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SCOPUS: le.j, info:eu-repo/semantics/published

Background It is unclear whether HIV infection affects the long‐term prognosis after an acute coronary syndrome (ACS). The objective of the current study was to compare rates of major adverse cardiac and cerebrovascular events after a first ACS between people living with HIV (PLHIV) and HIV‐uninfected (HIV−) patients, and to identify determinants of cardiovascular prognosis. Methods and Results Consecutive PLHIV and matched HIV− patients with a first episode of ACS were enrolled in 23 coronary intensive care units in France. Patients were matched for age, sex, and ACS type. The primary end point was major adverse cardiac and cerebrovascular events (cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke) at 36‐month follow‐up. A total of 103 PLHIV and 195 HIV− patients (mean age, 49 years [SD, 9 years]; 94.0% men) were included. After a mean of 36.6 months (SD, 6.1 months) of follow‐up, the risk of major adverse cardiac and cerebrovascular events was not statistically significant between PLHIV and HIV− patients (17.8% and 15.1%, P =0.22; multivariable hazard ratio [HR], 1.60; 95% CI, 0.67–3.82 [ P =0.29]). Recurrence of ACS was more frequent among PLHIV (multivariable HR, 6.31; 95% CI, 1.32–30.21 [ P =0.02]). Stratified multivariable Cox models showed that HIV infection was the only independent predictor for ACS recurrence. PLHIV were less likely to stop smoking (47% versus 75%; P =0.01) and had smaller total cholesterol decreases (–22.3 versus –35.0 mg/dL; P =0.04). Conclusions Although the overall risk of major adverse cardiac and cerebrovascular events was not statistically significant between PLHIV and HIV− individuals, PLHIV had a higher rate of recurrent ACS. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT00139958.

Objectives HIV-infected individuals are at increased risk of incident fractures. Evaluation of trabecular bone micro-architecture is an important tool to assess bone strength, but its use has not yet been reported in middle-aged HIV-infected male individuals. The aim of the study was to compare bone micro-architecture between HIV-infected and HIV-uninfected men. Methods In this cross-sectional study, 53 HIV-infected male individuals with a mean (± standard deviation) age of 49 ± 9 years who had been receiving antiretroviral therapy including tenofovir disoproxil fumarate (DF) for at least 60 months were compared with 50 HIV-uninfected male controls, matched for age and ethnic origin. We studied the volumetric bone density and micro-architecture of the radius and tibia using high-resolution peripheral quantitative computed tomography (HR-p QCT). Results Volumetric trabecular bone density was 17% lower in the tibia (P < 10−4) and 16% lower in the radius (P < 10−3) in HIV-infected patients compared with controls. By contrast, the cortical bone density was normal at both sites. The tibial trabecular micro-architecture differed markedly between patients and controls: bone volume/total volume (BV/TV) and trabecular number were each 13% lower (P < 10−4 for both). Trabecular separation and inhomogeneity of the network were 18% and 24% higher in HIV-infected patients than in controls, respectively. The radial BV/TV and trabecular thickness were each 13% lower (P < 10−3 and 10−2, respectively). Cortical thickness was not different between the two groups. Conclusions The findings of lower volumetric trabecular bone density and disrupted trabecular micro-architectural parameters in middle-aged male HIV-infected treated patients help to explain bone frailty in these patients.

Introduction Lors de la derniere decennie, le traitement antiretroviral (TARV) a permis de reduire significativement le taux de mortalite ainsi que l’incidence des infections opportunistes. Cependant, il peut etre responsable d’un syndrome de reconstitution immunitaire dont les manifestations peuvent etre variables et severes et doivent etre connues des cliniciens. Le syndrome d’activation macrophagique est une manifestation possible et rare du syndrome d’immunoreconstitution. Observation En septembre 2016, un patient de 43 ans se presente avec une pneumonie a pneumocystis jiroveci complique d’un SDRA revelant une infection a VIH au stade SIDA avec un taux de CD4 a 13,4/μl et une charge virale a 835000 copies/mL. Une retinite et une colite a CMV sont egalement retrouvees et traitees. Une TARV (emcitabine-tenofovir, ritonavir et darunavir) est initiee le 10 octobre 2016. Un mois plus tard, le patient se presente aux urgences avec des douleurs abdominales diffuses, de la fievre et des sudations nocturnes. La prise de sang met en evidence une pancytopenie (hemoglobine a 7,8 g/dL, des plaquettes a 116,103/μl, des globules blancs a 1,42.103/μl, un taux de neutrophiles a 0,92.103/μl), une CRP a 62 mg/L, une ferritine a 2299 μg/L, des LDH a 431UI/L, une cytolyse hepatique, un taux de CD4 a 46/μl et une charge virale a 190000 copies/mL. Le scanner abdominal revele une panniculite mesenterique et une hepatosplenomegalie. Une ponction medullaire avec des images d’hemophagocytose est retrouvee ainsi qu’une amplification en chaine par polymerase (ACP) du virus epstein barr (EBV) dans le sang. La pyrexie, l’hepatosplenomegalie, la pancytopenie, l’hyperferritinemie et les images d’hemophagocytose dans la moelle permettent de poser le diagnostic de syndrome d’activation macrophagique (SAM) secondaire. Ni la fonction cytotoxique mediee par les cellules NK ou le recepteur soluble de l’IL2 (sCD25) n’ont pu etre mesures. Devant ce tableau et une ACP EBV fortement positive, la recherche d’une pathologie lymphomateuse est entreprise. Un TEP/CT indique la presence d’adenopathies hypermetaboliques mediastinales et mesenteriques ainsi qu’un hypermetabolisme splenique, hepatique et medullaire. Une biopsie ganglionnaire par laparoscopie est enfin realisee montrant une lymphadenite granulomateuse necrotique hautement suspecte d’une tuberculose active. Aucune pathologie lymphomateuse n’est mise en evidence. La survenue d’un syndrome d’activation macrophagique quelques semaines apres l’initiation d’un traitement antiretroviral ainsi que la chute de la charge virale font suspecter la presence d’un syndrome d’immunoreconstituion (SIR). Ce syndrome d’activation macrophagique serait secondaire a une maladie a EBV sans pathologie lymphomateuse retrouvee. Une infection tuberculeuse pourrait egalement etre a l’origine de ce syndrome d’activation macrophagique dont les etiologies peuvent parfois etre multiples [1] . Devant la pyrexie persistante et la degradation de l’etat general du patient un traitement antituberculeux est instaure suivi d’une bonne reponse clinique et biologique. Finalement, l’ ACP et la culture ne permettront pas de mettre la tuberculose en evidence. Quelques mois plus tard, le patient suivi en consultation realise un scanner abdominal de controle montrant de multiples masses disseminees. Une nouvelle biopsie est realisee et un lymphome de Burkitt est retrouve. Conclusion Les infections virales a herpes virus, virus de l’EBV en tete, seraient responsable de pres de la moitie des cas de SAM post infectieux [1] . Cependant, chez les patients VIH positifs, il semble que l’EBV ne puisse a lui seul etre responsable d’un syndrome d’activation macrophagique (exception faite d’une primo-infection) et doit faire systematiquement rechercher une autre pathologie sous-jacente comme un lymphome ou une tuberculose [2] .

Background Amprenavir (APV) has been shown to be effective in naive or treatment-experienced HIV-1 infected patients. However, the safety and efficacy of the APV 600 mg/ritonavir (RTV) 100 mg twice a day (bid) combination, the usually recommended dosage for boosted APV, have been less well studied. We assessed the predictive factors associated with virological success of APV/RTV-based regimens. Methods Patients in the PharmAdapt study receiving an APV/RTV-containing regimen were included in the study. The predictivity of covariates on virological response at 4 months was analysed according to the data analysis plan. We processed logistic regression using bootstrapping to allow several covariates in the models. Results Forty patients received an APV/RTV-containing regimen, 38 of whom were male (95%). Risk factors were heterosexual contacts (four patients; 10%), homosexual contacts (31 patients; 78%), and intravenous drug use (four patients; 10%). Twenty-seven per cent of patients were Centers for Disease Control and Prevention Classification System (CDC) stage A, 38% were stage B and 35% were stage C. The median baseline CD4 count was 313 cells/μL [interquartile range (IQR) 211, 414], and the median baseline viral load was 4.4 log10 HIV-1 RNA copies/mL (IQR 3.7, 4.9). Patients were exposed to a median number of 7.5 (IQR 6, 9) drugs for a median number of 3.8 (IQR 3.3, 4.3) years. The baseline number of resistance mutations was 4 [IQR 3, 5 for nucleoside reverse transcriptase inhibitors (NRTIs), 1 (IQR 0, 2)] for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 6 [IQR 5, 8 for protease inhibitors (PIs)]. At month 4, median viral load decreased to 1.2 log10 copies/mL (IQR 0.3, 1.6); 50% of patients had a viral load

Differences in virological response between HIV-infected patients at different study centers were analyzed as a substudy of PharmAdapt, a multicenter prospective randomized study to evaluate the utility of therapeutic drug monitoring after a genotypic-based treatment adaptation.After 12 weeks, the percentage of patients participating in PharmAdapt with HIV RNA200 copies/mL ranged from 17% to 69% between centers providing antiretroviral care. In a multivariate analysis, independent factors predictive of viral load200 HIV RNA copies/mL at Week 12 included: lower baseline viral load, lower nonnucleoside reverse transcriptase inhibitor resistance, lower protease inhibitor resistance, and the center providing antiretroviral therapy. To evaluate the final factor, study sites were divided into two groups based on Week 12 HIV RNA values above or below the median.Using this definition, observed differences between centers included the use of stavudine, abacavir-, and/or efavirenz-based regimens and use of online expert advice.

Protease inhibitors (PIs) are substrates for the P-glycoprotein (P-gp/170) encoded by the multi-drug resistance gene (MDR-1). HIV infection is associated with increased expression of P-gp. The role of MDR gene overexpression in clinical pharmacokinetics is not known.We determined by HPLC, at trough and peak levels, the current PI concentrations in plasma (P) and in peripheral blood mononuclear cells (PBMCs) (intracellular concentration [IC]) from 49 HIV-infected patients receiving different treatment combinations: nelfinavir ([NFV] n = 12); indinavir ([IDV] n = 10); amprenavir ([APV] n = 5); ritonavir (RTV) 100 bid/IDV 800 mg bid (n = 6); RTV 400 bid/IDV 400 mg bid (n = 3); RTV 100 bid/saquinavir (SQV) 600 mg tid (n = 9); APV 600 bid/RTV 100 mg bid (n = 4). We determined the mean ratio of intracellular/plasma PI concentration for each treatment group. The MDR-1 gene expression was determined by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). HIV viral load was simultaneously measured.49 patients (mean age 41 +/- 8.7 years; mean CD4 cell count 418 [57-972]; mean HIV RNA 2.1 +/- 0.8 log(10)) were included in the study. Patients who overexpressed the MDR-1 gene had significantly lower trough intracellular PI levels (p =.02) or lower intracellular accumulation of PI (p =.042). Patients treated with low-dose RTV in combined regimens with detectable RTV intracellular concentration showed lack of MDR-1 gene expression (p =.01). Patients with HIV RNA40 copies/mL had significantly higher RTV intracellular accumulation (p =.029).In HIV-infected patients, IC of PI is inversely correlated with MDR-1 gene overexpression. Undetectable viral load was associated with the use of low-dose RTV, probably linked to better intracellular accumulation of the drug. Nevertheless, further investigation is needed to confirm these results.

This prospective study investigated the contributions of apoptosis and proliferation of CD4(+) T cells obtained by the introduction of a new antiretroviral treatment for human immunodeficiency virus infection. Virus load; T cell counts; apoptosis of T cell subsets, including naive cells; and proliferation were determined from treatment initiation to the third month in a cohort of patients. An increase in CD4(+) T cell count > or = 100 cells/microL over baseline was considered to be a satisfactory immune reconstitution. Sixty-nine patients completed the protocol, 22 of whom met our definition of a satisfactory immune reconstitution, showing a significantly more pronounced reduction in spontaneous CD4(+) T cell apoptosis at month 1 as well as month 3, compared with the other patients. In contrast, neither Fas-induced apoptosis down-regulation nor Fas-induced increased proliferation capacity was associated with a satisfactory immune reconstitution. Down-regulation of CD4(+) T cell apoptosis by antiretroviral treatment is the main mechanism associated with early CD4(+) T cell increase.

Resume Le patient, son medecin, les antiretroviraux et le virus VIH lui-meme sont tous impliques dans le developpement de la resistance du VIH aux antiretroviraux. La replication virale en presence d’antiretroviraux est la cause et la consequence de la resistance a ces medicaments. C’est le denominateur commun des quatre acteurs de la resistance. Mais ces acteurs subissent a leur tour les effets de la resistance aux antiretroviraux. Les causes et les consequences de la resistance du VIH sont abordees pour le patient, les antiretroviraux et le virus lui-meme. Les nouvelles strategies therapeutiques devront tenir compte des facultes adaptatives du virus et des facteurs lies au patient ou a la pharmacologie des antiretroviraux qui favorisent cette adaptation.

Objective In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy. Methods Patients failing combination therapy (HIV-1 RNA > 10,000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. 'Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 x IC95. Others were defined as 'optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint. Results A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: -0.23 +/- 0.29 log10 copies/ml (G1); -0.97 +/- 0.28 (G2); -0.68 +/- 0.37 (G3); -1.38 +/- 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017). Conclusion Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.

To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors. In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two- to threefold for each additional drug that was sensitive by phenotyping.

Objective We report the 12 months follow-up of the patients who participated in the Viradapt study. Methods A total of 108 HIV-infected patients failing antiretroviral (ARV) therapy (HIV RNA >10000 copies/ml, therapy >6 months with nucleoside reverse transcriptase inhibitors, >3 months with protease inhibitors (PIs) were randomized into two arms: standard of care in the control arm, and treatment according to the resistance mutations in the protease and reverse transcriptase genes in the study arm. After the first 6 months of the randomized study, open-label, genotype-guided treatment was offered in both arms. A multivariate analysis was performed to assess the predictive factors of treatment success (HIV RNA Results The two arms were comparable in terms of risk factors, age, sex, previous treatments, CD4 cell count and log10 HIV-1 RNA at baseline. At week 24, an interim combined analysis showed a statistically significant difference in the drop in viral load at months 3 and 6 ( P=0.015, repeated measures analysis of variance) in favour of the genotype group. Patients in both arms were then offered open-label genotyping. Genotype analysis was performed every 3 months, and treatment changes could accordingly be made. As some of the patients in the control arm had already progressed to months 9 or 12, only 69% (30/43) of these patients received genotype-guided treatment changes. In the genotype arm, the mean drop in HIV RNA of 1.15 log10 copies/ml, obtained at month 6, persisted at months 9 and 12 (1.15 log10 copies/ml ±0.17). In the control arm, an additional drop in HIV RNA to 0.98 log10 ±0.22 copies/ml was observed by month 12. In control patients receiving open-label genotype, the percentage of patients with HIV-1 RNA levels below detection limit (200 copies/ml) rose from 14% at month 6 to 30.5% at month 12. This percentage in the study arm remained stable at 31.3% and 30% at months 9 and 12, respectively. Genotype-guided therapy, primary protease mutations and PI plasma concentrations were significantly correlated with virological success. Conclusions In this heavily pretreated patient population, genotype-guided therapy resulted in a sustained reduction in HIV RNA of greater than one log10 throughout a 1 year follow-up period. Performance of genotype-guided therapy may have contributed to the additional viral load reduction seen in patients in the control group who received open-label genotyping after the 6 month point. Multivariate analysis showed that the presence of primary protease mutations, performance of genotype-guided treatment changes and PI plasma concentrations independently affected virological response.

OBJECTIVES: To investigate the prevalence of GB virus C (GBV-C)/hepatitis G virus (HGV) RNA and anti-E2 antibodies in different risk groups of HIV-infected patients compared to that in healthy blood donors, and to study the effects of possible interactions between HIV and GBV-C/HGV on the carrier state and hepatic changes. METHODS: Sera from 100 consecutive unselected HIV-infected outpatients and from 100 healthy blood donors were screened for GBV-C/HGV viremia and anti-E2 antibodies. Anti-E2 antibodies were detected using an immunoassay developed by Boehringer Mannheim according to the manufacturer's instructions. GBV-C/HGV RNA was extracted from sera and reverse transcribed. The resulting cDNA was amplified with a PCR developed in the laboratory with primers derived from the 5prime prime or minute noncoding region of the viral genome and detected with a specific capture probe. This procedure was validated by a French multicenter quality control group. RESULTS: Thirty-one of the 100 HIV-infected patients and 8% of the healthy blood donors displayed anti-E2 antibodies. Four HIV-infected patients and one healthy blood donor were found to be GBV-C/HGV viremic. When analyzed by risk factor for the acquisition of HIV, no differences in the prevalence of anti-E2 antibodies were found between intravenous drug users and homosexual and heterosexual patients. CONCLUSIONS: We found a high prevalence of GBV-C/HGV infection in the HIV-infected population, irrespective of the risk group factor for HIV infection, suggesting that the sexual route is as effective as the parenteral route for the acquisition of GBV-C/HGV. No biological alteration could be attributed to GBV-C/HGV, even in the viremic patients. HIV-infected patients were able to clear GBV-C/HGV viremia and to mount a humoral immune response.

International audience; High uptake of HIV voluntary counselling and testing (VCT) services is important for the success of HIV workplace programs in sub-Saharan Africa. From 2001 onwards Heineken, a multinational brewing company, implemented a comprehensive HIV prevention and treatment program for employees and their dependents of its African subsidiaries. Confidential in-house VCT is part of this program. VCT uptake dynamics over time, and factors associated with early uptake were studied. Between September 2001 and December 2007, 9,723 adult beneficiaries were tested for HIV in 14 company sites in 5 African countries. Three-hundred-and-seventy (3.8%) of tested persons were infected with HIV-1. During the first 12 months 1,412 tests were done, compared to 8,311 tests in the subsequent years. The annual average uptake of testing among eligible persons varied between 15% and 32%. The coverage was higher among female compared to male employees, and higher among female compared to male spouses. Distinct peaks in uptake were linked to specific local events. People aged 45 years or above, women, and HIV-1 infected persons were significantly more likely to be tested in the early period. The proportion of HIV-1 infected persons among testees was 8.8% in the first twelve months compared to 3.0% in the subsequent period (p

Background This study aimed to evaluate the effectiveness of an HIV workplace programme in sub-Saharan Africa. Methods The international brewing company, Heineken, introduced an HIV workplace programme in its African subsidiaries in 2001. Beneficiaries from 16 sites in 5 countries were eligible. HIV type-1 (HIV-1)-infected individuals were assessed clinically and immunologically, and started highly active antiretroviral therapy (HAART) if they had AIDS or had a CD4+ T-cell count + T-cell count and haemoglobin. Results Over the first 5 years of the programme, 431 adults were found to be HIV-1-infected. The mortality rate among those not yet taking HAART was 2.6 per 100 person-years of observation (pyo). By October 2006, 249 patients had started HAART at a median CD4+ T-cell count of 170 cells/μl; 59 (23.7%) patients were in CDC stage C. Among patients on HAART, 25 died and 7 were lost to follow-up. The mortality rate was 3.7 per 100 pyo overall, 14 per 100 pyo in the first 16 weeks and 2.5 per 100 pyo thereafter ( P+ T-cell count increased by a median of 153 and 238 cells/μl after 1 and 4 years of HAART, respectively. Conclusions In this HIV workplace programme in sub-Saharan Africa, long-term high survival was achieved.

Background. Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed. Methods. Baseline HIV- RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set. Results. A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L X 2) + E44D/A/G + T69D/S/N/A + (L210W X 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score ≤0), as having intermediate resistance (1-3), and as being resistant (≥4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log 10 copies/mL (95% confidence interval, +0.11 to +0.57; P =.004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation. Conclusion. The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.

Because of the increasing availability of antiretroviral (ARV) agents for HIV in low-income countries, many clinicians now need training on their use. This is especially true for clinicians caring for individuals with tuberculosis (TB), given its close relationship with HIV/AIDS. This article summarizes the key decisions facing clinicians who manage HIV-infected persons, with particular reference to issues regarding those dually infected with TB. Health care provider-initiated diagnostic testing using rapid HIV tests should be offered to all individuals with symptoms and signs suggesting HIV infection, including all persons with TB. Issues to be included in pre- and post-test counseling sessions are discussed. HIV-infected patients should be evaluated to determine clinical staging of HIV; certain laboratory examinations should ideally be performed to assess the degree of immunosuppression and to aid decisions about when best to start ARV therapy and preventive therapies. The recommended ARV regimens and guidance on proposed patient follow-up are presented. Good adherence to ARVs is required and factors that induce and reinforce compliance are suggested. The treatment of TB is a high priority, and follows the same principles whether the patient is HIV-infected or not. Suggestions are made about ARV use in patients with TB. A standardized and complementary information system should be developed to monitor management of HIV-TB patients and performance of joint TB and HIV care efforts. By diagnosing and managing additional HIV cases detected through the portal of the TB control programme, clinicians will contribute to diminishing the burden of HIV, and thus, TB.

To evaluate the frequency and the magnitude of lipid abnormalities (LA) in respect to the nature of the antiretroviral drug and its plasma concentrations.Trough concentrations (C(trough)) of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were assessed at Weeks 4, 8, 24, 28, and 32. Fasting triglycerides (TG) and total cholesterol (CH) were sampled at Weeks 0, 12, 20, and 32. We analyzed the probability of occurrence of grade 3-4 CH (7.8 mmol/L) and TG (8.4 mmol/L) during a 24-week period according to the drug taken using a Kaplan-Meier analysis and log rank test. Relation between Week 8 PI or NNRTI C(trough) and Week 12 lipid levels was assessed using the Kendall correlation measure.The PharmAdapt study included 252 patients (mean age 41 years, 83% males); the patients received a PI (73%), an NNRTI (50%), and/or a ritonavir (RTV) booster-containing (46%) regimen. Compared to any other regimen, use of lopinavir (LPV)/RTV or efavirenz (EFV) was associated with a higher risk of grade 3-4 CH. Use of LPV/RTV and RTV booster was associated with a higher risk of grade 3-4 TG. Use of any PI-containing regimen was associated with a higher risk for grade 3-4 CH and TG compared to non PI-based regimens. Kendall correlation coefficients for PI or NNRTI C(trough) and blood lipid levels were close to zero for all drugs and CH or TG, showing the absence of relation between drug concentrations and lipid levels.Severity of lipid abnormalities is related to the nature of the antiretroviral drug. There is no short-term relation between PI or NNRTI trough concentrations and blood lipid levels in heavily pretreated patients.

Objective: To monitor the disappearance of resistance-associated mutations and reappearance of wild-type (WT) virus during structured treatment interruptions (STI) using DNA sequencing and line probe assay. Methods: Eleven HIV-1-infected patients participating in the MUTAVIR study undergoing a 3-month STI after multi-HAART failure were monitored biweekly. Genotypes were assessed by sequencing and VERSANT® HIV-1 Resistance Assays (LiPA). Results: At treatment interruption, 54 mutations in total were identified with both methods among the patients. LiPA provided a result for 93.3% of the codons at baseline. For 37 mutations, a complete reversion of mutant to WT was observed with one of the two methods. Among these, LiPA detected mutations in 23 codons for 7 to 52 days longer, in 10 codons for the same period, and in four codons for a shorter time than sequencing. Similarly, LiPA detected 35 WT codons 8 to 86 days earlier, and 15 at the same time point as sequencing. A sharp reduction in the number of mutations was observed at the time of viral load increase in five of the 11 patients. Taking only the codons detected by LiPA into consideration, two patients showed a complete reversion to WT according to both genotyping assays at the end of the STI period. Conclusions: The determination of the timepoint at which a virus population of an HIV-1 patient undergoing STI reverts to WT is dependent on the assay used. The viral load increase in most patients is compatible with the outgrowth of virus with fewer or no mutations.

The emergence of HIV strains that are resistant to anti-retroviral drugs is a major cause of treatment failure. Two sets of mutations: the Q151M complex and the 69 insert, cause resistance to multiple nucleoside analogues. We report the response to treatment in 12 patients with multiple NRTI-resistant HIV-1 strains. Seven of 12 patients (58%) were able to maintain a viral load below 200 copies/ml at week 48. The patients most likely to obtain therapeutic success were those having no or low-level resistance to non-nucleoside reverse transcriptase inhibitors and/or protease inhibitors. New and more effective drugs are needed for patients with HIV-1 that is resistant to more than one of the current three classes of HIV drugs.

HIV resistance to antiretroviral agents is a major contributory cause of treatment failure. The dynamics of HIV replication, together with patient-, physician-, and drug-related factors, lead to emergence of HIV resistant strains in most of the patients. Phenotypic assays look for an increase in the antiretroviral drug (ARV) concentration that inhibits 50% of the growth of the tested HIV strain (IC 50 ), comparatively with a reference strain cultivated in parallel. Genotypic tests detect resistance mutations in the reverse transcriptase and protease genes by comparing the gene sequences of a resistant virus to those of a wildtype strain that has previously been described. The efficacy of each ARV class and each individual ARV is threatened by specific mutations and resistance mechanisms. In retrospective studies of genotypic or phenotypic resistance testing, baseline resistance tests results were correlated with virological outcomes. There is some evidence from prospective studies that resistance testing may have some benefits when used to choose salvage regimens. However, problems in the areas of test interpretation, patient compliance, availability of active drugs, and technical test performance limit the usefulness of resistance testing in clinical practice. This article reviews the mechanisms underlying HIV resistance, the principles of phenotypic and genotypic tests, and the use of these tests in clinical practice.

We report the case of an HIV-infected patient who presented with acute renal failure due to visceral leishmaniasis (VL). Although renal failure is the leading cause of death in dogs, the natural reservoir of Leishmania infantum, renal involvement is usually absent in human VL. However, L. infantum can be considered a cause of renal failure in HIV-infected patients.

The efficacy of treatment containing nonnucleoside reverse transcriptase inhibitors (NNRTIs) could be compromised in NNRTI-naïve patients already harboring a virus resistant to NNRTIs. On the contrary, hypersusceptibility to NNRTIs in patients having failed nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens has been described and has been associated with improved outcome.We assessed the prevalence of NNRTI resistance-associated mutations or polymorphisms in 146 antiretroviral-naïve patients and in 181 HIV-infected patients who were given an NNRTI-based regimen. We phenotypically evaluated the NNRTI susceptibility of 41 strains presenting with amino acid substitutions at positions involved in NNRTI resistance.In the 268 genotypically analyzable samples, the overall prevalence of NNRTI resistance-associated mutations was 2% (6/268 patients). The prevalence of strains with amino acid substitutions at reverse transcriptase (RT) gene positions (A98, K101, K103, V106, V108, V179) involved in NNRTI resistance was 15%. Hypersusceptibility to NNRTI was rare (2%, 1/41) in those samples. RT substitutions at positions involved in NNRTI resistance were not associated with a significantly worse virologic outcome in NNRTI-treated patients. Our understanding of small shifts in IC50 values (higher or lower) toward NNRTI is very limited. The significance of many RT mutations on NNRTI susceptibility is not clear.In contrast to resistance mutations, RT substitutions at positions involved in NNRTI resistance are frequent. They are not associated with a worse virologic outcome or with decreased phenotypic susceptibility to NNRTIs. It may be prudent not to rule out the use of NNRTIs in patients with small shifts in IC50 values or poorly understood mutations.

BACKGROUND: Costs of antiretroviral therapy for HIV-infected patients have increased at a time when most countries are attempting to contain health care costs. Part of this increase results from HIV drug resistance associated with virologic failure and a subsequent shift to more complex and costly therapies. Genotypic guided treatment is associated with better virologic outcome. However, it is not yet known whether it will be cost effective. METHODS: We present here an economic evaluation based on the results from the VIRADAPT study, a prospective, open-label, randomized trial comparing patients assigned to standard of care (n = 43), versus genotypic guided treatment (n = 64) for 6 months. Total follow-up for the extended trial was 1 year. Costs were computed from the viewpoint of the health care system. Hospitalization data were retrieved from the VIRADAPT study case report forms, costs were estimated from the cost of the corresponding diagnosis-related groups derived from the French national cost data base: these were actual costs and not charges. Data on the volume of tests prescribed, drugs, and clinic visits were retrieved from the VIRADAPT study database. The unit costs of tests and clinic visits were determined using the French national Social Security reimbursement price; costing of drugs used were based upon purchase price by either retail pharmacies or hospitals. Genotyping using TruGene HIV-1 assay was estimated at $500 per test from manufacturer's data (all figures in this paper are expressed in U.S. dollars). RESULTS: Total mean (standard deviation) yearly costs per patients were $20,412 (+/-$10, 129) in the standard of care group and $18,484 (+/-$9,652) in the genotyping group (p =.35). Drug costs represented 55% of total costs. There was a trend toward a decrease in drug costs in the genotyping arm (p =.07), the greatest reduction being in the decreased use of protease inhibitors in the genotyping arm. The additional expense of genotyping appeared to be offset by the savings obtained in drug costs. CONCLUSION: In our study, the cost of drug resistance testing is offset by a reduced use of protease inhibitors and their attendant costs. Although not reaching statistical significance, this trend in the reduction of drug costs and drug use presents a great interest for future trials.

We report the 12 months follow-up of the patients who participated in the Viradapt study.A total of 108 HIV-infected patients failing antiretroviral (ARV) therapy (HIV RNA10,000 copies/ml, therapy6 months with nucleoside reverse transcriptase inhibitors,3 months with protease inhibitors (PIs) were randomized into two arms: standard of care in the control arm, and treatment according to the resistance mutations in the protease and reverse transcriptase genes in the study arm. After the first 6 months of the randomized study, open-label, genotype-guided treatment was offered in both arms. A multivariate analysis was performed to assess the predictive factors of treatment success (HIV RNA200 copies/ml).The two arms were comparable in terms of risk factors, age, sex, previous treatments, CD4 cell count and log10 HIV-1 RNA at baseline. At week 24, an interim combined analysis showed a statistically significant difference in the drop in viral load at months 3 and 6 (P = 0.015, repeated measures analysis of variance) in favour of the genotype group. Patients in both arms were then offered open-label genotyping. Genotype analysis was performed every 3 months, and treatment changes could accordingly be made. As some of the patients in the control arm had already progressed to months 9 or 12, only 69% (30/43) of these patients received genotype-guided treatment changes. In the genotype arm, the mean drop in HIV RNA of 1.15 log10 copies/ml, obtained at month 6, persisted at months 9 and 12 (1.15 log10 copies/ml +/- 0.17). In the control arm, an additional drop in HIV RNA to 0.98 log10 +/- 0.22 copies/ml was observed by month 12. In control patients receiving open-label genotype, the percentage of patients with HIV-1 RNA levels below detection limit (200 copies/ml) rose from 14% at month 6 to 30.5% at month 12. This percentage in the study arm remained stable at 31.3% and 30% at months 9 and 12, respectively. Genotype-guided therapy, primary protease mutations and PI plasma concentrations were significantly correlated with virological success.In this heavily pretreated patient population, genotype-guided therapy resulted in a sustained reduction in HIV RNA of greater than one log10 throughout a 1 year follow-up period. Performance of genotype-guided therapy may have contributed to the additional viral load reduction seen in patients in the control group who received open-label genotyping after the 6 months point. Multivariate analysis showed that the presence of primary protease mutations, performance of genotype-guided treatment changes and PI plasma concentrations independently affected virological response.

Malignant arrhythmia, which is responsible for most of the out-of-hospital cardiac arrests, is ventricular fibrillation (VF). The best treatment of VF is a controlled electric shock on the chest administered in a short delay. The emergency medical technicians (EMTs) qualified to carry out this treatment in Belgium and in districts often succeed in arriving on the spot 8 minutes earlier than the people of the Service Mobile d'Urgence et de Réanimation (SMUR). The delegation of defibrillation to ambulance crew members however implies a specific teaching, training and a medical control. The Brussels experience shows that semi-automatic external defibrillation by EMT-Ds (SAED) is feasible when criteria for applying SAED in the pre-hospital phase are applicable.

In HIV-infected patients, ritonavir, a potent cytochrome P450 inhibitor, is increasingly used to improve the pharmacokinetic profile of the associated protease inhibitor. HIV physicians are often faced with potential drug-drug interaction while treating associated diseases. We report the case of an HIV-infected patient with clinical features of Cushing's syndrome due to the interaction of low dose ritonavir with inhaled fluticasone propionate (FP). Safety of life-long CYP450 inhibition has still to be demonstrated.