28-0.73, respectively). Risk factors for death were older age (aOR = 2.26, 1.36-3.77 for 40-49 years and 2.91, 1.75-4.84 for50 years vs. 18-39 years), male intravenous drug users (IVDU) transmission (2.24, 1.42-3.54 vs. MSM born in France), AIDS (2.75, 2.10-3.59), antiretroviral therapy initiation in earlier periods, time since HIV diagnosis1 year, low CD4 cell count nadir, hepatitis B virus and/or hepatitis C virus coinfection (1.69, 1.23-2.30), and psychiatric disorders (1.73, 1.27-2.38). Our study confirms the increasing frequency of non-AIDS-related deaths, mainly NaNH malignancies and CVD, in PLHIV, justifying overall and in some specific populations (psychiatric and IVDU) prevention and screening.

OBJECTIVES The aim of the study was to assess whether the timing of combination antiretroviral therapy (cART) initiation, the choice of cART and virological response differ in migrants versus European natives in the north and east of Paris area, after dissemination of French recommendations for universal treatment. METHODS Antiretroviral therapy-naive HIV-1-infected adults with at least two follow-up visits at one of 15 participating centres between 1 January 2014 and 31 March 2015 were included in the study. Factors associated with cART initiation before 31 March 2015, with protease inhibitor (PI)-containing cART among individuals initiating cART, and with 1-year virological success after cART initiation were assessed using multivariable logistic regression models. Sex, age, region of origin [Western Europe, sub-Saharan Africa (SSA) or other], HIV transmission group, baseline AIDS status, CD4 cell count and plasma viral load (VL), and hepatitis B and/or C virus infection were considered in the analyses. RESULTS Among 912 individuals, only 584 (64%) started cART during the study period. After adjustment, migrants from SSA were half as likely to initiate cART and to have a subsequent virological response compared with individuals from Western Europe [adjusted odds ratio (aOR) 0.54; 95% confidence interval (CI) 0.36-0.82; and aOR 0.52; 95% CI 0.28-0.98, respectively]. PI-containing cART was more frequently prescribed in migrants from SSA, in people with lower CD4 cell counts and in people with higher VL. CONCLUSIONS Even in the context of universal cART recommendations and of free access to care, migrants from SSA still have delayed access to cART and a lower virological response. Efforts are still necessary to provide immediate cART to all people living with HIV.

On-demand oral tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) has been approved for pre-exposure prophylaxis (PrEP) in MSM in France following the results of clinical studies, but data are limited on real-world experience.A single-center, open-label, prospective cohort study that recruited people at high risk of HIV infection in Paris.Participants were enrolled in a single hospital-based outpatient clinic and were proposed to start PrEP with daily or on demand TDF/FTC. At baseline and every 3 months thereafter, patients were tested for HIV and creatinine plasma levels, and data on sexual behavior, other sexually transmitted infections (STIs), and tolerability were collected.From 10 November 2015 to 30 April 2017, 1069 patients were screened and 1049 (98.1%) started PrEP. Median age was 36 years, 99.4% were MSM with a median number of partners of 10, and 793 (75.6%) opted for on demand PrEP. Over 486 person-years of follow-up, four HIV-infections were diagnosed in poorly or nonadherent patients (incidence 0.82/100 person-years). Rate of condomless sex at last intercourse increased from 53.3% at baseline to 79% at month 12 (P 10), but increase in bacterial STI rates was modest (14.6% at baseline vs. 19.2% at month 12; P 10). Most adverse events were gastrointestinal and did not lead to PrEP discontinuation.Most PrEP users were high-risk MSM and opted for on-demand PrEP. PrEP use was associated with a low HIV incidence and a high rate of condomless sex with a modest increase in bacterial STIs.

Given international interest in "treatment as prevention" (TasP) and the pertinence of optimizing antiretroviral treatment (ART) regimens for TasP, 19 French HIV experts were interviewed on their criteria for ART if used specifically for prevention with HIV-positive persons. Through content analysis of the interview material, nine criteria were identified. The most endorsed criteria, collectively, suggest a choice of treatment based on "minimal interference" where negative impacts of ART are minimized and ease of treatment integration maximized in the lives of people living with HIV/AIDS (PLHIV) for both the short and long term. These criteria were the tolerance, side effects, and/or toxicity profile of ART, simplicity (e.g., of treatment schedule, dosage form) and the individualization of treatment (e.g., adapted to lifestyle). While virologic efficacy (i.e., a durable, undetectable viral load) was also deemed important, several experts specified that it was virtually assured with current treatments. To a much lesser extent, experts endorsed diffusion of ART into the genital compartments, a strong genetic barrier (against resistance), validated treatments (as opposed to new classes of ART), a rapid reduction in HIV viral load, and treatment cost. Pharmacologically, minimal interference calls for further improvements in the tolerance, side effects and toxicity profile of ART and in the simplicity of ART administration. Clinically, it means avoiding a one-size-fits-all approach to ART in TasP and engagement with and of PLHIV in ART selection and side effects management. Strategically, it emphasises keeping the health and quality of life of PLHIV at the forefront of a TasP-oriented public health intervention.

Early use of highly active antiretroviral treatment (ART) in people living with HIV for HIV prevention has gained legitimacy but remains controversial. Nineteen French HIV experts with diverse specializations (over half of whom were clinicians) were qualitatively interviewed on their views about ART irrespective of CD4 count of more than 500 cells/mm3for purposes of HIV prevention, which is not systematically recommended in France. Content analysis identified 2 broad categories: individual considerations (subcategories: patient health and well-being; patient preparedness and choice) and collective considerations (subcategories: HIV transmission risk; impact on the epidemic; cost). Uncertainty surrounded many experts’ considerations, and unity was lacking on key issues (eg, candidacy for early preventive treatment, expected clinical- and population-level effects). An umbrella theme labeled “Weighing the merits of early ART in the face of uncertainties” was identified. Our analyses raise doubts about the current acceptability of widespread implementation of early ART for HIV prevention in France.

BACKGROUND once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine. METHODS the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of

To assess the evolution of triglyceride (TG) levels in HIV-infected patients receiving stable potent antiretroviral therapy treated with N-3 polyunsaturated fatty acids (PUFAs), a prospective double-blind randomized design for a reliable assessment of TG evolution was performed. One hundred twenty-two patients with TG levels2 g/L andor =10 g/L after a 4-week diet (baseline TG: 4.5 +/- 1.9 g/L) were randomized for 8 weeks to N-3 PUFAs (2 capsules containing 1 g of fish oil 3 times daily, n = 60), or placebo (1 g of paraffin oil capsules, n = 62). An 8-week open-label phase of N-3 PUFAs followed. Evaluation criteria were TG percent change at week 8, percentage of responders (normalization oror =20% TG decrease), and safety issues. Ten patients with baseline TG levels10 g/L were not randomized and received N-3 PUFAs as open treatment. The difference (PUFA - placebo) in TG percent change at week 8 was -24.6% (range: -40.9% to -8.4%; P = 0.0033), the median was -25.5% in the PUFA group versus 1% in the placebo group, and mean TG levels at week 8 were 3.4 +/- 1.8 g/L and 4.8 +/- 3.1 g/L, respectively. TG levels were normalized in 22.4% (PUFA) versus 6.5% (placebo) of patients (P = 0.013) with aor =20% reduction in 58.6% (PUFA) versus 33.9% (placebo) of patients (P = 0.007). Under the open-label phase of N-3 PUFAs, the decrease in TG levels was sustained at week 16 for patients in the PUFA group (mean TG: 3.4 +/- 1.7 g/L), whereas a 21.2% decrease in TG levels occurred for patients in the placebo group (mean TG: 3.3 +/- 1.4 g/L). No significant differences were observed between groups in the occurrence of adverse events. The median TG change at week 8 was -43.6% (range: Q1-Q3; 95% CI: -66.5% to -4.6%) for patients with baseline TG levels10 g/L. The difference in mean total cholesterol between groups (PUFA - placebo) at week 8 was -8.5% (P = 0.0117). This study demonstrated the efficacy of PUFAs to lower elevated TG levels in treated HIV-infected hypertriglyceridemic patients. N-3 PUFAs have a good safety profile.

Background Rilpivirine (RPV) is a second-generation once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) which has shown non-inferior antiviral activity to efavirenz in treatment-naive patients. Data in treatment-experienced patients are more limited. We wished to assess the efficacy and safety of a switch to RPV-based regimens in well-suppressed treatment-experienced patients. Methods Between September 2012 and June 2013, all antiretroviral therapy (ART)-experienced HIV-1-infected patients with a plasma HIV RNA level Results A total of 281 participants were studied and 97% received a combination of RPV/tenofovir disoproxil fumarate/emtricitabine. At month 12, the rate of virological success was 59% and increased to 72% using available data beyond month 12. Sixteen (6%) patients experienced virological failure, which was associated with the presence of the M184V/I resistance mutation in prior genotypes ( P=0.02) and the use of a non-NNRTI as third agent before the switch ( P=0.03). RPV-based regimens were overall well tolerated and only 23 (8%) patients discontinued ART because of adverse events, mostly neuropsychiatric adverse events. Switching to RPV was associated with significant but modest improvement of the lipid profile. Conclusions In patients fully suppressed on ART, a switch to an RPV-based regimen should only be considered in the absence of prior virological failure or resistance mutations to nucleoside reverse transcriptase inhibitors and NNRTIs to avoid virological failures.

Background Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. Methods We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. Results Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). Conclusions The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ ANRS] and others; ClinicalTrials.gov number, NCT01473472.)

Introduction We compared biological outcomes in anti-retroviral-naive patients with viral load (VL) >5,000 copies/ml starting combivir-based, three-drug highly active antiretroviral therapy regimens in 2001–2002 according to the third component, namely abacavir (ABC), nelfinavir (NFV), indinavir/ritonavir (IDV/r), lopinavir/ritonavir (LPV/r), nevirapine (NVP) or efavirenz (EFV). Methods We evaluated virological response (HIV RNA + T-cells/u, l) separately in patients with baseline VL Results Median follow up was 19 months. EFV had better virological efficacy than NFV and IDV/r among patients with baseline VL Conclusions For first-line therapy, in this observational setting, EFV, LPV/r and NVP, when added to the combivir backbone, were more likely to drive viral load

Tenofovir disoproxil fumarate (TDF) has shown in vitro activity against both HIV and hepatitis B virus (HBV). We retrospectively evaluated the efficacy of TDF (300 mg/d), administered as a part of anti-retroviral therapy, in a large cohort of HIV/HBV-coinfected patients. Sixty-five HIV/HBV-coinfected patients who received TDF for at least 6 months with serum HBV DNA levels above 2.3 log10 copies/mL at TDF initiation and who had stored serum samples before and during TDF therapy were included. Serum HBV DNA was measured on stored samples. The median follow-up period was 12 (Q1-Q3: 8-17) months. Serum hepatitis B e antigen (HBeAg) was positive in 54 patients (83.1%). Fifty-two patients (80.0%) were receiving lamivudine (LAM) (150 mg twice a day), and 68.8% had documented LAM resistance at baseline. Among HBeAg-positive patients, the median reduction from baseline (8.17; Q1-Q3 = 7.30-8.30 log10 copies/mL) of serum HBV DNA was 4.56 log10 copies/mL (Q1-Q3 = 3.33-5.55) (P < .0001). In HBeAg-negative patients, serum HBV DNA decline from baseline (4.83; Q1-Q3 = 2.69-6.40 log10 copies/mL) was 2.53 log10 copies/mL (Q1-Q3 = 0.39-4.10). At the end of the study, HBV DNA became undetectable in 29.6% and 81.6% of the HBeAg-positive and HBeAg-negative patients, respectively. Serum HBeAg became negative in 4 patients, 2 of whom acquired serum hepatitis B e antibody. In conclusion, this retrospective analysis demonstrates the efficacy of TDF against wild-type, presumed precore mutants and LAM-resistant HBV when used as a part of anti-retroviral therapy in HIV-coinfected patients.

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stayudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS A1424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing ≥48 weeks in trial BMS A1424-008 with a plasma HIV RNA viral load

Peptide insertions in codons 67–71 of the reverse transcriptase (RT) pol gene were detected in 11 (2.7%) of 414 genotypic analyses performed in a hospital cohort of 2900 outpatients with human immunodeficiency virus type 1 (HIV-1) infection. The duration of antiretroviral treatment (bi- or tri-therapy) before the detection of insertions ranged from 12 to 60 months. Dipeptide insertions were detected in ten patients, of which the most frequent was serine–serine. A monopeptide insertion was diagnosed once. The amino-acid composition patterns of insertions varied with time in five of the 11 patients. Peptide insertions were always associated with various patterns of pre-existing or appearing resistance mutations in the RT pol gene to different antiretroviral drugs. Genotypic-guided treatment resulted in virological and immunological improvement in two patients. In contrast, the remaining patients did not respond to any of the various antiretroviral regimens prescribed. Furthermore, various patterns of resistance mutations developed to the prescribed antiretroviral drugs, with AIDS-related conditions leading to death in two patients. It was concluded that peptide insertion in this region of the HIV-1 RT pol gene constitutes a rare cause of persistent therapeutic failure, and that management of such patients remains challenging despite successive genotypic analyses aimed at detecting mutations conferring antiretroviral drug resistance.

We report the emergence of HIV-1 mutated strains after long-term viral suppression in four patients who interrupted highly active antiretroviral therapy (HAART). In two cases, mutations pre-existed in proviral DNA before HAART interruption. All mutations were associated with resistance to nucleoside reverse transcriptase inhibitors, and three of the four patients had prolonged periods of monotherapy or dual therapy. Resistant strains may re-emerge rapidly even in patients harbouring a majority of wild-type virus in proviral DNA before treatment interruption.

OBJECTIVES Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART). METHODS We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index. RESULTS The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease. CONCLUSIONS These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.

Morphologic and metabolic changes associated with protease inhibitor (PI) therapy have been reported since the introduction of PIs for treatment of human immunodeficiency virus infection. These changes were measured 12-20 months after initiation of PI therapy in a cross-sectional study involving 614 patients from the Antiproteases Cohorte (APROCO) Study (Agence Nationale de Recherches sur le Sida-EP11). The prevalence was 21% for isolated peripheral atrophy, 17% for isolated fat accumulation, 24% for mixed syndrome, 23% for glucose metabolism alterations, 28% for hypertriglyceridemia (triglyceride level, > or =2.2 mM), and 57% for hypercholesterolemia (cholesterol level, > or =5.5 mM). Age was significantly associated with different phenotypes of lipodystrophy and metabolic alterations, but body-mass index, CD4(+) cell count, and type of nucleoside reverse-transcriptase inhibitor or PI received were not constantly associated with these changes. Furthermore, in all models tested, exposure to stavudine was associated with lipoatrophy and exposure of ritonavir was associated with hypertriglyceridemia. Detection and management of these disorders should be implemented to prevent further complications.

Summary Background Lipodystrophy is a major side-effect of antiretroviral therapy but its pathophysiology remains elusive. In-vitro studies show that HIV-1-protease inhibitors affect adipocyte differentiation at an early step involving sterol-regulatory-element-binding-protein-1 (SREBP1), but in-vivo studies are lacking. Methods We compared fat morphology and mRNA and protein expression of major adipocyte differentiation markers and cytokines in subcutaneous abdominal adipose tissue from 26 HIV-1-infected patients who developed peripheral lipoatrophy while on protease inhibitors and from 18 HIV-1-seronegative healthy controls. Findings Patients' fat contained a higher proportion of small adipocytes than control fat, together with lower mRNA concentrations of the adipogenic differentiation factors CCAAT-enhancer binding protein (C/EBP) β and α, peroxisome proliferator-activated receptor (PPAR) γ, and the 1c isoform of SREBP1, with a median decrease of 93% in the latter. The SREBP1 protein concentration was increased 2·6-fold, whereas the PPARγ protein concentration was decreased by 70%. The expression of adipocyte-specific markers, including leptin, was lower in fat from patients than in fat from controls, whereas expression of tumour necrosis factor (TNF) α was higher and correlated negatively with the expression of SREBP1c and downstream adipogenic factors. SREBP1c mRNA concentrations correlated negatively, and TNFα mRNA concentrations positively, with glycaemia and insulin resistance, but did not correlate with lipid variables. Interpretation The altered differentiation status of peripheral adipocytes in HIV-1-infected patients with antiretroviral-induced lipoatrophy is associated with greatly reduced SREBP1c expression. Since the differentiation factor SREBP1 is rapidly targeted by protease inhibitors in vitro, our results suggest that SREBP1c could be an important mediator of peripheral lipoatrophy in this setting, leading to metabolic alterations such as insulin resistance.

Introduction : Rilpivirine (RPV) is a new once-daily, non-nucleoside, reverse transcriptase inhibitor (NNRTI). In treatment-naive patients, RPV has shown non-inferior antiviral activity to efavirenz but data in treatment-experienced patients are more limited. We assessed the efficacy and safety of RPV in treatment-experienced patients switching to a RPV-based regimen. Methods : Between September 2012 and June 2013, all antiretroviral therapy (ART) experienced HIV-1 infected patients with a plasma HIV-RNA level

on behalf of the FHDH ANRS CO4 (French Hospital Database on HIV, Agence Nationale de Recherches sur le Sida, cohort 4); International audience; Introduction: We compared the effectiveness of tenofovir/emtricitabine (TDF/FTC) combined with either lopinavir/r (LPV/r) or another recommended third drug in the 2010 French guidelines in antiretroviral-naıve patients starting combination antiretroviral therapy in 2004Á2008 in the French Hospital Database on HIV.Methods: The outcomes were stop or switch of the third component, viral load (VL) B500 copies/ml, an increase of at least 100 CD4 cells/mm 3 , AIDS-defining event and non-AIDS-defining hospitalization or death. Propensity scores were estimated by logistic regression based on the clinical centre and other confounders. In each clinical centre, each patient initiating LPV/r was matched with a patient initiating another third drug (efavirenz or atazanavir/r) and having a close propensity score. Cox's proportional hazards models were then used, with treatment as covariate. Time was right-censored at four years.Results: 1269 patients started LPV/r plus TDF/FTC, and 890 could be matched to 890 patients receiving another third drug. Baseline characteristics were well balanced between these two groups. LPV/r was associated with a higher risk of third drug stop (hazard ratio (HR): 1.69; 95% confidence interval (CI), 1.42Á2.00) and with less rapid viral suppression (HR: 0.83; 95% CI, 0.72Á 0.95). There was no difference in the time required for a CD4 cell increment of at least 100/mm 3 , or to the occurrence of an AIDS-defining event. Non-AIDS-defining hospitalizations or deaths were more frequent with LPV/r (HR: 1.79; 95% CI, 1.33Á2.39).Conclusions: For first-line therapy, in this observational setting, TDF/FTC plus LPV/r were less durable than TDF/FTC plus another recommended third drug, led to a less rapid viral suppression and were associated with a higher risk of non-AIDS morbidity.

HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P

Objective: To assess the antiviral efficacy, safety and adherence in patients switched to an abacavir-containing nucleoside reverse transcriptase inhibitor (NRTI) regimen after long-term HIV-1 RNA suppression with a dual NRTI/protease inhibitor (PI) combination. Methods: In an open-label, multicentre study, patients receiving 2NRTI plus PI for at least 6 months, with a history of undetectable plasma HIV-1 RNA since the initiation of therapy and plasma HIV-1 RNA < 50 copies/ml at screening, were randomly assigned to replace the PI with abacavir (n = 105) or continue the same treatment In = 106). Clinical assessments included plasma HIV-1 RNA, chemistry, haematology, lymphocyte counts, and adverse event reports. Adherence to treatment was assessed by patient self-report. Results: A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm (P = 0.03) while treatment failure was experienced by significantly more patients in the PI arm: 24 (23%) versus 12 (12%) (P = 0.03) Therapy-limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms, respectively, whereas virological rebound was the cause in four versus two cases. Significant reductions in cholesterol and non-fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm (P< 0.001 and P= 0.035, respectively). The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm. Conclusion: The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV-1 RNA provides continued virological suppression, significant improvements in lipid abnormalities and enhanced ease of dosing.

Proviral human immunodeficiency virus type 1 (HIV-1) DNA could be a useful marker for exploring viral reservoirs and monitoring antiretroviral treatment, particularly when HIV-1 RNA is undetectable in plasma. A new technique was developed to quantify proviral HIV-1 using a TaqMan real-time PCR assay. One copy of proviral HIV-1 DNA could be detected with 100% sensitivity for five copies and the assay had a range of 6 log 10 . Reproducibility was evaluated in intra- and interassays using independent extractions of the 8E5 cell line harboring the HIV-1 proviral genome (coefficients of variation [CV], 13 and 27%, respectively) and peripheral blood mononuclear cells (PBMC) from a patient with a mean proviral load of 26 copies per 10 6 PBMC (CV, 46 and 56%, respectively). The median PBMC proviral load of 21 patients, measured in a cross-sectional study, was determined to be 215 copies per 10 6 PBMC (range, P = 0.004). In the remaining patient, proviral HIV-1 DNA was detectable but not quantifiable due to a point mutation at the 5′ end of the TaqMan probe. No correlation was observed between proviral load and levels of CD4 + cells or HIV-1 RNA in plasma. TaqMan PCR is sensitive and adaptable to a large series of samples. The full interest of monitoring proviral HIV-1 DNA can now be ascertained by its application to the routine monitoring of patients.

Epstein-Barr virus (EBV) reactivation is more likely to occur in immunocompromised patients with subsequent higher susceptibility to EBV-associated lymphoproliferations. In contrast to transplant recipients, limited data are available concerning the EBV load in HIV-infected patients, with or without AIDS-related non-Hodgkin's lymphomas. We developed a TaqMan real-time PCR assay, allowing both the EBV genome and a cellular gene to be quantified in order to obtain a reliable normalized measurement of the EBV load in peripheral blood mononuclear cells (PBMCs). With a wide 6-log10 quantification range and inter-assay variations of less than 24%, this quantitative PCR was sufficiently accurate and reproducible for routine follow-up. The EBV load was determined in PBMCs from 113 HIV-infected patients, 11 patients with primary HIV infection and 24 HIV-seronegative healthy controls. The rates of EBV detection were similar in the three groups. However, EBV loads were higher in the HIV-infected group (P

We designed a cohort in order to assess the long-term effects of triple-drug antiretroviral combinations in 608 patients infected with human immunodeficiency virus type 1 (HIV-1). We recruited patients who had been previously treated with nucleoside analogues as well as treatment-naive patients who were starting triple-drug antiretroviral combinations consisting of nucleoside analogues, either alone or in combination with a protease inhibitor. After a median follow-up time of 22 months, the incidence rates of acquired immune deficiency syndrome-defining events and death were, respectively, 6.9 (95% confidence interval [CI], 5.3-8.8) and 2.9 (95% CI, 1.9-4.2) per 100 person-years. Advanced clinical stage of disease (P=.004), a low CD4(+) cell count (P=.002), and a low quality-of-life score (P=.001) at baseline were independent predictors of clinical progression. The initial triple-drug combination was modified a total of 647 times in 321 patients. The only independent predictor of treatment modification was previous exposure to a nucleoside analogue in patients who did not receive a new nucleoside analogue at inclusion (P=.001). Plasma HIV RNA values below 500 copies/mL were obtained in 88% of the treatment-naive patients and in 57% of the previously treated patients (P or = 1 new nucleoside analogue at enrollment, previously treated patients who did not receive a new nucleoside analogue at enrollment were twice as likely to have plasma HIV RNA values >500 copies/mL at the last visit (adjusted odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.8), and the antiretroviral-naive patients were significantly less likely to have plasma HIV RNA values >500 copies/mL at the last visit (adjusted OR, 0.2; 95% CI, 0.1-0.4).

Objectives To demonstrate that lamivudine and zidovudine, given separately (lamivudine/zidovudine) or as a single combination tablet (Combivir™), had equivalent efficacy. To evaluate the safety and antiretroviral activity of intensification with abacavir in patients treated with lamivudine/zidovudine for ≥12 weeks. Design A 12-week, equivalence study of lamivudine/ zidovudine versus Combivir. Patients who completed this study could enter a 48-week, intensification study of Combivir plus abacavir. Methods In the equivalence study, treatment-naive patients were assessed for HIV-1 RNA, CD4 cell count and genotype. The same assessments plus phenotype were made in the intensification study. Serious adverse events were recorded in the equivalence study and all adverse events in the intensification study. Results Lamivudine/zidovudine ( n=40) and Combivir ( n=35) gave equivalent reductions in plasma HIV-1 RNA levels at week 12. An identical proportion of patients (74%) in each treatment group harboured virus with the M184V mutation after 12 weeks. Fifty-two patients entered the intensification study and 44 completed 48 weeks of treatment. At the time of intensification with abacavir, all 35 patients with evaluable isolates harboured HIV-1 containing M184V. Addition of abacavir to Combivir led to further decreases in plasma HIV-1 RNA and increases in CD4 cell counts compared with the start of intensification ( P

Objectives: During the last few years, AIDS has been the main cause of large pericardial effusions in urban settings. We have therefore had to perform surgical pericardial drainage for diagnostic and:or therapeutic purposes in AIDS patients. This study was designed to establish the diagnostic and therapeutic yield of pericardial drainage for these patients. Methods: We retrospectively reviewed the data of the 13 AIDS patients with a pericardial effusion, referred to our surgical department between December 1989 and December 1996 for surgical drainage and pericardial biopsy. Results: Cytological studies and searches for bacteria, mycobacteria and parasites were all negative. The histology of the 13 pericardial biopsies disclosed three pericardial locations of a Kaposi’s sarcoma (all three patients had a pre-existent extra-cardiac location of this sarcoma) and one pericardial location of an already known immature mediastinal teratoma. In the nine other cases, the lesions were aspecific. Four patients died of multivisceral failure within 30 days of surgery. For the survivors, surgical drainage afforded relief and there were no clinical signs of recurrent effusion. Conclusions: The cause of pericardial effusion in AIDS is still often unknown, even after pericardial biopsy. Here, aspecific pericarditis was the most common diagnosis. Although the prognosis of such effusion in these patients is known to be poor, surgical drainage provided relief for those who survived the post-operative period. © 1998 Elsevier Science B.V. All rights reserved.

Human cytomegalovirus (HCMV) is a well-known opportunistic agent that reactivates in human immunodeficiency virus (HIV)-seropositive subjects. Human herpesvirus 6 (HHV-6) and HHV-7 were discovered recently and, like HCMV, belong to the Betaherpesvirinae subfamily. We looked for the presence of HCMV, HHV-6, and HHV-7 by PCR with saliva and urine samples from 125 HIV-seropositive patients at different stages of HIV infection and with saliva and urine samples from 29 HIV-seronegative subjects. All three viruses were frequently detected in the saliva (overall rates of detection, 61, 43, and 63% for HCMV, HHV-6, and HHV-7, respectively) with no correlation with the stage of immune deficiency. In contrast, HCMV was detected in urine much more frequently than the two other herpesviruses (overall rates of detection, 37, 2, and 6.5% for HCMV, HHV-6, and HHV-7, respectively) and was associated with immune deficiency. This suggests that these three genetically related viruses differ from each other with regard to replication in the urinary tract.

We conducted a prospective observational study to determine the feasibility and impact of rifabutin prophylaxis (300 mg daily) for human immunodeficiency virus-infected patients whose CD4 cell counts were100/mm3. Three hundred seventy-one patients (65.2% of all patients with CD4 cell counts of100/mm3 [mean +/- SD, 30 +/- 25/mm3]) received rifabutin prophylaxis for a mean duration +/- SD of 35.5 +/- 34.2 weeks; 198 patients (mean CD4 cell count +/- SD, 51.6 +/- 32/mm3) did not receive prophylaxis. Rifabutin prophylaxis for 8.4% of patients was interrupted because of adverse events. Mycobacterium avium complex (MAC) bacteremia developed in 17 (4.6%) of 371 patients receiving rifabutin prophylaxis and in 22 (11.1%) of 198 patients not receiving rifabutin prophylaxis. The mean CD4 cell count +/- SD at the diagnosis of MAC bacteremia was lower in patients receiving prophylaxis than in those not receiving prophylaxis (11.5 +/- 6.8/mm3 vs. 34.7 +/- 36/mm3, respectively; P.01). MICs for MAC strains isolated from patients receiving prophylaxis were less than or equal to those for strains isolated from patients not receiving prophylaxis.

The aim of our work is to explore the use of IFN-beta for gene therapy in the HIV-infection. Transduction of various HIV target cells with a retroviral vector that carries the Hu-IFN-beta coding sequence under constitutive low expression control, confers resistance to HIV without affecting cell replication or function. After transduction, lymphocytes from HIV-infected patients develop resistance to the endogenous virus, provided the cells are derived from individuals with a CD4 cell count higher than 200 per mm3.

Objective To explore the possibility of gene therapy of HIV infection based on the multiple antiretroviral activities of interferon (IFN)-beta. Design We introduced into HIV target cells an IFN-beta gene placed under an expression control ensuring a low and constitutive expression, sufficient to confer a permanent antiviral state without impeding normal cell function. Methods We transformed, with an efficacy ranging from 20-55%, peripheral blood lymphocytes (PBL) derived from healthy, seronegative donors, and from asymptomatic HIV-infected individuals by the HMB-KbHuIFN beta retroviral vector carrying the human IFN-beta coding sequence driven by a fragment of the murine H-2Kb gene promoter. Results The replication rate of the IFN-beta-expressing cells was no different from that of untransformed controls during the 21-day period of in vitro observation. When IFN-beta-transformed, purified CD4+ lymphocytes from healthy donors were HIV-1LAI-infected, virus replication was inhibited and most of the cells survived, in contrast to untransformed CD4+ cells which were all destroyed 12 days after infection. Protection of CD4+ cells from the same donors was also observed in suspensions of IFN-beta-transformed total PBL that were infected with HIV-1LAI. In IFN-beta-transformed PBL from four HIV-infected donors, endogenous HIV replication was decreased and 28-69% of the CD4+ cells survived at the end of the 21 days in culture. In the untransformed control PBL suspensions, all CD4+ cells were destroyed. In long-term experiments, HIV-infected, IFN-beta-transformed cell populations of the lymphocytic CEM and the promonocytic U937 line were kept in culture for 60 days, during which time they remained resistant to HIV infection. Conclusion These results indicate that further exploration of autocrine IFN-beta production for somatic cell gene therapy of HIV infection is warranted.

International audience; Histoplasma capsulatum var. capsulatum infection is rare outside disease-endemic areas. Clinical presentation and outcome of acquired immunodeficiency syndrome-related histoplasmosis are unknown in non-endemic areas with wide access to highly active anti-retroviral therapy (HAART). Retrospective analysis of cases recorded at the French National Reference Center for Mycoses and Antifungals during two decades: pre-HAART (1985-1994) and HAART (1997-2006). Clinical features and outcome of all adults with proven acquired immunodeficiency syndrome-related histoplasmosis were compared between the two periods. One hundred four patients were included (40 during the pre-HAART era and 64 during the HAART era). Diagnosis was established a mean of 62 days after onset of symptoms. One-year overall mortality rates decreased from 53% (pre-HAART era) to 22% (HAART era). Diagnosis during the pre-HAART era and an older age were the only independent factors associated with death. Histoplasmosis is a rare invasive fungal infection outside disease-endemic areas. Its prognosis improved significantly during the HAART era.

Objectives and Methods: Retrospective study of all patients who started antiretroviral therapy (ART) in 2007 in a single center in Paris, with baseline characteristics and 1-year outcome, to assess adherence to national guidelines. Results: We analyzed 118 patients. Time of ART initiation was in agreement with the guidelines for only 64 (54.2%) patients. Fifty patients (42%) started ART with AIDS or a CD4 count 3. In all, 62 (52%) and 47 patients (40%) received a combination of 2 nucleoside analogues with efavirenz (EFV) and 1 ritonavir-boosted protease inhibitor (PI/r), respectively. Treatment regimens were in accordance with the guidelines for 114 patients (97%). At 1 year, 16 patients (13.5%) were lost to follow-up, only 5 (4.9%) experienced HIV disease progression or death, but 19 (18.6%) required hospitalization. Antiretroviral therapy was changed in 21 patients (21%). Ten patients (8.4%) experienced virologic failure. Conclusion: Antiretroviral therapy was in agreement with guidelines for the choice of combination but was often initiated too late.

ObjectiveTo evaluate the efficacy and safety of zidovudine (ZDV) at a maintenance dose of 250 mg every 6 h alone or as cotherapy with acyclovir (ACV; 800 mg every 6 h) as treatment for AIDS and AIDS-related complex (ARC).DesignDouble-blind, randomized, placebo-controlled clinical trial of up to 1 ye

The files of 45 human immunodeficiency virus-infected patients with ocular toxoplasmosis were reviewed, with a median follow-up of eight months. The condition was unilateral in 37 of the 45 patients (82%) and was bilateral in eight (18%). Inflammation of the anterior chamber and the vitreous was present in 32 of 53 eyes (60%) and 38 of 53 eyes (72%), respectively. Cytomegalovirus retinitis developed during the follow-up period in nine patients (20%). Cerebral toxoplasmosis was concurrently diagnosed with the ocular toxoplasmosis in 13 patients (29%). The efficacy of the combination of pyrimethamine and sulfadiazine or clindamycin was assessed in 42 patients for the induction therapy and in 38 patients for the maintenance therapy. Induction therapy was always effective within a median period of six weeks. During maintenance treatment, the 24-month relapse rates were 0.20 and 0.18 for the 50-mg/day and 25-mg/day dosage of pyrimethamine, respectively. The overall 12-month survival rate was 0.72. Our results suggested that ocular toxoplasmosis has a better ocular prognosis than cytomegalovirus retinitis, but that it requires appropriate treatment because life-threatening cerebral involvement is often associated.

Three patients who were seropositive for human immunodeficiency virus underwent surgery for infected aneurysm of the abdominal aorta. Fever and abdominal pain were the principal presenting clinical features. None of the patients had any opportunistic infections or endocarditis. In two cases, a ruptured aneurysm was demonstrated radiographically. In the remaining case, sonograms were diagnostic. The organisms responsible were salmonella, Hemophilus influenzae, and Mycobacterium tuberculosis. In two cases, the infectious origin was evidenced by bacteriologic examination of the aortic wall, which revealed the presence of Salmonella enteritidis and Koch's bacillus. Although Hemophilus influenzae was not found in the aortic wall of the remaining case, the infectious origin of the aneurysm was established because preoperative blood cultures were positive for this pathogen, and pathohistologic examination of the specimen showed destruction associated with leukocyte infiltration of the aneurysmal wall. An in situ prosthetic graft replacement protected by omentum was performed in all three cases. Antibiotic therapy was continued for several weeks. All patients are well with follow-up ranging from 10 to 21 months. Infectious aneurysm associated with human immunodeficiency virus seropositivity results in bacterial infestation of an atheromatous aorta. Infected phenomena are promoted by cellular immunodeficiency. Surgery was justified in these cases because of the immediate threat of rupture.

Forty-four patients with acquired immune deficiency syndrome with cytomegalovirus (CMV) retinitis (64 eyes) intolerant of or refusing systemic antiviral therapy received 710 intravitreal injections of ganciclovir at the dosage of 400 Ag per injection. The patients were followed for -a mean period of 9 weeks. Induction therapy consisted of two injections a week until healing. Maintenance therapy consisted of one injection a week until relapse. All but 1 of 53 induction courses led to cicatrization, after a mean of 6.6 injections. In 54 maintenance courses, the 8-week relapse rate was 53%. During intravitreal therapy, involvement of the fellow eye occurred in 11% of the patients and CMV infection developed in a nonocular site in 16% of the patients. Five retinal detachments and two intravitreal hemorrhages occurred. No endophthalmitis or cataract was noted. Intravitreal ganciclovir appears to be a safe and effective alternative in patients intolerant of intravenous anti-CMV drugs.

96 AIDS patients with fever and either acid-fast bacilli on microscopic examination of bacteriological samples or mycobacteria isolated by culture were treated with a daily 4-drug combination of 7–10 mg/kg rifabutin, 5 mg/kg isoniazid, 20 mg/kg ethambutol and 100 mg clofazimine. 46 patients were excluded from efficacy assessment: 13 died before or within the first days of treatment, 5 had negative initial cultures, 14 had initial cultures positive for M. tuberculosis, 4 for M. kansasii, 1 for M. flavescens, 1 for M. gordonae, 7 were lost to follow-up and 1 received no rifabutin. In the 50 remaining patients, 31 had disseminated disease due to M. avium intracellulare complex (MAIC) and 19 had apparently localised disease, due to MAIC in 15 cases and to M. xenopi in 4 cases. Side-effects led to withdrawal of isoniazid in 1 case (hepatic enzymes increased) and rifabutin in another (thrombocytopenia). After 1 month of treatment, fever decreased from 38.4 ± 0.6 °C to 37.7 ± 0.5 °C (p < 0.01) and patients stopped losing weight. After 3 months treatment, only 37 patients were alive and still under treatment. Cultures became negative in 16 of 23 patients with available bacteriological data (9 of 14 patients with disseminated disease and 7 of 9 patients with localised disease), relapse occurred before death in 4 patients. 34 patients died before treatment was completed. Death was considered to be related to mycobacterial infection in 5 cases. We conclude that the 4-drug combination is safe and, in some cases, it appears to be effective.

International audience; Two of the first human immunodeficiency virus type-1 (HIV-1) strains isolated were authenticated by reanalyzing original cultured samples stored at the Collection Nationale de Culture des Microorganismes as well as uncultured primary material. Cloned polymerase chain reaction products were used to analyze coding sequences of the V3 loop in the gp120 glycoprotein. The original isolate HIV-1 Bru, formerly called LAV, was derived from patient BRU. HIV-1 Lai was derived from patient LAI and contaminated a HIV-1 Bru culture between 20 July and 3 August 1983. The culture became, in effect, HIV-1 Lai, identifiable by a unique motif in the V3 loop. Because of this contamination two, rather than one, HIV-1 isolates were sent to the Laboratory of Tumor Cell Biology at the National Cancer Institute on 23 September 1983. Original HIV-1 Bru was indeed present in the sample marked JBB/LAV. However the M2T-/B sample harbored HIV-1 Lai, a strain capable of growing on established cell lines. The striking similarity between HIV-1 Lai (formerly LAV-Bru) and HTLV-3B sequences remains.

We studied the time course of immunological and virological markers after highly active antiretroviral therapy (HAART) interruption in chronically human immunodeficiency virus type 1 (HIV-1)-infected patients immunized with an HIV lipopeptide preparation. In a prospective open pilot study, 24 HIV-1-infected HAART-treated patients with undetectable plasma viral loads (pVLs) and CD4+T-cell counts above 350/mm3were immunized at weeks 0, 3, and 6 with a candidate vaccine consisting of six HIV lipopeptides. At week 24, patients with pVLs of 10copies/ml were invited to stop taking HAART. Antiretroviral therapy was resumed if the pVL rose above 4.47 log10copies/ml and/or if the CD4+cell count fell below 250/mm3. Immunological and virologic parameters were studied before and after HAART interruption. The median baseline and nadir CD4+cell counts were 482 (interquartile range [IQR], 195 to 826) and 313 (IQR, 1 to 481)/mm3, respectively. New specific CD8+cell responses to HIV-1 epitopes were detected after immunization in 13 (57%) of 23 assessable patients. Twenty-one patients were evaluated 96 weeks after HAART interruption. The median time to pVL rebound was 4 weeks (IQR, 2 to 6), and the median peak pVL was 4.26 (IQR, 3 to 5) log10copies/ml. Thirteen of these 21 patients resumed HAART a median of 60 weeks after immunization (IQR, 9.2 to 68.4 weeks), when the median pVL was 4.8 (IQR, 2.9 to 5.7) log10copies/ml and the median CD4+cell count was 551 (IQR, 156 to 778)/mm3. Eight patients were still off therapy at 96 weeks, with a median pVL of 4 (IQR, 1.7 to 4.6) log10copies/ml and a median CD4+cell count of 412 (IQR, 299 to 832)/mm3. No clinical disease progression had occurred. Despite the lack of a control arm, these findings warrant a randomized study of therapeutic vaccination with HIV lipopeptides followed by long-term HAART interruption in AIDS-free chronically infected patients.

One hundred and twenty patients suffering from an AIDS-related Kaposi's sarcoma treated by 18 million units of recombinant alpha-2A-interferon daily were followed prospectively for a period of between one and six years. An overall complete response was observed in 35% of these patients; the figure was significantly higher in those who did not have a visceral localization or opportunistic infections. Total lymphocyte count, CD4 lymphocyte count, and CD4/CD8 ratio were significantly higher, and beta-2-microglobuline significantly lower, in the responders than in the non-responders. A multivariate analysis showed that localization of KS and CD4 count had independent predictive value, with an odds ratio of 35 for patients who had more than 300 CD4 cells at the onset of treatment versus those with less than 150. Patients whose initially negative p24 antigenemia remained negative during treatment had the highest frequency of complete response. Among patients with initially positive p24 antigenemia, those whose percentage decrease in anti-genemia levels was greatest had a higher frequency of complete response. The cumulative probability of survival in responders was 62% at four years. These results demonstrate an anti-tumoral and anti-viral effect and prolonged survival in a group of patients whose initial immune parameters were relatively well preserved. However, these results do not permit us to conclude whether these well-responding patients were treated at the onset of illness, or whether their illness was naturally less evolutive.

heavy chains and free kappa light chains. The CD4 cell count was 20/mm3. A biopsy specimen of the abdominal cutaneous nodules showed a tumoral proliferation in the dermis, consisting of round large cells with anisocaryosis of the nucleus containing numerous nucleoli. Immunohistochemical staining of the atypical plasma cells was positive for anti-IgA and κ sera (Fig 2). Epstein-Barr virus (EBV) DNA was detected by polymerase chain reaction (PCR) in the cutaneous biopsy specimen (the negative control for EBV PCR was performed on an EBV-negative B-lymphocyte cell line DG75). Immunofluorescence was negative for latency (EBNA2, LMP) and replication proteins (VCA, LMA), with a positive control performed on an EBV-positive B-lymphocyte cell line (B95). In situ hybridization was negative for EBER small RNA detection. A diagnosis of multiple myeloma was considered. Histologic examination and immunohistochemical staining of the skin biopsy specimen led to a diagnosis of secondary EMP secreting IgA κ. The skin involvement progressed rapidly, and a rapidly growing third nodule appeared in the left temporal region. Chemotherapy with melphalan and cortisone was initiated. After 3 cycles, the initial plasmacytomas had grown, and numerous other lesions had appeared on his arms, face, and chest. Osteolytic lesions appeared without hypercalcemia or renal failure. The patient died 3 weeks later. There is a broad spectrum of hematologic and immunologic abnormalities in HIV-1 infection. Although the incidence of B-cell–associated lymphomas is increased in HIV infection, fewer than 30 cases of multiple myeloma (MM) have been reported in persons infected with HIV.1-11 Unlike classic plasma cell tumors, the disease often has extramedullary involvement with unusual clinical presentation and a short latency period. Skin involvement is present in only 4% to 8% of HIVnegative patients11 with extramedullary plasmacytomas (EMPs). We describe a case of MM presenting with primary cutaneous plasmacytomas and spinal cord compression in a 53-year-old man positive for HIV.