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Commentaries for This Article from The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels

BackgroundSame-day HIV testing and antiretroviral therapy (ART) initiation is being widely implemented. However, the optimal timing of ART among patients with tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment would be superior to standard care in this population.Methods and FindingsWe conducted an open-label randomized trial among adults with TB symptoms at initial HIV diagnosis at GHESKIO in Haiti. Participants were randomized in a 1:1 ratio to same-day treatment (same-day TB testing with same-day treatment [TB medication if TB; ART if no TB]) vs. standard care. In both groups, ART was initiated two weeks after TB treatment. The primary outcome was retention in care with 48-week HIV-1 RNA ConclusionsIn patients with TB symptoms at HIV diagnosis, same-day treatment is not associated with superior retention and viral suppression. A short delay in ART initiation, which facilitates more feasible TB testing, does not compromise outcomes.Trial RegistrationThis study is registered withClinicalTrials.govNCT03154320

Background Cytology-based cervical cancer screening followed by confirmation and treatment of biopsy-proven high-grade squamous intraepithelial lesions (bHSIL) is difficult to implement in resource-constrained settings. We hypothesized that high-risk human papillomavirus (hrHPV) testing followed by immediate cryotherapy of women with hrHPV (HPV screen-and-treat) may improve outcomes. Methods Randomized, open-label, phase 2, multinational clinical trial enrolling women with human immunodeficiency virus (HIV) age 18 or older with cervical hrHPV and having no cervical lesions or lesions appropriate for cryotherapy. Women were randomized to immediate cryotherapy (Arm A) or cytology-based screening (Arm B). For Arm A, cervical biopsies were obtained followed by cervical cryotherapy, and in Arm B, women with abnormal cytology underwent colposcopy followed by loop electroexcision procedure (LEEP) if bHSIL was detected. Women were followed through 30 months. The primary outcome was time to bHSIL detected from Month 6 through study completion. Results In total, 288 women (145 in Arm A, 143 in Arm B) were randomized: median age 35 years, 84% on antiretroviral therapy, median CD4 501 cells/mm3. In Arm A, 39 (27%) of women had bHSIL at entry, and in Arm B, 88 (62%) had abnormal cytology, 22 (15%) were diagnosed with bHSIL, 12 (8%) underwent LEEP. In follow-up, 30 (21%) and 31 (22%) developed bHSIL; time to bHSIL was similar between arms (P=.94). The prevalence of hrHPV at Month 6 was similar between arms (61% and 70%, P=.13). Conclusions HPV test-and-treat was not associated with improved bHSIL outcomes as compared to cytology-based screening. More effective treatment options are required to improve outcomes from screen-and-treat programs. Clinical Trials Registration NCT01315363.

Summary Background & aims Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. Methods We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naive adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B6, B12, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. Results In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (−14.9 cells/mm3, 95% CI: −27.9, −1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm3, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm3, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm3, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. Conclusions In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.

Growth hormone (GH)/insulin-like growth factor (IGF)-1 axis abnormalities have been associated with body composition changes among HIV-infected persons with wasting or lipodystrophy. Little is known of GH/IGF-1 axis alterations with antiretroviral therapy (ART) initiation or differing ART therapies. The AIDS Clinical Trials Group Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) study was a prospective, randomized clinical trial of ART initiation with emtricitabine/tenofovir + efavirenz (FTC/TDF+EFV) versus lamivudine/zidovudine + efavirenz (3TC/ZDV+EFV) in HIV-1-infected individuals from resource-diverse settings. IGF-1 was measured from baseline, week 48, and week 96 stored serum samples. Multivariate models were constructed. 415 participants were included: 170 (41%) were randomized to FTC/TDF+EFV and 245 (59%) to 3TC/ZDV+EFV. The mean age was 35 years, 60% were black, 42% women. The mean IGF-1 level did not change significantly from baseline to week 96 (−0.65 ng/ml; 95% confidence interval (CI) −5.18–3.87), p = .78 and there were no differences by treatment arm at week 96, p = .74. Lower baseline IGF-1 was associated with age, non-white race, greater waist–hip ratio (WHR), low CD4 count, and lower baseline albumin (all p

BackgroundPeople with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death.MethodsThe REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma.ResultsIn total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1β, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1β, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-β) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87–.94) and a specificity of 0.71(95% CI: .68–.75) with an area under the curve (AUC) of 0.81 (95% CI: .78–.83) for incident TB.ConclusionAmong people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions.Clinical Trials RegistrationNCT01380080

Objective Tenofovir disoproxyl fumarate (TDF) disoproxyl fumarate (TDF) has in vitro activity against herpes simplex virus type 2 (HSV-2) and reduced HSV-2 acquisition as preexposure prophylaxis. Whether TDF-containing antiretroviral therapy (ART) reduces HSV-2 acquisition is unknown. Design Secondary analysis of AIDS Clinical Trials Group A5175, a randomized, open-label study of 3 ART regimens among 1571 participants. Methods HSV-2 serostatus was assessed at baseline, at study exit, and before a change in ART regimen. Results Of 365 HSV-2-seronegative persons, 68 acquired HSV-2, with 24 receiving TDF-containing ART and 44 receiving ART without TDF (HSV-2 seroconversion incidence, 6.42 and 6.63 cases/100 person-years, respectively; hazard ratio, 0.89; 95% confidence interval, .55-1.44). Conclusions HSV-2 acquisition was not reduced in HIV-infected, HSV-2-uninfected persons during TDF-containing ART.

HIV-infected adults have increased risk of several individual micronutrient deficiencies. However, the prevalence and risk factors of concurrent and multiple micronutrient deficiencies and whether micronutrient concentrations change after antiretroviral therapy (ART) initiation have not been well described. The objective of this study was to determine the prevalence and risk factors of individual, concurrent and multiple micronutrient deficiencies among ART-naïve HIV-infected adults from nine countries and assess change in micronutrient status 48 weeks post-ART initiation.A random sub-cohort (n = 270) stratified by country was selected from the multinational PEARLS clinical trial (n = 1571 ART-naïve, HIV-infected adults). We measured serum concentrations of vitamins A, D (25-hydroxyvitamin), E, carotenoids and selenium pre-ART and 48 weeks post-ART initiation, and measured vitamins B6, B12, ferritin and soluble transferrin receptor at baseline only. Prevalence of single micronutrient deficiencies, concurrent (2 coexisting) or conditional (a deficiency in one micronutrient given a deficiency in another) and multiple (≥3) were determined using defined serum concentration cutoffs. We assessed mean changes in micronutrient concentrations from pre-ART to week 48 post-ART initiation using multivariable random effects models.Of 270 participants, 13.9%, 29.2%, 24.5% and 32.4% had 0, 1, 2 and multiple deficiencies, respectively. Pre-ART prevalence was the highest for single deficiencies of selenium (53.2%), vitamin D (42.4%), and B6 (37.3%) with 12.1% having concurrent deficiencies of all three micronutrients. Deficiency prevalence varied widely by country. 48 weeks post-ART initiation, mean vitamin A concentration increased (p 0.001) corresponding to a 9% decrease in deficiency. Mean concentrations also increased for other micronutrients assessed 48 weeks post-ART (p 0.001) but with minimal change in deficiency status.Single and multiple micronutrient deficiencies are common among HIV-infected adults pre-ART initiation but vary between countries. Importantly, despite increases in micronutrient concentrations, prevalence of individual deficiencies remains largely unchanged after 48 weeks on ART. Our results suggest that ART alone is not sufficient to improve micronutrient deficiency.

A case-cohort analysis of human immunodeficiency virus (HIV)–infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C-reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as ≥ 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies.

Mark W. Tenforde, MD, MPH,* Ashish Yadav, MBBS, MD, MPH,† David W. Dowdy, MD, PhD, Nikhil Gupte, PhD,§ Rupak Shivakoti, PhD, MSPH,§ Wei-Teng Yang, MD, MPH,k Noluthando Mwelase, MBChB, Cecilia Kanyama, MD,# Sandy Pillay, MBChB,** Wadzanai Samaneka, MBChB, MSc,†† Breno Santos, MD,‡‡ Selvamuthu Poongulali, MBBS,§§ Srikanth Tripathy, MBBS,kk Cynthia Riviere, MD, Sima Berendes, MD, MPH,##*** Javier R. Lama, MD, MPH,††† Sandra W. Cardoso, MD,‡‡‡ Patcharaphan Sugandhavesa, MD,§§§ Rarul Christian, DrPH, MSc,† Richard D. Semba, MD, MPH,kkk Thomas B. Campbell, MD, and Amita Gupta, MD, MHS,†§ the NWCS319 and ACTG 5175 study team From the *Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, WA; Departments of †International Health; ‡Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; §Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; kDepartment of Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, CT; Department of Medicine, University of Witwatersrand, Johannesburg, South Africa; #UNC Lilongwe, Lilongwe, Malawi; **Durban International Clinical Research Site, Durban University of Technology, Durban, South Africa; ††University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; ‡‡Hospital Nossa Senhora de Conceicao, Porto Alegre, Brazil; §§YR Gaitonde Centre for AIDS Research and Education, Chennai, India; kkNational AIDS Research Institute, Pune, India; Les Centres GHESKIO, Port-Au-Prince, Haiti; ##Malawi College of Medicine, Johns Hopkins University Research Project, Blantyre, Malawi; ***Liverpool School of Tropical Medicine, Liverpool, United Kingdom; †††Asociacion Civil Impacta Salud y Educacion, Lima, Peru; ‡‡‡STD/AIDS Clinical Research Laboratory, Instituto de Pesquisa Clinica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil; §§§Research Institute for Health Sciences, Chiang Mai, Thailand; kkkDepartment of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD; and Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.

Background Attrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression. Methods and findings We conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA, In a randomized unblinded trial in Port-au-Prince, Haiti, Serena Koenig and colleagues investigate whether initiating ART on the day of HIV diagnosis improved retention in care and viral suppression., Author summary Why was this study done? Multiple visits for counseling, laboratory testing, and other procedures to prepare patients for initiation of antiretroviral therapy (ART) are burdensome and contribute to the high rate of attrition during the period from HIV testing to ART initiation. The World Health Organization (WHO) recently changed their guidelines to recommend ART for all persons living with HIV, facilitating ART initiation. This study was conducted to determine if ART initiation on the day of HIV diagnosis could improve treatment initiation rates, retention in care, and HIV viral suppression for patients with asymptomatic or minimally symptomatic HIV disease. What did the researchers do and find? We randomly assigned patients who presented for HIV testing at a clinic in Port-au-Prince, Haiti to standard ART initiation or same-day HIV testing and ART initiation (356 in the standard and 347 in the same-day groups). The standard group had 3 weekly visits with a social worker and physician and then started ART 21 days after the date of HIV diagnosis; the same-day ART group initiated ART on the day of HIV diagnosis. All participants in the same-day ART group and 92% of participants in the standard group initiated ART. At 12 months after HIV testing, a higher proportion of participants in the same-day ART group were retained in care (80% versus 72%), and a higher proportion were retained in care with viral load

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Background: Women progress to death at the same rate as men despite lower plasma HIV RNA (viral load). We investigated sexspecific differences in immune activation and inflammation as a potential explanation. Methods: Inflammatory and immune activation markers [interferon-γ, tumor necrosis factor (TNF) α, IL-6, IL-18, IFN-γ- induced protein 10, C-reactive protein (CRP), lipopolysaccharide, and sCD14] were measured at weeks 0, 24, and 48 after combination antiretroviral therapy (cART) in a random subcohort (n = 215) who achieved virologic suppression in ACTG A5175 (Prospective Evaluation of Antiretrovirals in Resource-Limited Settings). Association between sex and changes in markers postcART was examined using random effects models. Average marker differences and 95% confidence intervals were estimated using multivariable models. Results: At baseline, women had lower median log10viral load (4.93 vs 5.18 copies per milliliter, P = 0.01), CRP (2.32 vs 4.62 mg/L, P = 0.01), detectable lipopolysaccharide (39% vs 55%, P = 0.04), and sCD14 (1.9 vs 2.3 μg/mL, P = 0.06) vs men. By week 48, women had higher interferon -γ (22.4 vs 14.9 pg/mL, P = 0.05), TNF-α (11.5 vs 9.5 pg/mL, P = 0.02), and CD4 (373 vs 323 cells per cubic millimeter, P = 0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared with men. Conclusions: With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

Leadership positions in global health are greatly skewed toward men; the imbalance is more pronounced in low- and middle-income countries (LMICs). The under-representation of women in leadership is a threat to gender equality, and also impacts the improvement of women's health outcomes globally. In this perspectives piece, we assert that the promotion and retention of women in global health leadership has a ripple effect that can achieve improvement in global health outcomes. We present pragmatic, actionable solutions to promote and retain female global health leaders in this field.Les positions de dirigeant dans la santé du monde sont largement orientées vers les hommes et ce déséquilibre est encore plus prononcé dans les pays à revenu faible et moyen. La sous-représentation des femmes en termes de dirigeant menace l'égalité des genres et a également un impact sur l'amélioration de l'état de santé des femmes dans le monde. Dans cette perspective, nous affirmons que la promotion et la rétention des femmes au sein du leadership de la santé dans le monde a un effet d'entraînement qui peut aboutir à une amélioration de l'état de santé dans le monde. Nous présentons des solutions pragmatiques et réalisables pour promouvoir et retenir des leaders féminins en matière de santé dans le monde.Los puestos directivos en materia de salud mundial se asignan de manera desproporcionada a los hombres; este desequilibrio es aun más notorio en los países de ingresos bajos y medianos. La subrepresentación de las mujeres en los cargos de responsabilidad pone en peligro la equidad entre los hombres y las mujeres y tiene además repercusiones en los resultados de salud de las mujeres en el mundo. En el presente artículo de opinión, se sostiene que promover a las mujeres a las funciones directivas relacionadas con la salud mundial y facilitar su permanencia en ellas genera una reacción en cadena que puede dar lugar a mejores resultados de salud a escala mundial. Se proponen soluciones viables y prácticas encaminadas a estimular la presencia de las mujeres en los cargos de responsabilidad en materia de salud mundial y a respaldar su permanencia en esta actividad.

© 2016 The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. Background. Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown. Methods. Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models. Results. Of 246 participants, 27% were overweight/obese (BMI, ≥ 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P =. 01), and the decreases in both CRP (P =. 01) and interleukin 18 (P =. 02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10increase in soluble CD14 level (P =. 05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P =. 001). Conclusions. Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation.

Human immunodeficiency virus (HIV-1) infection causes chronic inflammation. COX-2–derived prostaglandin E2 (PGE2) has been linked to both inflammation and carcinogenesis. We hypothesized that HIV-1 could induce COX-2 in cervical tissue and increase systemic PGE2 levels and that these alterations could play a role in AIDS-related cervical cancer. Levels of cervical COX-2 mRNA and urinary PGE-M, a biomarker of systemic PGE2 levels, were determined in 17 HIV-negative women with a negative cervical human papilloma virus (HPV) test, 18 HIV-infected women with a negative HPV test, and 13 HIV-infected women with cervical HPV and high-grade squamous intraepithelial lesions on cytology. Cervical COX-2 levels were significantly associated with HIV and HPV status (P = 0.006 and 0.002, respectively). Median levels of urinary PGE-M were increased in HIV-infected compared with uninfected women (11.2 vs. 6.8 ng/mg creatinine, P = 0.02). Among HIV-infected women, urinary PGE-M levels were positively correlated with plasma HIV-1 RNA levels (P = 0.003). Finally, levels of cervical COX-2 correlated with urinary PGE-M levels (P = 0.005). This study shows that HIV-1 infection is associated with increased cervical COX-2 and elevated systemic PGE2 levels. Drugs that inhibit the synthesis of PGE2 may prove useful in reducing the risk of cervical cancer or systemic inflammation in HIV-infected women. Cancer Prev Res; 5(1); 34–40. ©2011 AACR.

Background. Laboratory monitoring for toxicity among patients receiving antiretroviral therapy (ART) in less-developed settings is technically challenging and consumes significant resources. Methods. We conducted a cohort study of the 1800 adult patients who initiated ART at the Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO) in Haiti from 2003 to 2006, using baseline data to establish the prevalence and using follow-up data to establish the incidence of hepatitis, renal insufficiency, hyperglycemia, anemia, neutropenia, and thrombocytopenia. We determined how frequently routine (not symptom-driven) testing detected significant laboratory abnormalities and calculated the cost per disability-adjusted life year (DALY) averted by detection of these events in the asymptomatic stage, compared with a strategy of symptom-prompted testing only. Results. Forty-eight patients (3.5%) had severe anemia at baseline testing and consequently did not receive zidovudine. Fifty-three patients receiving zidovudine therapy developed severe anemia during follow-up (incidence, 2.5 cases/100 person-years). Monitoring for asymptomatic anemia with hematocrit testing was cost-saving at baseline and had a cost-effectiveness ratio of US$317/DALY averted during follow-up; with a complete blood count, costs increased to US$1182 and $10,781/DALY averted, respectively. With glucose monitoring, 11 patients were diagnosed with new-onset hyperglycemia during follow-up (incidence, 0.7 cases/100 person-years), resulting in a cost-effectiveness ratio of US$9845 per DALY averted. Monitoring for asymptomatic hepatitis and renal insufficiency was expensive and rarely affected care. Conclusions. Resource-poor countries should select which laboratory tests to perform on the basis of the cost-effectiveness of each test. This will depend on the national ART drug regimen and the prevalence of other comorbidities. Routine monitoring with multitest hematological and chemistry panels is unlikely to be cost-effective.

Background. We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings. Methods. We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4+ T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis. Results. Among 99 cases and 234 controls, median baseline CD4+ T-cell count was 181 cells/µL, and HIV RNA was 5.05 log10 cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27–7.20), sCD14 (IRR, 2.17; 95% CI, 1.02–4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01–0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated. Conclusions. Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.

Author(s): Balagopal, Ashwin; Asmuth, David M; Yang, Wei-Teng; Campbell, Thomas B; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R; Lalloo, Umesh G; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B; Semba, Richard D; Thomas, David L; Bollinger, Robert C; Gupta, Amita; ACTG PEARLS and NWCS 319 Study team | Abstract: BACKGROUND:Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. METHODS:A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count l300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. RESULTS:Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). CONCLUSIONS:Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts l300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.

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

SETTING Port-au-Prince, Haiti. OBJECTIVE To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was

A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (&lt, 85 μg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 μg/L (Interquartile range (IQR): 57.28–99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86–95.10 μg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50, 95% confidence intervals (CI): 1.30–9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium.

BACKGROUND Treatment protocols and prices of antiretroviral therapy (ART) have changed over time. Yet, limited data exist to evaluate the impact of these changes on patient outcomes and treatment costs in resource-poor settings. METHODS We compared patient-level data on outcomes, utilization, and cost for the first 2 years of ART for a cohort of adult patients initiating ART in 2003-2004 and a cohort initiating ART in 2006-2008 at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections clinic (GHESKIO) in Port-au-Prince, Haiti. Costs were measured from the health center perspective. Multivariate analyses were conducted to account for the potential impact of differences in disease severity at baseline. RESULTS With the exclusion of patients who transferred care, 92% (167/181) of patients in the 2006-2008 cohort and 75% (150/200) in the 2003-2004 cohort were alive and in care at the end of the study period. The mean cost per patient for the 2-year study period was US$723 for the 2006-2008 cohort vs. US$1191 for the 2003-2004 cohort, a cost difference of US$468 (P < 0.0001). The mean cost per patient alive and in care at the end of the 2-year study period was US$744 for the 2006-2008 cohort vs. US$1489 for the 2003-2004 cohort (P < 0.0001). CONCLUSIONS HIV treatment outcomes in Haiti have improved over time while treatment costs declined by over 50% per patient alive and in care at the end of the 2-year study period. The major drivers in the reduction of treatment costs were the lower price of ART, lower costs for laboratory testing, and lower overhead costs.

We analyzed mortality among 201 patients with AIDS and tuberculosis in Haiti. Patients who received a diagnosis of tuberculosis during the first 3 months after the initiation of antiretroviral therapy were 3.25 times more likely to die than were other patients with AIDS and tuberculosis. Failure to recognize active tuberculosis at initiation of antiretroviral therapy leads to increased mortality.

BACKGROUND Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. METHODS This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. RESULTS Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). CONCLUSIONS TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study.

Haiti has some of the most challenging sociopolitical and economic problems in the world. The country has been affected by political instability and recurrent natural disasters (1, 2). It is also one of the countries most affected by HIV/AIDS and tuberculosis (TB) (3). Operational research has been essential to mount a successful response against these diseases. In 1982, the Haitian Study Group on Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO) was created with a mission of conducting operational research, training, and patient care for HIV/AIDS and associated infections. Thirty-one years later, Dr. Kathleen Sebelius, the US Health and Human Services Secretary, and Dr. Florence Guillaume, the Haitian Minister of Health (MOH), summarized the role played by GHESKIO in Haiti by saying: “We expect GHESKIO to develop public health models that can be scaled-up at the national level.” How did GHESKIO acquire these credentials?

This cost-effectiveness study comparing early versus standard antiretroviral treatment (ART) for HIV, based on randomized clinical trial data from Haiti, reveals that the new WHO guidelines for early ART initiation can be cost-effective in resource-poor settings., Background In a randomized clinical trial of early versus standard antiretroviral therapy (ART) in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, early ART decreased mortality by 75%. We assessed the cost-effectiveness of early versus standard ART in this trial. Methods and Findings Trial data included use of ART and other medications, laboratory tests, outpatient visits, radiographic studies, procedures, and hospital services. Medication, laboratory, radiograph, labor, and overhead costs were from the study clinic, and hospital and procedure costs were from local providers. We evaluated cost per year of life saved (YLS), including patient and caregiver costs, with a median of 21 months and maximum of 36 months of follow-up, and with costs and life expectancy discounted at 3% per annum. Between 2005 and 2008, 816 participants were enrolled and followed for a median of 21 months. Mean total costs per patient during the trial were US$1,381 for early ART and US$1,033 for standard ART. After excluding research-related laboratory tests without clinical benefit, costs were US$1,158 (early ART) and US$979 (standard ART). Early ART patients had higher mean costs for ART (US$398 versus US$81) but lower costs for non-ART medications, CD4 cell counts, clinically indicated tests, and radiographs (US$275 versus US$384). The cost-effectiveness ratio after a maximum of 3 years for early versus standard ART was US$3,975/YLS (95% CI US$2,129/YLS–US$9,979/YLS) including research-related tests, and US$2,050/YLS excluding research-related tests (95% CI US$722/YLS–US$5,537/YLS). Conclusions Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS, Editors' Summary Background AIDS has killed more than 25 million people since 1981, and about 33 million people (most of them living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available and, for people living in affluent countries HIV/AIDS became a chronic condition. However, ART was extremely expensive and so a diagnosis of HIV infection remained a death sentence for people living in developing countries. In 2003, this situation was declared a global health emergency, and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. In 2009, more than a third of people in low- and middle-income countries who needed ART were receiving it, on the basis of guidelines that were in place at that time. Why Was This Study Done? Until recently, the World Health Organization (WHO) recommended that all HIV-positive patients with CD4 cell count below 200/mm3 blood or an AIDS-defining illness such as Kaposi's sarcoma should be given ART. Then, in 2009, the CIPRA HT-001 randomized clinical trial, which was undertaken in Haiti, reported that patients who started ART when their CD4 cell count was between 200 and 350 cells/mm3 (“early ART”) had a higher survival rate than patients who started ART according to the WHO guidelines (“standard ART”). As a result, WHO now recommends that ART is started in HIV-infected people when their CD4 cell count falls below 350 cells/mm3. But is this new recommendation cost-effective? Do its benefits outweigh its costs? Policy-makers need to know the cost-effectiveness of interventions so that they can allocate their limited resources wisely. A medical intervention is generally considered cost-effective if it costs less than three times a country's per capita gross domestic product (GDP) per year of life saved (YLS). In this study, the researchers assess the cost-effectiveness of early versus standard ART in the CIPRA HT-001 trial. What Did the Researchers Do and Find? The researchers used trial data on the use and costs of ART, other medications, laboratory tests, outpatient visits, radiography, procedures, and hospital services to evaluate the costs associated with early ART and standard ART among the 816 CIPRA HT-001 trial participants. The average total costs per patient after a maximum of 3 years treatment were US$1,381 for early ART and US$1,033 for standard ART. These figures dropped to US$1,158 and US$979, respectively, when the costs of research-related tests without clinical benefit were excluded. Patients who received early ART had higher average costs for ART but lower costs for other aspects of their treatment than patients who received standard ART. The incremental cost-effectiveness ratio after 3 years for early ART compared to standard ART was US$3,975/YLS if the costs of research-related tests were included in the calculation. That is, the cost of saving one year of life by starting ART early instead of when the CD4 cell count dropped below 200/mm3 was nearly US$4,000. Importantly, exclusion of the costs of research-related tests reduced the incremental cost-effectiveness ratio of early ART compared to standard ART to US$2,050/YLS. What Do These Findings Mean? Because the Haitian GDP per capita is US$785, these findings suggest that, in Haiti, early ART is a cost-effective intervention over a 3-year period. That is, the incremental cost per year of life saved of early ART compared to standard ART after exclusion of research-related tests is less than three times Haiti's per capita GDP. The researchers note that their incremental cost-effectiveness ratios are likely to be conservative because they did not consider the clinical benefits of early ART that continue beyond 3 years—early ART is associated with lower longer-term mortality than standard ART—or the effect of early ART on disability and quality of life. Cost-effectiveness studies now need to be undertaken at different sites to determine whether these findings are generalizable but, for now, this cost-effectiveness study suggests that the new WHO guidelines for ART initiation can be cost-effective in resource-poor settings, information that should help policy-makers in developing countries allocate their limited resources. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001095. Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS HIV InSite has comprehensive information on all aspects of HIV/AIDS Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV/AIDS in the Caribbean, and on HIV/AIDS treatment and care (in English and Spanish) WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded More information about the CIPRA HT-001 clinical trial is available Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline More information about GHESKIO is available from Weill Cornell Global Health

OBJECTIVE: To assess outcomes after antiretroviral therapy (ART) in adolescents and youth in Haiti, a country with a generalized epidemic of infection with HIV-1. METHODS: An assessment was made of survival, plasma HIV-1 ribonucleic acid (RNA) concentrations and HIV-1 drug resistance patterns after 12 months of ART in patients aged 13-25 years who presented to a clinic in Port-au-Prince, Haiti, with AIDS between 1 March 2003 and 31 December 2005. Participants received ART in accordance with WHO guidelines. Kaplan-Meier analysis was used to estimate survival probabilities and their 95% confidence intervals (CI) for the period from ART initiation to death. FINDINGS: Of a total of 146 patients, 96 (66%) were female; the median CD4+ T-cell count at baseline was 129 cells/ml. By Kaplan-Meier analysis, 13% of the patients had died at 12 months, 17% at 24 months and 20% at 36 months. A plasma HIV-1 RNA concentration > 50 copies/ml was seen in 40 (51%) of 79 patients 12 months after treatment initiation and was associated with poor ART adherence. Among 29 patients with > 1000 copies/ml at 12 months, resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 23 cases (79%); to both NNRTIs and lamivudine in 21 (72%) cases; and to NNRTIs, lamivudine and other nucleoside reverse transcriptase inhibitors in 10 (35%) cases. One hundred and six participants (73%) reported sexual intercourse without condoms, and 35 of the 96 women (36%) were pregnant during follow-up. CONCLUSION: Adolescents and youth with AIDS receiving ART are at risk of virologic failure and disease progression and can therefore transmit HIV-1 to sexual partners and infants. Strategies to target the special needs of this age group are urgently needed.

Background We determined direct medical costs, overhead costs, societal costs, and personnel requirements for the provision of antiretroviral therapy (ART) to patients with AIDS in Haiti. Methods We examined data from 218 treatment-naïve adults who were consecutively initiated on ART at the GHESKIO Center in Port-au-Prince, Haiti between December 23, 2003 and May 20, 2004 and calculated costs and personnel requirements for the first year of ART. Results The mean total cost of treatment per patient was $US 982 including $US 846 in direct costs, $US 114 for overhead, and $US 22 for societal costs. The direct cost per patient included generic ART medications $US 355, lab tests $US 130, nutrition $US 117, hospitalizations $US 62, pre-ART evaluation $US 58, labor $US 51, non-ART medications $US 39, outside referrals $US 31, and telephone cards for patient retention $US 3. Higher treatment costs were associated with hospitalization, change in ART regimen, TB treatment, and survival for one year. We estimate that 1.5 doctors and 2.5 nurses are required to treat 1000 patients in the first year after initiating ART. Conclusion Initial ART treatment in Haiti costs approximately $US 1,000 per patient per year. With generic first-line antiretroviral drugs, only 36% of the cost is for medications. Patients who change regimens are significantly more expensive to treat, highlighting the need for less-expensive second-line drugs. There may be sufficient health care personnel to treat all HIV-infected patients in urban areas of Haiti, but not in rural areas. New models of HIV care are needed for rural areas using assistant medical officers and community health workers.