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BackgroundLatent tuberculosis infection (LTBI) has been associated with increased cardiovascular risk. We investigated the activation and pro-inflammatory profile of monocytes in individuals with LTBI and their association with coronary artery disease (CAD).MethodsIndividuals 40–70 years old in Lima, Peru, underwent QuantiFERON-TB testing to define LTBI, completed a coronary computed tomography angiography to evaluate CAD, and provided blood for monocyte profiling using flow cytometry. Cells were stimulated with lipopolysaccharide to assess interleukin-6 (IL-6) and tumor necrosis factor (TNF)–α responses.ResultsThe clinical characteristics of the LTBI (n = 28) and non-LTBI (n = 41) groups were similar. All monocyte subsets from LTBI individuals exhibited higher mean fluorescence intensity (MFI) of CX3CR1 and CD36 compared with non-LTBI individuals. LTBI individuals had an increased proportion of nonclassical monocytes expressing IL-6 (44.9 vs 26.9; P = .014), TNF-α (62.3 vs 35.1; P = .014), and TNF-α+IL-6+ (43.2 vs 36.6; P = .042). Among LTBI individuals, CAD was associated with lower CX3CR1 MFI on classical monocytes and lower CD36 MFI across all monocyte subsets. In multivariable analyses, lower CD36 MFI on total monocytes (b = −0.17; P = .002) and all subsets remained independently associated with CAD in LTBI.ConclusionsIndividuals with LTBI have distinct monocyte alterations suggestive of an exacerbated inflammatory response and tissue migration. Whether these alterations contribute to cardiovascular disease pathogenesis warrants further investigation.

La terapia de la infección por el vrn ha tenido una evolución sorprendente, pasando desde el uso medidas paliativas, a lo actual, en que el tratamiento antirretroviral permite la recuperación de la salud del paciente con las consecuencias positivas para su familia y la sociedad. Un beneficio adicional esque eltratamiento disminuye elriesgo de contagio a otras personas, lo cual implica que la epidemia podria ser controlada si una amplia proporción de personas :infectadas están bajo un tratamiento eficaz.

We performed a comprehensive review of recent publications about type 2 diabetes mellitus (T2DM) in Peru, including studies among people living at high altitude above the sea level. An increase in the prevalence of T2DM in Peru has been reported, the reasons are multifactorial and coinciding with the strong economic growth that our country has experienced over the last 20 years along with migration from the Andean regions to the coast and the adoption of a lifestyle that is a known to be a risk factor for obesity and insulin resistance. Scarce information is available in Peru about the prevalence of chronic complications of T2DM such as retinopathy, neuropathy, and nephropathy. There is a need for a health care plan based on early diagnosis of T2DM to reduce social and economic problems, as recommended by the WHO and the United Nations.

Background Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)–naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. Methods PLWH with a CD4+ count Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. Results Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. Conclusions Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

We evaluated health-related quality of life (QoL) and self-reported incomplete adherence as predictors of early second-line antiretroviral (ART) virological failure (VF) (confirmed HIV-1 RNA [VL]>400 c/mL after 24 weeks of ART). ACTG A5273 was a randomized clinical trial of second-line ART comparing lopinavir/ritonavir (LPV/r) + raltegravir with LPV/r + nucleos(t)ide reverse transcriptase inhibitors in participants failing a first-line regimen at 15 sites in 9 resource-limited settings. Participants completed the ACTG SF-21 which has 8 QoL domains with a standard score ranging from 0 (worst) to 100 (best). We used exact logistic regression to assess the association of QoL at baseline and week 4 with early VF adjusted for self-reported adherence. Of 500 individuals (51% women, median age 39 years) in this analysis, 79% and 75% self-reported complete adherence (no missing doses in the past month) at weeks 4 and 24, respectively. Early VF was experienced by 7% and more common among those who self-reported incomplete adherence. Participants with low week 4 QoL scores had higher rates of early VF than participants with high scores. After adjusting for self-reported adherence at week 4, viral load and CD4 at baseline, cognitive functioning, pain and mental health domains were significantly associated with subsequent early VF. In this post-hoc analysis, poorer QoL adds to self-reported incomplete adherence after 4 weeks of second-line ART in predicting VF at week 24. Evaluation is needed to assess whether individuals with poorer QoL might be targeted for greater support to reduce risk of VF.

Background: There is scarcity of data about the prevalence of non-AIDS defining comorbidities among stable HIV-infected patients in Peru. Objective: We aimed to describe the most frequent cardiometabolic comorbidities found among ambulatory adults on ARV in Peru. Methods: A review of records for patients attending regular visits at 5 clinics in Lima-Callao in January-February 2016 is presented. Patients were adults on ARV for >6 months, with no recent AIDS-defining condition. Results: Three hundred and five medical charts were reviewed. Most patients were male (73.1%, n=223) with a mean age of 46.0 years. Mean time from HIV diagnosis was 9.41 yrs. and mean duration of ARV was 7.78 yrs. Most patients were on an NNRTI-based first line regimen (76.4%, n=233), and 12.1% (n=37) were on rescue regimens. Median CD4 count was 614.2 cells/µL and the proportion of patients with viral load Conclusion: A high proportion of metabolic comorbidities was found, with dyslipidemia being the most frequent, followed by obesity and diabetes. In contrast, cardiovascular disease was documented less frequently. Medical treatment was started for only a third of dyslipidemia patients. HIV care policies need to consider proper management of chronic comorbidities to optimize long-term outcomes.

BACKGROUND: AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)–infected participants in resource-limited settings treated with 3 World Health Organization–recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. METHODS: Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. RESULTS: Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/μL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P < .001) and fingertapping nondominant hand (P < .01). TB was associated with diffuse CNS disease (P < .05). Furthermore, those with TB had 9.27 times (P < .001) higher odds of reporting decreased quality of life, and had 8.02 times (P = .0005) higher odds of loss of productivity. CONCLUSIONS: TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. CLINICAL TRIALS REGISTRATION: NCT00096824.

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4

Practical issues, including cost, hinder implementing virologic monitoring of patients on antiretroviral therapy (ART) in resource-limited settings. We evaluated factors that might guide monitoring frequency and efforts to prevent treatment failure after initial virologic suppression.Participants were the 911 HIV-infected antiretroviral-naïve adults with CD4 count 300 cells/μL who started efavirenz-based ART in the international A5175/PEARLS trial and achieved HIV-1 RNA 1000 copies/mL at 24 weeks. Participant report of ART adherence was evaluated using a structured questionnaire in monthly interviews. Adherence and readily available clinical and laboratory measures were evaluated as predictors of late virologic failure (late VF: confirmed HIV-1 RNA ≥1000 copies/mL after 24 weeks).During median follow-up of 3.5 years, 82/911 participants (9%) experienced late VF. Of 516 participants reporting missed doses during the first 24 weeks of ART, 55 (11%) experienced late VF, compared with 27 (7%) of 395 participants reporting no missed doses (hazard ratio: 1.73; 95% CI: 1.08, 2.73). This difference persisted in multivariable analysis, in which lower pre-ART hemoglobin and absence of Grade ≥3 laboratory results prior to week 24 were also associated with higher risk of late VF.In this clinical trial, the late VF rate after successful suppression was very low. If achievable in routine clinical practice, virologic monitoring involving infrequent (e.g. annual) measurements might be considered; the implications of this for development of resistance need evaluating. Patients reporting missed doses early after ART initiation, despite achieving initial suppression, might require more frequent measurement and/or strategies for promoting adherence.

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

Understanding patterns of antiretroviral adherence and its predictors is important for designing tailored interventions. Alcohol use is associated with non-adherence. This study aimed to evaluate: (1) if there was a difference in weekday compared with weekend adherence in HIV-infected individuals from low and middle income countries (LMIC), and (2) whether binge drinking was associated with this difference.Data from a randomized trial conducted at 9 sites in 8 LMIC were analyzed. Microelectronic monitors were used to measure adherence. Differences between weekday and weekend adherence in each quarter (successive 12-week periods) were compared using Wilcoxon signed rank tests and predictors of adherence, including baseline binge drinking, were evaluated using Generalized Estimating Equations.Data from 255 participants were analyzed: 49.8% were male, median age was 37 years and 28.6% enrolled in Haiti. At study entry, only 2.7% reported illicit substance use, but 22.3% reported binge drinking at least once in the 30 days prior to enrollment. Adherence was higher on weekdays than weekends (median percent doses taken: 96.0% vs 94.4%; 93.7% vs 91.7%; 92.6% vs 89.7% and 93.7% vs 89.7% in quarters 1-4 respectively, all p0.001). Binge drinking at baseline and time on study were both associated with greater differences between weekday and weekend adherence.Adherence was worse on weekends compared to weekdays: difference was small at treatment initiation, increased over time and was associated with binge drinking. Screening and new interventions to address binge drinking, a potentially modifiable behavior, may improve adherence in HIV-infected individuals in LMIC.

BACKGROUND: Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment. METHODS: The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations. RESULTS: Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168. CONCLUSIONS: Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments. CLINICAL TRIALS REGISTRATION: NCT00096824.

Objective: During effective antiretroviral therapy (ART), low-level plasma viremias (LLV) (HIV RNA >30–1000 copies/ml) can be detected intermittently. We hypothesized that systemic inflammation is associated with LLV either as the cause or result of the production of virions from clonally expanded cells. Methods: Prospective cohort study of HIV-infected ART-naive Peruvians enrolled prior to ART and followed for 2 years. Plasma HIV RNA and peripheral blood mononuclear cell (PBMC) HIV DNA concentrations were quantified pre-ART from individuals whose plasma HIV RNA was ART-suppressed. Inflammatory biomarker concentrations were measured pre and during ART. Single-genome amplification (SGA) derived HIV env and pol genotypes from pre-ART and LLV specimens. Antiretroviral levels during ART assessed adherence. Statistical associations and phylogenetic relationships were examined. Results: Among 82 participants with median plasma HIV RNA less than 30 copies/ml, LLV were detected in 33 of 82 (40%), with a LLV median HIV RNA of 73 copies/ml. Participants with vs. without LLV had significantly higher pre-ART plasma HIV RNA (P

We evaluated health-related quality of life (QoL) in HIV infection participants with virologic failure (VF) on first-line antiretroviral therapy (ART) in 9 resource-limited settings (RLS). ACTG SF-21 was completed by 512 participants at A5273 study entry; 8 domains assessed: general health perceptions (GHP), physical functioning (PF), role functioning (RF), social functioning (SF), cognitive functioning (CF), pain (P), mental health (MH), and energy/fatigue (E/F); each was scored between 0 (worst) to 100 (best). Mean QoL scores ranged from 67 (GHP) to 91 (PF, SF, CF). QoL varied by country; high VL and low CD4 were associated with worse QoL in most domains, except RF (VL only), SF (CD4 only) and CF (neither). Number of comorbidities, BMI and history of AIDS were associated with some domains. Relationships between QoL and VL varied among countries for all domains. The association of worse disease status with worse QoL may reflect low QoL when ART was initiated and/or deterioration associated with VF.

We evaluated improvement of quality of life (QoL) after 1 year of second-line antiretroviral therapy (ART) use in resource-limited settings (RLS) among adult men and women, comparing two randomized treatment arms.The AIDS Clinical Trial Group A5273 was a randomized clinical trial of second-line ART comparing lopinavir/ritonavir (LPV/r) + raltegravir with LPV/r + nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in participants failing a non-NRTI-containing regimen at 15 sites in nine RLS. Participants completed the AIDS Clinical Trial Group short-form-21 which has eight QoL domains with a standard score ranging from 0 (worst) to 100 (best).Differences in QoL by randomized arm, as well as by demographic and clinical variables, were evaluated by regression models for baseline and week 48 QoL scores fitted using the generalized estimating equations method.A total of 512 individuals (49% men, median age 39 years) were included. A total of 512 and 492 participants had QoL assessments at baseline and week 48, respectively. QoL improved significantly from baseline to week 48 (P 0.001 for all domains). There was no significant difference between treatment arms for any domain. Individuals with higher viral load and lower CD4 cell count at baseline had lower mean QoL at baseline but larger improvements such that mean QoL was similar at week 48.Improvements in QoL were similar after starting second-line ART of LPV/r combined with either raltegravir or NRTIs in RLS. QoL scores at baseline were lower among participants with worse disease status prior to starting second-line, but after 1 year similar QoL scores were achieved.

Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites.Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL)1000 copies/mL. Cox proportional hazards models estimated resistance-failure association.In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98).In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible.NCT00084136.

Summary Background Adherence is key to the success of antiretroviral therapy. Enhanced partner support might benefit patients with previous treatment failure. We aimed to assess whether an enhanced partner-based support intervention with modified directly observed therapy would improve outcomes with second-line therapy in HIV-infected patients for whom first-line therapy had failed. Methods We did a multicentre, international, randomised clinical trial at nine sites in Botswana, Brazil, Haiti, Peru, South Africa, Uganda, Zambia, and Zimbabwe. Participants aged 18 years or older for whom first-line therapy had failed, with HIV RNA concentrations greater than 1000 copies per mL and with a willing partner, were randomly assigned (1:1), via computer-generated randomisation, to receive partner-based modified directly observed therapy or standard of care. Randomisation was stratified by screening HIV RNA concentration (≤10 000 copies per mL vs >10 000 copies per mL). Participants and site investigators were not masked to group assignment. Primary outcome was confirmed virological failure (viral load >400 copies per mL) by week 48. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00608569. Findings Between April 23, 2009, and Sept 29, 2011, we randomly assigned 259 participants to the modified directly observed therapy group (n=129) or the standard-of-care group (n=130). 34 (26%) participants in the modified directly observed therapy group achieved the primary endpoint of virological failure by week 48 compared with 23 (18%) participants in the standard-of-care group. The Kaplan-Meier estimated cumulative probability of virological failure by week 48 was 25·1% (95% CI 17·7–32·4) in the modified directly observed therapy group and 17·3% (10·8–23·7) in the standard-of-care group, for a weighted difference in standard of care versus modified directly observed therapy of −6·6% (95% CI −16·5% to 3·2%; p=0·19). 36 (14%) participants reported at least one grade 3 or higher adverse event or laboratory abnormality (n=21 in the modified directly observed therapy group and n=15 in the standard-of-care group). Interpretation Partner-based training with modified directly observed therapy had no effect on virological suppression. The intervention does not therefore seem to be a promising strategy to increase adherence. Intensive follow-up with clinic staff might be a viable approach in this setting. Funding AIDS Clinical Trials Group and the National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4350 cells/μL). BMD was measured annually at the lumbar spine and hip by dual-energy X-ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent-to-treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow-up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non-white, 26% women, median CD4 count 642 cells/μL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow-up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow-up, immediate ART resulted in greater BMD declines than deferred ART at the hip (-2.5% versus -1.0%; difference -1.5%, 95% confidence interval [CI] -2.2 to -0.8, p0.001) and spine (-1.9% versus -0.4%; difference -1.6%, 95% CI -2.2 to -1.0, p0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV-related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer-term consequences of the observed reductions in BMD is needed.NCT00867048. © 2017 American Society for Bone and Mineral Research.

Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

Summary Background For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. Methods A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. Findings Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5–14·0) in the raltegravir group and 12·4% (8·3–16·5) in the NRTI group, with a weighted difference of −3·4% (−8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. Interpretation In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. Funding National Institutes of Health.

Transmission of drug-resistant HIV (TDR) has been associated with virologic failure of "first-line," nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). A national ART program began in Peru in 2004. We evaluated the prevalence of TDR in individuals initiating ART and their virologic outcome during 2 years of ART. HIV-infected, ARV-naive subjects who met criteria to start ART in Lima, Peru were enrolled in a longitudinal observational study between July 2007 and February 2009. Blood plasma and cells obtained prior to ART initiation were assessed for antiretroviral (ARV) resistance by an oligonucleotide ligation assay (OLA) sensitive to 2% mutant at reverse transcriptase (RT) codons K103N, Y181C, G190A, and M184V and a subset by consensus sequencing. A total of 112 participants were enrolled; the mean CD4 was 134 ± 89 cells/μl and the median plasma HIV RNA was 93,556 copies/ml (IQR 62,776-291,364). Drug resistance mutations conferring high-level resistance to ARV were rare, detected in one of 96 (1%) evaluable participants. This subject had the Y181C mutation detected in both plasma and peripheral blood mononuclear cells (PBMCs) at a concentration of 100% by OLA and consensus sequencing; nevertheless nevirapine-ART suppressed her viral replication. Consensus sequencing of 37 (19%) participants revealed multiple polymorphisms that occasionally have been associated with low-level reductions in ARV susceptibility. A low prevalence of TDR was detected among Peruvians initiating ART. Given the increasing availability of ART, continuing surveillance is needed to determine if TDR increases and the mutant codons associated with virologic failure.

BACKGROUND Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART. METHODS A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin

Human T-cell lymphotropic virus type-II (HTLV-II) infection is endemic in indigenous groups in the Americas and injection drug users (IDUs) worldwide. In Peru, HTLV-II infection was previously identified in two indigenous Amazonians. We examined risk factors for HTLV-II infection in 2,703 Peruvian men who have sex with men (MSM): 35 (1.3%) were HTLV-II positive. HTLV-II infection was associated with syphilis, HSV-2 infection, unprotected receptive anal intercourse, and older age. This is the first report of HTLV-II in a non-indigenous non-IDU population in Peru. Additional studies are needed to determine if HTLV-II is a sexually transmitted infection in this and other sexually active populations.

Nearly 2 million people are infected with human immunodeficiency virus (HIV) in Latin America. However, information regarding population-scale outcomes from a regional perspective is scarce. We aimed to describe the baseline characteristics and therapeutic outcomes of newly-treated individuals with HIV infection in Latin America. A Retrospective cohort study was undertaken. The primary explanatory variable was combination antiretroviral therapy based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The main outcome was defined as the composite of all-cause mortality and the occurrence of an AIDS-defining clinical event or a serious non-AIDS-defining event during the first year of therapy. The secondary outcomes included the time to a change in treatment strategy. All analyses were performed according to the intention to treat principle. A total of 937 treatment-naive patients from four participating countries were included (228 patients with PI therapy and 709 with NNRTI–based treatment). At the time of treatment initiation, the patients had a mean age of 37 (SD: 10) years and a median CD4 + T-cell count of 133 cells/mm3 (interquartile range: 47.5–216.0). Patients receiving PI-based regimens had a significantly lower CD4 + count, a higher AIDS prevalence at baseline and a shorter time from HIV diagnosis until the initiation of treatment. There was no difference in the hazard ratio for the primary outcome between groups. The only covariates associated with the latter were CD4 + cell count at baseline, study site and age. The estimated hazard ratio for the time to a change in treatment (NNRTI vs PI) was 0.61 (95% CI 0.47–0.80, p

Mediante gascromatografia accoppiata alla spettrometria di massa (GC/MS) è stato tracciato il profilo aromatico varietale delle uve Mavrud, Bouquet e Rubin e dei corrispondenti vini ottenuti dalle uve vinificate in purezza. Nelle uve sono stati identificati 33 composti appartenenti alla classe dei benzenoidi, dei terpeni e dei norisoprenoidi; tra i composti più interessanti sono stati trovati il cis e trans-8-OH-linalolo, il p-ment-1-ene-7,8-diolo, il 3-OH-β-damascone, il 3-oxo-α-ionolo, il grassopperchetone e il vomifoliolo. Nelle frazioni volatili libere dei vini sono stati identificati circa 60 composti, per la gran parte composti di fermentazione quali esteri, acetati, alcoli, benzenoidi e lattoni, oltre a terpeni e norisoprenoidi varietali. Nella frazione legata dei vini, ottenuta dopo idrolisi enzimatica sono stati trovati 30 composti varietali.

Adenoviruses are increasingly recognized pathogens that affect blood and marrow transplant (BMT) recipients. Experiences with 2889 adult BMT recipients were reviewed to study the incidence, clinical spectrum, risk factors for dissemination, response to therapy, and outcome of adenovirus infections. Eight-five patients (3%) were diagnosed by means of culture (n=85) or culture and histopathological examination (n=6). Nine patients had asymptomatic viruria, and 76 had symptomatic infections, which included upper respiratory tract infection (n=20), enteritis (n=18), hemorrhagic cystitis (n=10), pneumonia (n=15), and disseminated disease (n=13). The overall mortality rate was 26%. A higher mortality rate was observed among patients with pneumonia (73%) and disseminated disease (61%). Risk factors for dissemination included receipt of an allogeneic transplant, presence of graft-versus-host disease (GVHD), and receipt of concurrent immunosuppressive therapy. Intravenous ribavirin was not associated with an appreciable benefit among 12 patients who received this treatment. In conclusion, adenovirus infections are an important cause of morbidity and mortality in adult BMT recipients, particularly allogeneic transplant recipients with GVHD who are receiving immunosuppressive therapy. The need for an effective, nontoxic antiviral therapy is apparent.

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naive individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p

(See the article by Kalayjian et al, on pages 1796-1805, and the editorial commentary by Dubé and Sattler, on pages 1783-1785.) Background. Human immunodeficiency virus (HIV) replication and immune activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers in persons with and without HIV infection. Methods. For persons 45-76 years of age, levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, D-dimer, and cystatin C were compared in 494 HIV-infected individuals in the Strategies for Management of Anti-Retroviral Therapy (SMART) study and 5386 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study. For persons 33-44 years of age, hsCRP and IL-6 levels were compared in 287 participants in the SMART study and 3231 participants in the Coronary Artery Development in Young Adults (CARDIA) study. Results. hsCRP and IL-6 levels were 55% (P

This paper describes an approach to hardware/software design space exploration for reconfigurable processors. The existing compiler tool-chain, because of the user-definable instructions, needs to be extended in order to offer developers an easy way to explore the design space. Such extension often is not easy to use for developers who have only a software background, and are not familiar with reconfigurable architecture details or hardware design. Our approach differs from others because it is based on a simple extension of the standard programming model well known to software developers. We illustrate it by using a real case study, a software implementation of a UMTS turbo-decoder that achieves a 11× speed-up of the whole application, by exploiting user-defined instructions on the dynamically reconfigurable portion of the datapath.

This paper introduces an architectural simulation environment, aimed at defining the best SOC architecture for complex system-level applications. The application is modeled using an abstract timing modeling language, that describes the requests (e.g., memory accesses, I/Os, etc.) that the application makes to the architecture. The abstract architecture is modeled at the cycle-accurate level using a mixture of Esterel (a synchronous language) and C. We discuss the results of the application of this tool to a GSM/GPRS application, including a dramatic speed-up of the architectural exploration phase.

A randomized, open, controlled clinical trial was designed to evaluate the efficacy, tolerance, and safety of sodium stibogluconate plus allopurinol and sodium stibogluconate alone as treatment of patients with mucocutaneous leishmaniasis. In phase 1 of the study, all 22 patients with severe disease had improvement of their lesions, but only two had clinical cure (both of these patients received sodium stibogluconate alone). In phase 2, which included 59 patients with moderate disease, the cure rate among sodium stibogluconate recipients was 75% (21 of 28) compared with 63.6% (14 of 22) among the sodium stibogluconate plus allopurinol recipients. The rates of clinical adverse events were similar among both groups. Thrombocytopenia was more frequent in the sodium stibogluconate plus allopurinol recipients, but the difference was not statistically significant. Eight patients (two sodium stibogluconate recipients and six sodium stibogluconate plus allopurinol recipients) withdrew from the study because of severe thrombocytopenia. In this study, the addition of allopurinol to sodium stibogluconate provided no clinical benefit as treatment of mucocutaneous leishmaniasis.

BackgroundAntiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and findings1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; pConclusionEFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial registrationwww.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

SummaryBackgroundHematological abnormalities are common manifestations of advanced HIV-1 infection that could affect the outcomes of highly-active antiretroviral therapy (HAART). Although most HIV-1-infected individuals live in resource-constrained countries, there is little information about the frequency of hematological abnormalities such as anemia, neutropenia, and thrombocytopenia among individuals with advanced HIV-1 disease.MethodsThis study compared the prevalence of pre-antiretroviral therapy hematological abnormalities among 1571 participants in a randomized trial of antiretroviral efficacy in Africa, Asia, South America, the Caribbean, and the USA. Potential covariates for anemia, neutropenia, and thrombocytopenia were identified in univariate analyses and evaluated in separate multivariable models for each hematological condition.ResultsThe frequencies of neutropenia (absolute neutrophil count ≤1.3×109/l), anemia (hemoglobin ≤10g/dl), and thrombocytopenia (platelets ≤125×109/l) at initiation of antiretroviral therapy were 14%, 12%, and 7%, respectively, and varied by country (p