Publications by authors named "Alberto La Rosa"

30 Publications

  • Page 1 of 1

Type 2 diabetes mellitus in Peru: A literature review including studies at high-altitude settings.

Diabetes Res Clin Pract 2021 Dec 8;182:109132. Epub 2021 Nov 8.

Clínica Ricardo Palma, Peru.

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.
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http://dx.doi.org/10.1016/j.diabres.2021.109132DOI Listing
December 2021

Poor quality of life and incomplete self-reported adherence predict second-line ART virological failure in resource-limited settings.

AIDS Care 2021 10 23;33(10):1340-1349. Epub 2021 Jan 23.

LapClin-AIDS, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (INI-FIOCRUZ), Rio de Janeiro, Brazil.

We evaluated health-related quality of life (QoL) and self-reported incomplete adherence as predictors of early second-line antiretroviral (ART) virological failure (VF). ACTG A5273 study participants completed the ACTG SF-21 measure which has 8 QoL domains. 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, VL 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. ClinicalTrials.gov identifier: NCT01352715.
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http://dx.doi.org/10.1080/09540121.2021.1874275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298588PMC
October 2021

Genital Shedding of Human Immunodeficiency Virus Type-1 (HIV) When Antiretroviral Therapy Suppresses HIV Replication in the Plasma.

J Infect Dis 2020 08;222(5):777-786

Seattle Children's Research Institute, Seattle, Washington, USA.

Background: During antiretroviral treatment (ART) with plasma HIV RNA below the limit of quantification, HIV RNA can be detected in genital or rectal secretions, termed discordant shedding (DS). We hypothesized that proliferating cells produce virions without HIV replication.

Methods: ART-naive Peruvians initiating ART were observed for DS over 2 years. HIV env and pol genomes were amplified from DS. Antiretrovirals and cytokines/chemokines concentrations were compared at DS and control time points.

Results: Eighty-two participants had ART suppression. DS was detected in 24/82 (29%) participants: 13/253 (5%) cervicovaginal lavages, 20/322 (6%) seminal plasmas, and 6/85 (7%) rectal secretions. HIV RNA in DS specimens was near the limit of quantification and not reproducible. HIV DNA was detected in 6/13 (46%) DS cervicovaginal lavages at low levels. Following DNase treatment, 5/39 DS specimens yielded HIV sequences, all without increased genetic distances. Women with and without DS had similar plasma antiretroviral levels and DS in 1 woman was associated with inflammation.

Conclusions: HIV RNA and DNA sequences and therapeutic antiretroviral plasma levels did not support HIV replication as the cause of DS from the genital tract. Rather, our findings infer that HIV RNA is shed due to proliferation of infected cells with virion production.
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http://dx.doi.org/10.1093/infdis/jiaa169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399698PMC
August 2020

Distal Sensory Peripheral Neuropathy in Human Immunodeficiency Virus Type 1-Positive Individuals Before and After Antiretroviral Therapy Initiation in Diverse Resource-Limited Settings.

Clin Infect Dis 2020 06;71(1):158-165

Neurological HIV Center, University of North Carolina, Chapel Hill, North Carolina, USA.

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 <300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once.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.
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http://dx.doi.org/10.1093/cid/ciz745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312215PMC
June 2020

Metabolic and Cardiovascular Comorbidities Among Clinically Stable HIV Patients on Long-Term ARV Therapy in Five Ambulatory Clinics in Lima-Callao, Peru.

Open AIDS J 2018 17;12:126-135. Epub 2018 Oct 17.

MSD Peru Medical Affairs, Lima, Peru.

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 <40 c/mL was 90.8% (n=277). Most frequent metabolic diagnoses were dyslipidemia (51.5%, n=157), obesity (11.1%, n=34), and diabetes mellitus (7.2%, n=22). Hypertension was diagnosed in 8.9% (n=27). Other diagnoses of cardiovascular disease were documented in 3.3% (n=10). Pharmacologic treatment was prescribed in 91.3% of patients with diabetes or hypertension, but in only 29.3% of patients with dyslipidemia.

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.
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http://dx.doi.org/10.2174/1874613601812010126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198417PMC
October 2018

Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study.

BMC Med 2018 09 24;16(1):161. Epub 2018 Sep 24.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Various individual biomarkers of inflammation and micronutrient status, often correlated with each other, are associated with adverse treatment outcomes in human immunodeficiency virus (HIV)-infected adults. The objective of this study was to conduct exploratory factor analysis (EFA) on multiple inflammation and micronutrient biomarkers to identify biomarker groupings (factors) and determine their association with HIV clinical treatment failure (CTF) and incident active tuberculosis (TB).

Methods: Within a multicountry randomized trial of antiretroviral therapy (ART) efficacy (PEARLS) among HIV-infected adults, we nested a case-control study (n = 290; 124 cases, 166 controls) to identify underlying factors, based on EFA of 23 baseline (pre-ART) biomarkers of inflammation and micronutrient status. The EFA biomarker groupings results were used in Cox proportional hazards models to study the association with CTF (primary analysis where cases were incident World Health Organization stage 3, 4 or death by 96 weeks of ART) or incident active TB (secondary analysis).

Results: In the primary analysis, based on eigenvalues> 1 in the EFA, three factors were extracted: (1) carotenoids), (2) other nutrients, and (3) inflammation. In multivariable-adjusted models, there was an increased hazard of CTF (adjusted hazard ratio (aHR) 1.47, 95% confidence interval (CI)1.17-1.84) per unit increase of inflammation factor score. In the secondary incident active TB case-control analysis, higher scores of the high carotenoids and low interleukin-18 factor was protective against incident active TB (aHR 0.48, 95% CI 0.26-0.87).

Conclusion: Factors identified through EFA were associated with adverse outcomes in HIV-infected individuals. Strategies focused on reducing adverse HIV outcomes through therapeutic interventions that target the underlying factor (e.g., inflammation) rather than focusing on an individual observed biomarker might be more effective and warrant further investigation.
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http://dx.doi.org/10.1186/s12916-018-1150-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151930PMC
September 2018

Human Immunodeficiency Virus-associated Neurocognitive Impairment in Diverse Resource-limited Settings.

Clin Infect Dis 2019 05;68(10):1733-1738

Frontier Science & Technology Research Foundation, Buffalo, New York.

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.
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http://dx.doi.org/10.1093/cid/ciy767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495019PMC
May 2019

Human Immunodeficiency Virus Type 1 and Tuberculosis Coinfection in Multinational, Resource-limited Settings: Increased Neurological Dysfunction.

Clin Infect Dis 2019 05;68(10):1739-1746

AIDS Neurological Center, Neurology, University of North Carolina, Chapel Hill.

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.
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http://dx.doi.org/10.1093/cid/ciy718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495021PMC
May 2019

Monotypic low-level HIV viremias during antiretroviral therapy are associated with disproportionate production of X4 virions and systemic immune activation.

AIDS 2018 07;32(11):1389-1401

Department of Pediatrics, University of Washington (UW).

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 < 0.001) and PBMC HIV DNA (P < 0.007); but, during ART, their antiretroviral drug levels were similar. LLV env sequences were monotypic in 17 of 28 (61%) and diverse in 11 of 28 (39%) participants. Those with the monotypic vs. diverse LLV pattern had elevated hsCRP and sCD163 (P = 0.004) and LLV with more X4 variants (P = 0.02).

Conclusion: In individuals with monotypic LLV sequences, higher levels of pre-ART HIV DNA and RNA, systemic inflammation and X4 viruses suggest an interaction between inflammation and the production of virions from proliferating infected cells, and that naïve T cells may be a source of LLV.
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http://dx.doi.org/10.1097/QAD.0000000000001824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039404PMC
July 2018

Quality of life among HIV-infected individuals failing first-line antiretroviral therapy in resource-limited settings.

AIDS Care 2018 08 18;30(8):954-962. Epub 2018 Jan 18.

a Center for Biostatistics in AIDS Research , Harvard T. H. Chan School of Public Health , Boston , MA , USA.

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.
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http://dx.doi.org/10.1080/09540121.2018.1427207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100767PMC
August 2018

Quality of life improvement in resource-limited settings after one year of second-line antiretroviral therapy use among adult men and women.

AIDS 2018 03;32(5):583-593

Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Objective: 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.

Design: 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).

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1097/QAD.0000000000001738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832593PMC
March 2018

Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial.

J Bone Miner Res 2017 Sep 26;32(9):1945-1955. Epub 2017 Jun 26.

St Vincent's Hospital, Sydney, Australia.

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 <350 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, p < 0.001) and spine (-1.9% versus -0.4%; difference -1.6%, 95% CI -2.2 to -1.0, p < 0.001). 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.

Clinical Trials Registration: NCT00867048. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555813PMC
September 2017

Predictors of late virologic failure after initial successful suppression of HIV replication on efavirenz-based antiretroviral therapy.

HIV Clin Trials 2016 29;17(5):173-180. Epub 2016 Jul 29.

c Center for Biostatistics in AIDS Research , Harvard T.H. Chan School of Public Health , Boston , MA , USA.

Background: 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.

Methods: 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).

Results: 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.

Discussion: 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.
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http://dx.doi.org/10.1080/15284336.2016.1201300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5276794PMC
July 2016

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

AIDS 2016 06;30(10):1607-15

aVanderbilt University School of Medicine, Nashville, Tennessee bCenters for Disease Control and Prevention, Atlanta, Georgia, USA cHospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain dInstituto Nacional de Infectologia, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil eAsociacion Civil Impacta Salud y Educacion, Lima, Peru fVeterans Affairs Medical Center gGeorge Washington University, Washington, District of Columbia hUniversity of California at San Diego, California iJohns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899978PMC
http://dx.doi.org/10.1097/QAD.0000000000001098DOI Listing
June 2016

Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.

Lancet HIV 2016 06 18;3(6):e247-58. Epub 2016 Apr 18.

University of Washington, Seattle, WA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/S2352-3018(16)30011-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914044PMC
June 2016

Binge drinking is associated with differences in weekday and weekend adherence in HIV-infected individuals.

Drug Alcohol Depend 2016 Feb 24;159:174-80. Epub 2015 Dec 24.

Department of Medicine (Infectious Diseases) and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: 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.

Methods: 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.

Results: 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 p<0.001). Binge drinking at baseline and time on study were both associated with greater differences between weekday and weekend adherence.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860880PMC
February 2016

Partner-based adherence intervention for second-line antiretroviral therapy (ACTG A5234): a multinational randomised trial.

Lancet HIV 2015 01 11;2(1):e12-9. Epub 2014 Dec 11.

University of Washington, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1016/S2352-3018(14)00007-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313760PMC
January 2015

Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy.

AIDS 2015 Aug;29(13):1617-22

aHospital Nacional dos de Mayo, Lima, Peru bDepartment of Pediatrics, University of Washington cCenter for Global Infectious Disease Research, Seattle Children's Hospital Research Institute dDepartment of Global Health eDepartment of Obstetrics and Gynecology, University of Washington, Seattle, Washington fInvestigaciones Médicas en Salud (INMENSA), Lima, Peru gDepartment of Medicine hDepartment of Laboratory Medicine, University of Washington, Seattle, Washington, USA. *Eduardo Ticonaa and Marta E. Bull contributed equally to the writing of this article. †Currently involved with the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) program, Seattle Children's Hospital, Seattle, Washington, USA. ‡Currently with the Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Inflammatory biomarkers associated with cardiovascular disease are elevated in HIV-infected persons. These biomarkers improve with antiretroviral therapy (ART) but do not normalize to values observed in HIV-uninfected adults. Little is known regarding biomarkers of inflammation in HIV-infected Peruvians, in whom an increased burden of infectious diseases may exacerbate inflammation, and women, in whom sex difference may alter inflammation compared with men.

Methods: Peruvians initiating first-line ART were enrolled in a prospective observational study. Individuals with suppression of HIV RNA plasma loads to less than 30 copies/ml when determined quarterly over 24 months of ART, had biomarkers of inflammation and cellular activation measured pre-ART and at 24-months of ART, and evaluated for associations with sex and clinical parameters.

Results: Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0 mg/l) more frequently compared with women (P = 0.02); most women's values were in the low/average-risk categories. At 24 months of suppressive ART, hsCRP concentrations decreased in men (P = 0.03), but tended to increase in women, such that the proportion with high-risk hsCRP did not differ by sex. Pre-ART, soluble CD163 concentrations were higher in women compared with men (P = 0.02), and remained higher after 24 months of suppressive ART (P = 0.02). All other inflammatory biomarkers (P < 0.03) decreased across sexes. Biomarker concentrations were not associated with BMI or coinfections.

Conclusion: Elevated inflammatory biomarkers persisted despite 24 months of suppressive ART in a subset of Peruvians, and to a greater extent in women compared with men. These findings suggest that lifestyle or pharmacologic interventions may be required to optimize the health of HIV-infected Peruvians, particularly women.
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http://dx.doi.org/10.1097/QAD.0000000000000758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823992PMC
August 2015

Concurrent Anemia and Elevated C-Reactive Protein Predicts HIV Clinical Treatment Failure, Including Tuberculosis, After Antiretroviral Therapy Initiation.

Clin Infect Dis 2015 Jul 31;61(1):102-10. Epub 2015 Mar 31.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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 <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP ≥ 10 mg/L) with clinical failure were assessed using multivariable Cox models.

Results: Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation.

Conclusions: ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening.
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http://dx.doi.org/10.1093/cid/civ265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542913PMC
July 2015

Clinical outcomes of first-line antiretroviral therapy in Latin America: analysis from the LATINA retrospective cohort study.

Int J STD AIDS 2016 Feb 3;27(2):118-26. Epub 2015 Mar 3.

CICAL, Buenos Aires, Argentina Hospital José M. Ramos Mejía, Buenos Aires, Argentina.

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/mm(3) (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 < 0.01). This study concluded that patients living with HIV in Latin America present with similar clinical outcomes regardless of the choice of initial therapy. Patients treated with PIs are more likely to require a treatment change during the first year of follow up.
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http://dx.doi.org/10.1177/0956462415575621DOI Listing
February 2016

Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial.

Clin Infect Dis 2015 May 13;60(10):1541-9. Epub 2015 Feb 13.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: 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.

Methods: 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.

Results: 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).

Conclusions: In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible.

Clinical Trials Registration: NCT00084136.
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http://dx.doi.org/10.1093/cid/civ102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425827PMC
May 2015

Outcomes among HIV-1 infected individuals first starting antiretroviral therapy with concurrent active TB or other AIDS-defining disease.

PLoS One 2013 31;8(12):e83643. Epub 2013 Dec 31.

Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.

Background: Tuberculosis (TB) is common among HIV-infected individuals in many resource-limited countries and has been associated with poor survival. We evaluated morbidity and mortality among individuals first starting antiretroviral therapy (ART) with concurrent active TB or other AIDS-defining disease using data from the "Prospective Evaluation of Antiretrovirals in Resource-Limited Settings" (PEARLS) study.

Methods: PARTICIPANTS WERE CATEGORIZED RETROSPECTIVELY INTO THREE GROUPS ACCORDING TO PRESENCE OF ACTIVE CONFIRMED OR PRESUMPTIVE DISEASE AT ART INITIATION: those with pulmonary and/or extrapulmonary TB ("TB" group), those with other non-TB AIDS-defining disease ("other disease"), or those without concurrent TB or other AIDS-defining disease ("no disease"). Primary outcome was time to the first of virologic failure, HIV disease progression or death. Since the groups differed in characteristics, proportional hazard models were used to compare the hazard of the primary outcome among study groups, adjusting for age, sex, country, screening CD4 count, baseline viral load and ART regimen.

Results: 31 of 102 participants (30%) in the "TB" group, 11 of 56 (20%) in the "other disease" group, and 287 of 1413 (20%) in the "no disease" group experienced a primary outcome event (p = 0.042). This difference reflected higher mortality in the TB group: 15 (15%), 0 (0%) and 41 (3%) participants died, respectively (p<0.001). The adjusted hazard ratio comparing the "TB" and "no disease" groups was 1.39 (95% confidence interval: 0.93-2.10; p = 0.11) for the primary outcome and 3.41 (1.72-6.75; p<0.001) for death.

Conclusions: Active TB at ART initiation was associated with increased risk of mortality in HIV-1 infected patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083643PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877069PMC
August 2014

Transmitted HIV resistance to first-line antiretroviral therapy in Lima, Peru.

AIDS Res Hum Retroviruses 2012 Apr 5;28(4):333-8. Epub 2011 Aug 5.

Hospital Nacional Dos de Mayo, Lima, Peru.

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.
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http://dx.doi.org/10.1089/aid.2011.0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316114PMC
April 2012

A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings.

J Neurovirol 2011 Oct 23;17(5):438-47. Epub 2011 Jul 23.

University of North Carolina, Chapel Hill, NC 27599-7025, USA.

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 naïve 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 < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.
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http://dx.doi.org/10.1007/s13365-011-0044-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362044PMC
October 2011

Comparisons of anemia, thrombocytopenia, and neutropenia at initiation of HIV antiretroviral therapy in Africa, Asia, and the Americas.

Int J Infect Dis 2010 Dec 18;14(12):e1088-92. Epub 2010 Oct 18.

Department of Medicine/Clinical HIV Research Unit, University of Witwatersrand, Postnet suite 176, Private Bag X2600, Johannesburg 2041, South Africa.

Background: Hematological 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.

Methods: This 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.

Results: The 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<0.0001 for each). In multivariable models, anemia was associated with gender, platelet count, and country; neutropenia was associated with CD4+ lymphocyte and platelet counts; and thrombocytopenia was associated with country, gender, and chronic hepatitis B infection.

Conclusions: Differences in the frequency of pretreatment hematological abnormalities could have important implications for the choice of antiretroviral regimen in resource-constrained settings.
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http://dx.doi.org/10.1016/j.ijid.2010.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021118PMC
December 2010

Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection.

J Infect Dis 2010 Jun;201(12):1788-95

University of Minnesota, Minneapolis, Minnesota 55414 , USA.

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 < . 001) and 62 (P < . 001) higher among HIV-infected participants than among CARDIA study participants. Compared with levels noted in MESA study participants, hsCRP, IL-6, D-dimer, and cystatin C levels were 50%, 152%, 94%, and 27% higher, respectively (P < . 001, for each), among HIV-infected participants. HIV-infected participants receiving antiretroviral therapy who had HIV RNA levels 400 copies/mL had levels higher (by 21% to 60%) (P < . 001) than those in the general population, for all biomarkers.

Conclusions: hsCRP, IL-6, D-dimer, and cystatin C levels are elevated in persons with HIV infection and remain so even after HIV RNA levels are suppressed with antiretroviral therapy. Additional research is needed on the pathophysiology of HIV-induced activation of inflammatory and coagulation pathways, to guide potential interventions.
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http://dx.doi.org/10.1086/652749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872049PMC
June 2010

Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV.

AIDS 2010 Mar;24(5):697-706

University of Minnesota, Minneapolis, Minnesota, USA.

Objectives: Among patients with HIV, the risk of death associated with different AIDS events has been quantified, but the risk of death associated with non-AIDS events has not been examined. We compared the risk of all-cause mortality following AIDS versus serious non-AIDS (SNA) events in the Strategies for Management of Antiretroviral Therapy (SMART) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT).

Design: Data from 9583 HIV-infected participants, 5472 with a CD4 cell count more than 350 cells/microl enrolled in SMART and 4111 with a CD4 cell count 300 cells/microl or more enrolled in ESPRIT, were analyzed.

Methods: Cumulative mortality 6 months after AIDS and SNA events (cardiovascular, renal, hepatic disease, and malignancies) was estimated using the Kaplan-Meier method. Cox models were used to estimate hazard ratios associated with AIDS and SNA events on the risk of death overall and by treatment group within study.

Results: AIDS and SNA events occurred in 286 and 435 participants with 47 (16%) and 115 (26%) subsequent deaths, respectively. Six-month cumulative mortality was 4.7% [95% confidence interval (CI) 2.8-8.0] after experiencing an AIDS event and 13.4% (95% CI 10.5-17.0) after experiencing an SNA event. The adjusted hazard ratio for all-cause mortality for those who experienced AIDS versus those who did not was 4.9 (95% CI 3.6-6.8). The corresponding hazard ratio for SNA was 11.4 (95% CI 9.0-14.5) (P < 0.001 for difference in hazard ratios). Findings were similar for both treatment groups in SMART and both treatment groups in ESPRIT.

Conclusion: Among HIV-infected persons with higher CD4 cell counts, SNA events occur more frequently and are associated with a greater risk of death than AIDS events. Future research should be aimed at comparing strategies to reduce morbidity and mortality associated with SNA events for HIV-infected persons.
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http://dx.doi.org/10.1097/QAD.0b013e3283365356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897168PMC
March 2010

Retroviral infection in Peruvian men who have sex with men.

Clin Infect Dis 2009 Jul;49(1):112-7

Ministry of Health, Lima, Peru.

We tested 2655 Peruvian men who have sex with men for the presence of retroviral infection. Human T cell lymphotropic virus type 1 (HTLV-1) was detected in 48 (1.8%) of the patients, HTLV-2 was detected in 28 (1.1%), and HTLV-1 and HTLV-2 were both detected in 5 (0.2%). Human immunodeficiency virus infection was detected in 329 (12.4%) of the patients; 24 (7.3%) had HTLV coinfection. Risk factors for HTLV-1 and HTLV-2 infection varied with sexual role.
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http://dx.doi.org/10.1086/599609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770590PMC
July 2009

Risk factors for HTLV-II infection in Peruvian men who have sex with men.

Am J Trop Med Hyg 2006 May;74(5):922-5

Department of Neurology, Center for AIDS and STD, University of Washington School of Medicine, Seattle, Washington, USA.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695970PMC
May 2006
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