Inflammation and Change in Body Weight With Antiretroviral Therapy Initiation in a Multinational Cohort of HIV-Infected Adults.

BACKGROUND: Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown. METHODS: Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models. RESULTS: Of 246 participants, 27% were overweight/obese (BMI, ≥ 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P = .01), and the decreases in both CRP (P = .01) and interleukin 18 (P = .02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10 increase in soluble CD14 level (P = .05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P = .001). CONCLUSIONS: Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation.

Differences in antiretroviral safety and efficacy by sex in a multinational randomized clinical trial.

BACKGROUND AND OBJECTIVE: Worldwide, 50% of human immunodeficiency virus (HIV)-infected people are women. This study was to evaluate whether the safety and efficacy outcomes of three initial antiretroviral regimens (ARVs) differed by sex. METHODS: Antiretroviral regimen naive participants from nine countries in four continents were assigned to ARVs with efavirenz (EFV) plus lamivudine-zidovudine, atazanavir (ATV) plus didanosine (ddI)-EC/emtricitabine (FTC) or EFV plus FTC-tenofovir-DF. The primary objective was to estimate the sex difference on efficacy outcome of treatment failure defined as one of the following: 1. Time to 1st of confirmed virologic failure, 2. WHO Stage 4 progression or 3. death with hazard ratio (HR) and 95% confidence interval (CI) from adjusted Cox regression models. RESULTS: In all, 739 (47%) women and 832 (53%) men with HIV were evaluated. Women had higher pretreatment CD4+(182 vs 165 cells/mm(3); P < 0.001) and lower HIV-1 RNA (4.9 log10 vs 5.2 log10 copies/ml; P < 0.001) compared to men. Association of sex with time to regimen failure differed by treatment arm (P = 0.018). For atazanavir plus didanosine-EC plus emtricitabine, women had a longer time to treatment failure compared to men [adjusted HR (aHR) = 0.59; 95% CI 0.40-0.87]. Women were less likely to prematurely discontinue treatment prematurely (aHR = 0.74; 95% CI 0.56-0.98). Women assigned to efavirenz plus lamivudine-zidovudine were more likely to have a primary safety event compared to men (aHR = 1.49; 95% CI 1.18-1.88). CONCLUSION: Antiretroviral efficacy and safety differed by sex in this study. Consideration of potential effects of sex on antiretroviral outcomes is important for the design of future clinical trials and for HIV treatment guidelines.

Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons.

OBJECTIVE: Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and isoniazid under direct observation (3HP) versus 9 months of daily isoniazid (9H) in HIV-infected persons. DESIGN: Prospective, randomized, and open-label noninferiority trial. SETTING: The United States , Brazil, Spain, Peru, Canada, and Hong Kong. PARTICIPANTS: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases. INTERVENTION: 3HP versus 9H. MAIN OUTCOME MEASURES: The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction. RESULTS: Median baseline CD4 cell counts were 495 (IQR 389-675) and 538 (IQR 418-729) cells/µl in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; P = 0.79) in 3HP and 9H, respectively. CONCLUSION: Among HIV-infected persons with median CD4 cell count of approximately 500 cells/µl, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated.

Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation.

BACKGROUND: Women progress to death at the same rate as men despite lower plasma HIV RNA (viral load). We investigated sex-specific differences in immune activation and inflammation as a potential explanation. METHODS: Inflammatory and immune activation markers [interferon γ, tumor necrosis factor (TNF) α, IL-6, IL-18, IFN-γ-induced protein 10, C-reactive protein (CRP), lipopolysaccharide, and sCD14] were measured at weeks 0, 24, and 48 after combination antiretroviral therapy (cART) in a random subcohort (n = 215) who achieved virologic suppression in ACTG A5175 (Prospective Evaluation of Antiretrovirals in Resource-Limited Settings). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95% confidence intervals were estimated using multivariable models. RESULTS: At baseline, women had lower median log10 viral load (4.93 vs 5.18 copies per milliliter, P = 0.01), CRP (2.32 vs 4.62 mg/L, P = 0.01), detectable lipopolysaccharide (39% vs 55%, P = 0.04), and sCD14 (1.9 vs 2.3 µg/mL, P = 0.06) vs men. By week 48, women had higher interferon γ (22.4 vs 14.9 pg/mL, P = 0.05), TNF-α (11.5 vs 9.5 pg/mL, P = 0.02), and CD4 (373 vs 323 cells per cubic millimeter, P = 0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared with men. CONCLUSIONS: With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV-positive individuals: a nested substudy within the multicentre, international, randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial.

BACKGROUND: Observational data have been conflicted regarding the potential role of HIV antiretroviral therapy (ART) as a causative factor for, or protective factor against, COPD. We therefore aimed to investigate the effect of immediate versus deferred ART on decline in lung function in HIV-positive individuals. METHODS: We did a nested substudy within the randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial at 80 sites in multiple settings in 20 high-income and low-to-middle-income countries. Participants were HIV-1 infected individuals aged at least 25 years, naive to ART, with CD4 T-cell counts of more than 500 per µL, not receiving treatment for asthma, and without recent respiratory infections (baseline COPD was not an exclusion criterion). Participants were randomly assigned to receive ART (an approved drug combination derived from US Department of Health and Human Services guidelines) either immediately, or deferred until CD4 T-cell counts decreased to 350 per µL or AIDS developed. The randomisation was determined by participation in the parent START study, and was not specific to the substudy. Because of the nature of our study, site investigators and participants were not masked to the treatment group assignment; however, the assessors who reviewed the outcomes were masked to the treatment group. The primary outcome was the annual rate of decline in lung function, expressed as the FEV1 slope in mL/year; spirometry was done annually during follow-up for up to 5 years. We analysed data on an intention-to-treat basis, and planned separate analyses in smokers and non-smokers because of the known effects of smoking on FEV1 decline. The substudy was registered at ClinicalTrials.gov number NCT01797367. FINDINGS: Between March 11, 2010, and Aug 23, 2013, we enrolled 1026 participants to our substudy, who were then randomly assigned to either immediate (n=518) or deferred (n=508) ART. Median baseline characteristics included age 36 years (IQR 30-44), CD4 T-cell count 648 per µL (583-767), and HIV plasma viral load 4·2 log10 copies per mL (3·5-4·7). 29% were female and 28% were current smokers. Median follow-up time was 2·0 years (IQR 1·9-3·0). We noted no differences in FEV1 slopes between the immediate and deferred ART groups either in smokers (difference of -3·3 mL/year, 95% CI -38·8 to 32·2; p=0·86) or in non-smokers (difference of -5·6 mL/year, -29·4 to 18·3; p=0·65) or in pooled analyses adjusted for smoking status at each study visit (difference of -5·2 mL/year, -25·1 to 14·6; p=0·61). INTERPRETATION: The timing of ART initiation has no major short-term effect on rate of lung function decline in HIV-positive individuals who are naive to ART, with CD4 T-cell counts of more than 500 per µL. In light of updated WHO recommendations that all HIV-positive individuals should be treated with ART, regardless of their CD4 T-cell count, our results suggest an absence of significant pulmonary harm with such an approach. FUNDING: US National Heart Lung and Blood Institute, US National Institute of Allergy and Infectious Diseases, Division of AIDS, Agence Nationale de Recherches sur le SIDA et les Hipatites Virales (France), Australian National Health and Medical Research Council, Danish National Research Foundation, European AIDS Treatment Network, German Ministry of Education and Research, UK Medical Research Council and National Institute for Health Research, and US Veterans Health Administration Office of Research and Development.

Treatment failure in intestinal strongyloidiasis: an indicator of HTLV-I infection.

BACKGROUND: The association of severe strongyloides with HTLV-I is well known; however, the seroprevalence of HTLV-I in other groups with strongyloidiasis is still unknown. We conducted a prospective study in patients with intestinal strongyloidiasis without known immunodepression who failed to respond to standard therapy with ivermectin or thiabendazole (failure was defined as one positive stool examination at the post-therapy follow up). All these patients were tested for HTLV-I by ELISA and Western Blot. RESULTS: Forty seven patients were evaluated: 74.5% (35 out of 47) were HTLV-I positive, without significant difference between males (76%) and females (72.7%). CONCLUSIONS: We recommend that all patients with uncomplicated intestinal strongyloidiasis, who fail standard therapy, be studied for HTLV-I infection.

Combination antiretroviral treatment for women previously treated only in pregnancy: week 24 results of AIDS clinical trials group protocol a5227.

BACKGROUND: Women with HIV and prior exposure to combination antiretroviral therapy (cART) solely for prevention of mother-to-child transmission (pMTCT) need to know whether they can later be treated successfully with a commonly used regimen of efavirenz (EFV) and coformulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). METHODS: Nonpregnant women with plasma HIV-1 RNA of ≥500 copies per milliliter, previously cART exposed for pMTCT only, were eligible if they were off ART for ≥24 weeks before entry, were without evidence of drug resistance on standard genotyping, and were ready to start EFV plus FTC/TDF. The primary endpoint was virologic response (defined as plasma HIV RNA <400 copies/mL) at 24 weeks. RESULTS: Fifty-four women were enrolled between October 2007 and December 2009; 52 of 54 completed 24 weeks of follow-up. Median baseline CD4 T-cell count was 265/mm and baseline plasma HIV-1 RNA was 4.6 log10 copies per milliliter. Median prior cART duration was 14 weeks, and median time elapsed from the last pMTCT dose to entry was 22 months. Virologic response at 24 weeks was observed in 42 of 52 women or 81% (exact 95% confidence interval: 68% to 90%). There were no differences in response by country, by number, or class of prior pMTCT exposures. Although confirmed virologic failure occurred in 8 women, no virologic failures were observed in women reporting perfect early adherence. CONCLUSIONS: In this first prospective clinical trial studying combination antiretroviral retreatment in women with a history of pregnancy-limited cART, the observed virologic response to TDF/FTC and EFV at 24 weeks was 81%. Virologic failures occurred and correlated with self-reported nonadherence.

Clinical significance and epidemiologic analyses of Mycobacterium avium and Mycobacterium intracellulare among patients without AIDS.

The clinical significance and prevalence of Mycobacterium avium and Mycobacterium intracellulare were analyzed in a cohort of 7,472 patients who, from 1999 to 2003, sought care at the University of Texas M.D. Anderson Cancer Center, Houston, and had cultures performed for mycobacteria. Patients were stratified for age, sex, and underlying diseases, and bacteria were identified by 16S rRNA gene sequencing. M. avium was isolated in 62 (0.83%) of 7,472 patients and M. intracellulare in 65 (0.87%). Clinically, only 10 of the 62 (16.2%) patients with M. avium had probable to definite evidence of infection, whereas the majority (83.8%) had weak evidence of infection. Sex and age did not affect the isolation or infection of M. avium. Hematological tumors predisposed to M. avium colonization but not infection. In contrast, 41 of the 65 (63.1%) patients with M. intracellulare had probable to definite infection, a level much higher than those with M. avium (P < 0.001). M. intracellulare was more prevalent in women (1.33% of 3,311) than in men (0.50% of 4,161) (P < 0.001), and underlying diseases had no effect in women. Men with lung cancer had a higher prevalence (1.37%) than men without (0.34%) (4.0-fold; P < 0.001), but it was similar to that in women. A marked age trend for the isolation of M. intracellulare among women was noted: 0.27% (1-fold) for ages of <50 years, 0.85% (3.1-fold) for ages 50 to 59 years, 1.50% (5.6-fold) for ages 60 to 69 years, and 3.74% (13.9-fold) for ages >/=70 years (trend, P < 0.001). The combined rate for women >/=50 was 1.86% (95% confidence interval [1.30 to 2.42%]) (6.9-fold). Together, these results suggest that, among non-AIDS patients, M. intracellulare is more pathogenic and tends to infect women increasingly beyond menopause (age >/=50 years) regardless of underlying disease. The prevalence rate of 1.86% in postmenopausal women suggests the need to further investigate the public health significance of M. intracellulare.

Enteroaggregative Escherichia coli diarrhea in travelers: response to rifaximin therapy.

BACKGROUND AND AIMS: We have recently shown that enteroaggregative Escherichia coli (EAEC) strains commonly cause travelers' diarrhea. The study was designed to determine whether U.S. travelers with EAEC diarrhea responded to rifaximin therapy. METHODS: In a multicenter placebo-controlled clinical trial of travelers' diarrhea without non-EAEC pathogens we evaluated 2 doses of rifaximin. EAEC was sought in stool samples in enrolled subjects by HEp-2 cell assay. Response to rifaximin (both groups combined) and placebo were evaluated in EAEC-positive and EAEC-negative patient groups. RESULTS: Compared with placebo, rifaximin shortened the postenrollment illness in travelers with EAEC diarrhea (median, 22 vs. 72 hours; P = 0.03). In subjects with EAEC-negative diarrhea, the median duration of post-treatment diarrhea was shorter with rifaximin (33 hours) than with placebo (52 hours), but this difference was not significantly different (P = 0.14). CONCLUSIONS: Improvement of EAEC-mediated diarrhea with antibiotic treatment supports the pathogenicity of this organism in travelers to developing countries. The study provides information on the value of the poorly absorbed drug rifaximin in therapy of travelers' diarrhea.

Analgesia intrarticular postoperatoria con bupivacaina, fentanilo y la combinación de ambos en cirugía / artroscopica ambulatoria de rodilla / Analgesia to intrarticular postoperating with bupivacaina, fentanilo and the combination of both in ambulatory artroscopica surgery of knee

El dolor postoperatorio en la artroscopia de rodilla producen junto a factores mecánicos, impotencia funcional del miembro afectado, además de las implicaciones fisiopatológicas sistémicas que están relacionadas con el dolor. La inyeccion intrarticular permite lograr una rehabilitación articular precoz determinar el efecto analgésico intra-articular del fentanyl, bupivacaína y la mezcla de ambos después de la artroscopía bajo anestesia espinal en el paciente ambulatorio. Este estudio se realizó en el Servicio de Anestesiología del Hospital Clínico Quirúrgico "Joaquín Albarrán" durante el período comprendido de julio de 2001 a diciembre del 2002, con la finalidad de demostrar el efecto analgésico de la bupivacaína (Grupo 1), el fentanyl (Grupo 2), y la mezcla de ambos (Grupo 3). Administrados intra-articularmente, a 90 pacientes ambulatorios, seleccionados aleatoriamente, de ambos sexos, menores de 60 años, clasificados como ASA I y II, que se les practicó artroscopía de la rodilla. Se evaluó la calidad de la analgesia mediante la Escala Visual Analógica. La analgesia en el Grupo 3 fue buena en 93.3(por ciento) de los casos, en 6.7(por ciento) regular, no calificándose ninguna de mala. En el Grupo 1, 56.7(por ciento) se calificó como buena, 36.7(por ciento) como regular y 6.6(por ciento) como mala. En el Grupo 2, 33.3(por ciento) fue buena, 63.3(por ciento)regular y 3.4(por ciento) mala. La duración de la analgesia postoperatoria fue mayor en el Grupo 3 con21.76±2.51 horas, en el Grupo 1 se prolongó 11.33±3.42 horas y en el grupo 2 duró 9.9±3.31 horas. Los requerimientos de analgesia suplementaria fueron muy bajos en el Grupo 3 (6.7(por ciento), seguidos por el Grupo 1 (46.7(por ciento) y el Grupo 2, con 46.7(por ciento). No hubo modificaciones hemodinámicas ni efectosindeseables en ninguno de los grupos. Se concluyó que la efectividad del método de analgesia postoperatoria por administración intra-articular de los dos medicamentos estudiados, resultó superior con la mezcla de bupivacaína y fentanyl(AU)