Derivation and external validation of a risk score for predicting HIV-associated tuberculosis to support case finding and preventive therapy scale-up: A cohort study.

BACKGROUND: Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV-TB care. METHODS AND FINDINGS: We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/µL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/µL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) <18.5kg/m2 (2 points), and severe anemia (hemoglobin <8g/dL) (3 points). Sensitivity using WHO 4-symptom TB screen was 73%, 80%, 94%, and 94% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, but increased to 88%, 87%, 97%, and 97%, when a clinical score of ≥2 was used. Negative predictive value (NPV) also increased 1%, 0.3%, 1.6%, and 1.7% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, when the clinical score of ≥2 replaced WHO 4-symptom TB screen. Categorizing risk scores into low (<2), moderate (2 to 10), and high-risk categories (>10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. CONCLUSIONS: The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV-TB care to maximize impact of available resources.

Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial.

BACKGROUND: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. METHODS: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. RESULTS: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/µL in SOC, 246/µL in EC, and 241/µL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. CONCLUSIONS: Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. TRIAL REGISTRATION: Retrospectively registered: ClinicalTrials.gov (NCT02538952).

Risk scores for predicting early antiretroviral therapy mortality in sub-Saharan Africa to inform who needs intensification of care: a derivation and external validation cohort study.

BACKGROUND: Clinical scores to determine early (6-month) antiretroviral therapy (ART) mortality risk have not been developed for sub-Saharan Africa (SSA), home to 70% of people living with HIV. In the absence of validated scores, WHO eligibility criteria (EC) for ART care intensification are CD4 < 200/µL or WHO stage III/IV. METHODS: We used Botswana XPRES trial data for adult ART enrollees to develop CD4-independent and CD4-dependent multivariable prognostic models for 6-month mortality. Scores were derived by rescaling coefficients. Scores were developed using the first 50% of XPRES ART enrollees, and their accuracy validated internally and externally using South African TB Fast Track (TBFT) trial data. Predictive accuracy was compared between scores and WHO EC. RESULTS: Among 5553 XPRES enrollees, 2838 were included in the derivation dataset; 68% were female and 83 (3%) died by 6 months. Among 1077 TBFT ART enrollees, 55% were female and 6% died by 6 months. Factors predictive of 6-month mortality in the derivation dataset at p < 0.01 and selected for the CD4-independent score included male gender (2 points), ≥ 1 WHO tuberculosis symptom (2 points), WHO stage III/IV (2 points), severe anemia (hemoglobin < 8 g/dL) (3 points), and temperature > 37.5 °C (2 points). The same variables plus CD4 < 200/µL (1 point) were included in the CD4-dependent score. Among XPRES enrollees, a CD4-independent score of ≥ 4 would provide 86% sensitivity and 66% specificity, whereas WHO EC would provide 83% sensitivity and 58% specificity. If WHO stage alone was used, sensitivity was 48% and specificity 89%. Among TBFT enrollees, the CD4-independent score of ≥ 4 would provide 95% sensitivity and 27% specificity, whereas WHO EC would provide 100% sensitivity but 0% specificity. Accuracy was similar between CD4-independent and CD4-dependent scores. Categorizing CD4-independent scores into low (< 4), moderate (4-6), and high risk (≥ 7) gave 6-month mortality of 1%, 4%, and 17% for XPRES and 1%, 5%, and 30% for TBFT enrollees. CONCLUSIONS: Sensitivity of the CD4-independent score was nearly twice that of WHO stage in predicting 6-month mortality and could be used in settings lacking CD4 testing to inform ART care intensification. The CD4-dependent score improved specificity versus WHO EC. Both scores should be considered for scale-up in SSA.

Implementation of a pragmatic, stepped-wedge cluster randomized trial to evaluate impact of Botswana's Xpert MTB/RIF diagnostic algorithm on TB diagnostic sensitivity and early antiretroviral therapy mortality.

BACKGROUND: In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package". METHODS: The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ≤52.5 % and post-Xpert sensitivity ≥82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ≥13/100 person-years. DISCUSSION: Only one small previous trial (N = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov: NCT02538952 .

Antiretroviral therapy enrollment characteristics and outcomes among HIV-infected adolescents and young adults compared with older adults--seven African countries, 2004-2013.

Although scale-up of antiretroviral therapy (ART) since 2005 has contributed to declines of about 30% in the global annual number of human immunodeficiency (HIV)-related deaths and declines in global HIV incidence, estimated annual HIV-related deaths among adolescents have increased by about 50% and estimated adolescent HIV incidence has been relatively stable. In 2012, an estimated 2,500 (40%) of all 6,300 daily new HIV infections occurred among persons aged 15-24 years. Difficulty enrolling adolescents and young adults in ART and high rates of loss to follow-up (LTFU) after ART initiation might be contributing to mortality and HIV incidence in this age group, but data are limited. To evaluate age-related ART retention challenges, data from retrospective cohort studies conducted in seven African countries among 16,421 patients, aged ≥15 years at enrollment, who initiated ART during 2004-2012 were analyzed. ART enrollment and outcome data were compared among three groups defined by age at enrollment: adolescents and young adults (aged 15-24 years), middle-aged adults (aged 25-49 years), and older adults (aged ≥50 years). Enrollees aged 15-24 years were predominantly female (81%-92%), commonly pregnant (3%-32% of females), unmarried (54%-73%), and, in four countries with employment data, unemployed (53%-86%). In comparison, older adults were more likely to be male (p<0.001), employed (p<0.001), and married, (p<0.05 in five countries). Compared with older adults, adolescents and young adults had higher LTFU rates in all seven countries, reaching statistical significance in three countries in crude and multivariable analyses. Evidence-based interventions to reduce LTFU for adolescent and young adult ART enrollees could help reduce mortality and HIV incidence in this age group.

Randomized controlled trial of an intervention to prevent adherence failure among HIV-infected patients initiating antiretroviral therapy.

OBJECTIVE: Compare the efficacy of a multicomponent social support intervention to standard-of-care counseling on medication adherence among HIV-infected patients initiating antiretroviral therapy. DESIGN: Randomized controlled trial. Generalized estimating equations tested for differences in the percentage of participants achieving 90% adherence. MAIN OUTCOME MEASURES: Pill-taking, electronically monitored over 6 consecutive months; plasma viral load (VL), assessed at 3 and 6 months following initiation of therapy. RESULTS: Of 226 participants who were randomized and began the trial, 87 (38%) were lost to the study by 6 months. The proportion of adherent participants declined steadily over time, with no time by group interaction. Sustained adherence was associated with increased odds of achieving an undetectable VL (OR=1.78; 95% CI=1.01, 3.13). In intention-to-treat analyses, a larger proportion of the intervention group than the control group was adherent (40.15% vs. 27.59%, p=.02) and achieved an undetectable VL p=.04). However, the majority of participants who remained on study experienced some reduction in VL (>or=1-log drop or undetectable), regardless of experimental condition. CONCLUSION: The multicomponent social support intervention significantly improved medication adherence over standard-of-care counseling; evidence for improved virologic outcomes was inconsistent. Early discontinuation of care and treatment may be a greater threat to the health of HIV patients than imperfect medication-taking.

High rates of loss to follow-up during the first year of pre-antiretroviral therapy for HIV patients at sites providing pre-ART care in Nigeria, 2004-2012.

BACKGROUND: With about 3.4 million HIV-infected persons, Nigeria has the second highest number of people living with HIV (PLHIV) in the world. However, antiretroviral treatment (ART) coverage in Nigeria remains low with only 748,846 (22%) of PLHIV on ART by the end of 2014. Retention of HIV-infected patients in pre-ART care is essential to ensure timely ART initiation. We assessed outcomes of patients enrolled in Nigeria's pre-ART program during 2004-2012. METHODS: We conducted a nationally representative retrospective cohort study among adults (≥15 years old), enrolling in pre-ART programs supported by the U.S. President's Emergency Plan for AIDS Relief in Nigeria. A total of 35 sites enrolling ≥50 patients in pre-ART were selected using probability proportional-to-size sampling; 2,415 eligible medical records at these sites were randomly selected for abstraction. Determinants of loss to follow-up (LTFU) and mortality during pre-ART care were estimated using Cox proportional hazards regression models. RESULTS: The median age at enrollment was 32 years (interquartile range (IQR) 27-40). A total of 1,216 (51.4%) initiated ART by the time of data abstraction. Among the remaining 1,199 patients, 898 (74.9%) had been LTFU, 180 (15.0%) were alive and in pre-ART care, 71 (5.9%) had died, 50 (4.2%) had transferred out or stopped care. Baseline markers of advanced disease, including weight <45 kg (adjusted hazard ration (AHR) = 4.23; 95% confidence interval (CI): 1.51-15.58) and more advanced WHO disease stage, were predictive of pre-ART mortality. Compared with patients aged 15-24, patients aged 35-44 (AHR = 0.67; 95% CI: 1.0.47-0.95) and age 45-54 (AHR = 0.66; 95% CI: 0.48-0.91) had lower LTFU rates. Compared with attending facilities in North Central geopolitical zone, attending facility locations in South East (AHR = 0.44; 95% CI: 0.24-0.83) was protective against LTFU. CONCLUSIONS: About half of patients enrolling in HIV program during 2004-2012 in Nigeria had not initiated ART by 2013. Key strategies to improve early ART initiation among pre-ART enrollees include implementation of the WHO test and treat guidelines, earlier HIV testing, and better monitoring to improve ART initiation rates. Further research to understand regional variations in pre-ART outcomes is warranted.

Correction: Outcomes of Nigeria's HIV/AIDS Treatment Program for Patients Initiated on Antiretroviral Treatment between 2004-2012.

[This corrects the article DOI: 10.1371/journal.pone.0165528.].

Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes.

CONTEXT: The Zambian Ministry of Health has scaled-up human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care and treatment services at primary care clinics in Lusaka, using predominately nonphysician clinicians. OBJECTIVE: To report on the feasibility and early outcomes of the program. DESIGN, SETTING, AND PATIENTS: Open cohort evaluation of antiretroviral-naive adults treated at 18 primary care facilities between April 26, 2004, and November 5, 2005. Data were entered in real time into an electronic patient tracking system. INTERVENTION: Those meeting criteria for antiretroviral therapy (ART) received drugs according to Zambian national guidelines. MAIN OUTCOME MEASURES: Survival, regimen failure rates, and CD4 cell response. RESULTS: We enrolled 21,755 adults into HIV care, and 16,198 (75%) started ART. Among those starting ART, 9864 (61%) were women. Of 15,866 patients with documented World Health Organization (WHO) staging, 11,573 (73%) were stage III or IV, and the mean (SD) entry CD4 cell count among the 15,336 patients with a baseline result was 143/microL (123/microL). Of 1142 patients receiving ART who died, 1120 had a reliable date of death. Of these patients, 792 (71%) died within 90 days of starting therapy (early mortality rate: 26 per 100 patient-years), and 328 (29%) died after 90 days (post-90-day mortality rate: 5.0 per 100 patient-years). In multivariable analysis, mortality was strongly associated with CD4 cell count between 50/microL and 199/microL (adjusted hazard ratio [AHR], 1.4; 95% confidence interval [CI], 1.0-2.0), CD4 cell count less than 50/microL (AHR, 2.2; 95% CI, 1.5-3.1), WHO stage III disease (AHR, 1.8; 95% CI, 1.3-2.4), WHO stage IV disease (AHR, 2.9; 95% CI, 2.0-4.3), low body mass index (<16; AHR,2.4; 95% CI, 1.8-3.2), severe anemia (<8.0 g/dL; AHR, 3.1; 95% CI, 2.3-4.0), and poor adherence to therapy (AHR, 2.9; 95% CI, 2.2-3.9). Of 11,714 patients at risk, 861 failed therapy by clinical criteria (rate, 13 per 100 patient-years). The mean (SD) CD4 cell count increase was 175/microL (174/microL) in 1361 of 1519 patients (90%) receiving treatment long enough to have a 12-month repeat. CONCLUSION: Massive scale-up of HIV and AIDS treatment services with good clinical outcomes is feasible in primary care settings in sub-Saharan Africa. Most mortality occurs early, suggesting that earlier diagnosis and treatment may improve outcomes.

HIV/AIDS care and treatment in three provinces in northern Thailand before the national scale-up of highly-active antiretroviral therapy.

In 2003, Thailand launched a program to place 50,000 persons on highly active antiretroviral therapy (HAART) by the end of 2004, following a series of efforts since the early 1990s to develop comprehensive HIV/AIDS care services. To evaluate existing services and needs in advance of the national HAART scale-up, in 2002 we surveyed 31 hospitals and 389 community health centers in three northern Thai provinces, and interviewed 1,015 HIV-infected patients attending outpatient clinics. All hospitals offered voluntary HIV counseling and testing, 84% provided primary prophylaxis for Pneumocystis carinii pneumonia, 58% for tuberculosis, 39% for cryptococcal meningitis, and 87% had some experience providing antiretroviral therapy. Community health centers provided more limited service coverage. Of patients interviewed, 63% had been diagnosed with symptomatic HIV disease, and of these, 32% reported ever receiving antiretroviral therapy; 51 % of all patients had received a CD4 T-lymphocyte count. Thailand's current national HAART scale-up is being performed in a setting of well-developed hospital-based services introduced over the course of the epidemic.

Decentralizing Access to Antiretroviral Therapy for Children Living with HIV in Swaziland.

BACKGROUND: In 2007, Swaziland initiated a hub-and-spoke model for decentralizing antiretroviral therapy (ART) access for HIV-infected children (<15 years old). Decentralization was facilitated through (1) down referral of stable children on ART from overburdened central facilities (hubs) to primary healthcare clinics (spokes) and (2) pediatric ART initiation at spokes (spoke initiation). METHODS: We conducted a nationally representative retrospective cohort study among children starting ART during 2004-2010 to assess effect of down referral and spoke initiation on rates of loss to follow-up (LTFU), death and attrition (death or LTFU). Twelve of 28 pediatric ART hubs were randomly selected using probability-proportional-to-size sampling. Seven selected facilities had initiated hub-and-spoke decentralization by study start; at these facilities, 901 of 1893 hub-initiated and maintained (hub-maintained) children and 495 of 1105 down-referred or spoke-initiated children were randomly selected for record abstraction. At the 5 hub-only facilities, 612 of 1987 children were randomly selected. Multivariable proportional hazards regression was used to estimate adjusted hazard ratios (AHR) for effect of down referral (a time-varying covariate) and spoke initiation on outcomes. RESULTS: Among 2008 children at ART initiation, median age was 5.0 years, median CD4% 12.0%, median CD4 count 358 cells/µL and median weight-for-age Z score -1.91. Controlling for known confounders, down referral was strongly protective against LTFU (AHR: 0.40; 95% confidence interval: 0.20-0.79) and attrition (AHR: 0.46; 95% confidence interval: 0.26-0.83) but not mortality. Compared with hub-only children or hub-maintained children, spoke-initiated children had similar outcomes. CONCLUSIONS: Decentralization of pediatric ART through down referral and spoke initiation within a hub-and-spoke system should be continued and might improve program outcomes.

A Decade of Antiretroviral Therapy Scale-up in Mozambique: Evaluation of Outcome Trends and New Models of Service Delivery Among More Than 300,000 Patients Enrolled During 2004-2013.

BACKGROUND: During 2004-2013 in Mozambique, 455,600 HIV-positive adults (≥15 years old) initiated antiretroviral therapy (ART). We evaluated trends in patient characteristics and outcomes during 2004-2013, outcomes of universal treatment for pregnant women (Option B+) implemented since 2013, and effect on outcomes of distributing ART to stable patients through Community ART Support Groups (CASG) since 2010. METHODS: Data for 306,335 adults starting ART during 2004-2013 at 170 ART facilities were analyzed. Mortality and loss to follow-up (LTFU) were estimated using competing risks models. Outcome determinants were estimated using proportional hazards models, including CASG participation as a time-varying covariate. RESULTS: Compared with ART enrollees in 2004, enrollees in 2013 were more commonly female (55% vs. 73%), more commonly pregnant if female (<1% vs. 30%), and had a higher median baseline CD4 count (139 vs. 235/µL). During 2004-2013, observed 6-month mortality declined from 7% to 2% but LTFU increased from 24% to 30%. Pregnant women starting ART with CD4 count >350/µL and WHO stage I/II under Option B+ guidelines in 2013 had low 6-month mortality (0.1%) but high 6-month LTFU (38%). During 2010-2013, 6766 patients joined CASGs. In multivariable analysis, compared with nonparticipation in CASG, CASG participation was associated with 35% lower LTFU but similar mortality. CONCLUSIONS: Initiation of ART at earlier disease stages in later calendar years might explain observed declines in mortality. Retention interventions are needed to address trends of increasing LTFU overall and the high LTFU among Option B+ pregnant women specifically. Further expansion of CASG could help reduce LTFU.

Outcomes of Nigeria's HIV/AIDS Treatment Program for Patients Initiated on Antiretroviral Treatment between 2004-2012.

BACKGROUND: The Nigerian Antiretroviral therapy (ART) program started in 2004 and now ranks among the largest in Africa. However, nationally representative data on outcomes have not been reported. METHODS: We evaluated retrospective cohort data from a nationally representative sample of adults aged ≥15 years who initiated ART during 2004 to 2012. Data were abstracted from 3,496 patient records at 35 sites selected using probability-proportional-to-size (PPS) sampling. Analyses were weighted and controlled for the complex survey design. The main outcome measures were mortality, loss to follow-up (LTFU), and retention (the proportion alive and on ART). Potential predictors of attrition were assessed using competing risk regression models. RESULTS: At ART initiation, 66.4 percent (%) were females, median age was 33 years, median weight 56 kg, median CD4 count 161 cells/mm3, and 47.1% had stage III/IV disease. The percentage of patients retained at 12, 24, 36 and 48 months was 81.2%, 74.4%, 67.2%, and 61.7%, respectively. Over 10,088 person-years of ART, mortality, LTFU, and overall attrition (mortality, LTFU, and treatment stop) rates were 1.1 (95% confidence interval (CI): 0.7-1.8), 12.3 (95%CI: 8.9-17.0), and 13.9 (95% CI: 10.4-18.5) per 100 person-years (py) respectively. Highest attrition rates of 55.4/100py were witnessed in the first 3 months on ART. Predictors of LTFU included: lower-than-secondary level education (reference: Tertiary), care in North-East and South-South regions (reference: North-Central), presence of moderate/severe anemia, symptomatic functional status, and baseline weight <45kg. Predictor of mortality was WHO stage higher than stage I. Male sex, severe anemia, and care in a small clinic were associated with both mortality and LTFU. CONCLUSION: Moderate/Advanced HIV disease was predictive of attrition; earlier ART initiation could improve program outcomes. Retention interventions targeting men and those with lower levels of education are needed. Further research to understand geographic and clinic size variations with outcome is warranted.

Wide Variations in Compliance with Tuberculosis Screening Guidelines and Tuberculosis Incidence between Antiretroviral Therapy Facilities - Côte d'Ivoire.

BACKGROUND: In Côte d'Ivoire, tuberculosis (TB) is a common cause of death among HIV-infected antiretroviral therapy (ART) enrollees. Ivorian guidelines recommend screening for TB and initiation of TB treatment before ART initiation. Compliance with these guidelines can help reduce TB-related mortality during ART and possibly nosocomial TB transmission. METHODS AND FINDINGS: In a retrospective cohort study among 3,682 randomly selected adults (≥15 years old) starting ART during 2004-2007 at 34 randomly selected facilities, documentation of TB screening completion, prevalence of active TB at ART initiation, and incidence of TB during ART were evaluated. At ART initiation, median age was 36 years, 67% were female, and median CD4 count was 135 cells/µL. Among all 3,682 enrollees, 73 (2%) were on TB treatment at the time of referral to the ART facility. Among the 3,609 not on TB treatment, 1,263 (36%) were documented to receive some TB screening before ART initiation; 21% were screened for cough, 21% for weight loss, 18% for fever, 18% for TB contacts, and 12% for night sweats. Among the 1,263 screened, 111 (11%) were diagnosed with TB and started TB treatment before ART. No associations between patient characteristics and probability of being screened were noted. However, documentation of TB screening completion before ART varied widely by ART facility from 0-100%. TB incidence during ART was 3.0 per 100 person-years but varied widely by ART facility from 0/100 person-year to 13.1/100 person-years. CONCLUSIONS: Screening for TB before ART initiation was poorly documented. Facility-level variations in TB screening documentation suggest facility-level factors, such as investment in training programs, might determine documentation practices. Targeting under-performing ART facilities with improvement activities is needed. Variations among facilities in TB incidence warrant further research. These incidence variations could reflect differences between facilities in TB screening, diagnostic tests, documentation practices, or TB risk possibly related to infection control practices or local community TB incidence.

Temporal Trends in Patient Characteristics and Outcomes Among Children Enrolled in Mozambique's National Antiretroviral Therapy Program.

BACKGROUND: During 2004-2009, >12,000 children (<15 years old) initiated antiretroviral therapy (ART) in Mozambique. Nationally representative outcomes and temporal trends in outcomes were investigated. METHODS: Rates of death, loss to follow-up (LTFU) and attrition (death or LTFU) were evaluated in a nationally representative sample of 1054 children, who initiated ART during 2004-2009 at 25 facilities randomly selected using probability-proportional-to-size sampling. RESULTS: At ART initiation during 2004-2009, 50% were male; median age was 3.3 years; median CD4% was 13%; median CD4 count was 375 cells/µL; median weight-for-age Z score was -2.1. During 2004-2009, median time from HIV diagnosis to care initiation declined from 33 to 0 days (P = 0.001); median time from care to ART declined from 93 to 62 days (P = 0.004); the percentage aged <2 at ART initiation increased from 16% to 48% (P = 0.021); the percentage of patients with prior tuberculosis declined from 50% to 10% (P = 0.009); and the percentage with prior lymphocytic interstitial pneumonia declined from 16% to 1% (P < 0.001). Over 2652 person-years of ART, 183 children became LTFU and 26 died. Twelve-month attrition was 11% overall but increased from 3% to 22% during 2004-2009, mainly because of increases in 12-month LTFU (from 3% to 18%). CONCLUSION: Declines in the prevalence of markers of advanced HIV disease at ART initiation probably reflect increasing ART access. However, 12-month LTFU increased during program expansion, and this negated any program improvements in outcomes that might have resulted from earlier ART initiation.

Implementation and Operational Research: Evaluation of Swaziland's Hub-and-Spoke Model for Decentralizing Access to Antiretroviral Therapy Services.

BACKGROUND: In 2007, Swaziland initiated a hub-and-spoke model for decentralizing antiretroviral therapy (ART) access. Decentralization was facilitated through (1) down-referral of stable ART patients from overburdened central facilities (hubs) to primary health care clinics (spokes) and (2) ART initiation at spokes (spoke initiation). METHODS: We conducted a nationally representative retrospective cohort study among adult ART enrollees during 2004-2010 to assess the effect of down-referral and spoke-initiation on rates of loss to follow-up (LTFU), death, and attrition (death or LTFU). Sixteen of 31 hubs were randomly selected using probability-proportional-to-size sampling. Seven selected facilities had initiated the hub-and-spoke model by study start. At these facilities, 1149 of 24,782 hub-initiated and maintained and 878 of 7722 down-referred or spoke-initiated patient records were randomly selected and analyzed. At the 9 hub-only facilities, 483 of 6638 records were randomly selected and analyzed. Multivariable proportional hazards regression was used to assess effect of down-referral (a time-varying covariate) and spoke-initiation on outcomes. RESULTS: At ART initiation, median age was 35, 65% were female, and median CD4 count was 147 cells per microliter. Controlling for known confounders, down-referral was strongly protective against LTFU [adjusted hazard ratio (AHR) 0.38; 95% confidence interval (CI): 0.29 to 0.50] and attrition (AHR = 0.50; 95% CI: 0.34 to 0.76) but not mortality. Compared with hub-initiated and maintained patients, spoke-initiated patients had lower LTFU (AHR 0.59; 95% CI: 0.45 to 0.77) and attrition rates (AHR 0.60; 95% CI: 0.47 to 0.77), but not mortality. CONCLUSIONS: Down-referral and spoke-initiation within a hub-and-spoke ART decentralization model were protective against LTFU and overall attrition and could facilitate future ART program expansion.

Temporal trends in treatment outcomes for HIV-1 and HIV-2-infected adults enrolled in Côte d'Ivoire's national antiretroviral therapy program.

BACKGROUND: In Côte d'Ivoire during 2004-2007, numbers of ART enrollees increased from <5,000 to 36,943. Trends in nationally representative ART program outcomes have not yet been reported. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective chart review to assess trends in patient characteristics and attrition [death or loss to follow-up (LTFU)] over time, among a nationally representative sample of 3,682 adults (≥15 years) initiating ART during 2004-2007 at 34 health facilities. Among ART enrollees during 2004-2007, median age was 36, the proportion female was 67%, the proportion HIV-2-infected or dually HIV-1&2 reactive was 5%, and median baseline CD4+ T-cell (CD4) count was 135 cells/µL. Comparing cohorts initiating ART in 2004 with cohorts initiating ART in 2007, median baseline weight declined from 55 kg to 52 kg (p = 0.008) and the proportion weighing <45 kg increased from 17% to 22% (p = 0.014). During 2004-2007, pharmacy-based estimates of the percentage of new ART enrollees ≥95% adherent to ART declined from 74% to 60% (p = 0.026), and twelve-month retention declined from 86% to 69%, due to increases in 12-month mortality from 2%-4% and LTFU from 12%-28%. In univariate analysis, year of ART initiation was associated with increasing rates of both LTFU and mortality. Controlling for baseline CD4, weight, adherence, and other risk factors, year of ART initiation was still strongly associated with LTFU but not mortality. In multivariate analysis, weight <45 kg and adherence <95% remained strong predictors of LTFU and mortality. CONCLUSIONS: During 2004-2007, increasing prevalence among ART enrollees of measured mortality risk factors, including weight <45 kg and ART adherence <95%, might explain increases in mortality over time. However, the association between later calendar year and increasing LTFU is not explained by risk factors evaluated in this analysis. Undocumented transfers, political instability, and patient dissatisfaction with crowded facilities might explain increasing LTFU.

Temporal trends in mortality and loss to follow-up among children enrolled in Côte d'Ivoire's national antiretroviral therapy program.

BACKGROUND: During 2004-2008, >2000 children (<15 years old) initiated antiretroviral therapy (ART) in Côte d'Ivoire. Nationally representative outcomes, temporal trends in outcomes during 2004-2008 and site-level outcome determinants have not been investigated. METHODS: Incidence rates of death, loss to follow-up (LTFU) and attrition (death or LTFU) were evaluated in a nationally representative, retrospective cohort study among 2,110 children, who initiated ART at 29 facilities in Côte d'Ivoire during 2004-2008. RESULTS: At ART initiation, 54% were male, 1% was HIV-2-infected and median age was 5.1 years. Median CD4% was 11%, and 61% had weight-for-age Z-score (WAZ) ≤-2. Vaccination completion was documented for 9% of children. Eleven of 29 facilities had an integrated nutrition program. Over 4585 person-years of ART, 237 children died and 427 became LTFU. Twelve-month attrition was 22% overall, but increased from 4% to 34% during 2004-2008, due to increases in 12-month mortality (from 3-11%) and 12-month LTFU (from 2% to 23%). In adjusted analysis, compared with enrollees in 2004, enrollees in 2008 had nearly 4-fold higher mortality and 8-fold higher LTFU. World Health Organization stage III/IV, CD4% <10%, WAZ ≤ 2 and hemoglobin <8 g/dL, were predictive of mortality. Incomplete vaccination was predictive of mortality and LTFU. Facilities with nutrition programs had lower LTFU and mortality rates. Clinics reporting nurse dissatisfaction with working conditions had higher LTFU rates. CONCLUSION: Investigation of causes of increasing mortality and LTFU is needed. Ensuring earlier ART initiation, vaccination completion, scale-up of site-level nutrition programs and nurse work-environment satisfaction, could improve pediatric ART program outcomes.

Incidence and determinants of tuberculosis among adults initiating antiretroviral therapy--Mozambique, 2004-2008.

BACKGROUND: In Mozambique, tuberculosis (TB) is thought to be the most common cause of death among antiretroviral therapy (ART) enrollees. Monitoring proportions of enrollees screened for TB, and incidence and determinants of TB during ART can help clinicians and program managers identify program improvement opportunities. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective cohort study among a nationally representative sample of the 79,500 adults (>14 years old) initiating ART during 2004-2007 to estimate clinician compliance with TB screening guidelines, factors associated with active TB at ART initiation, and incidence and predictors of documented TB during ART follow-up. Of 94 sites enrolling >50 adults on ART, 30 were selected using probability-proportional-to-size sampling; 2,596 medical records at these sites were randomly selected for abstraction and analysis. At ART initiation, median age of patients was 34, 62% were female, median baseline CD4(+) T-cell count was 153/µL, and 11% were taking TB treatment. Proportions of records with TB screening documentation before ART initiation improved from 31% to 66% during 2004-2007 (p<0.001). TB screening compliance varied widely by ART clinic [n = 30, 2%-98% (p<0.001)] and supporting non-Governmental Organization (NGO) [n = 7, 27%-83% (p<0.001)]. Receiving TB treatment at ART enrollment was associated with male sex (p<0.001), weight <45 kg (p<0.001) and CD4<50/µL (p = 0.001). Isoniazid preventive therapy (IPT) was prescribed to <1% of ART enrollees not taking TB treatment. TB incidence during ART was 2.32 cases per 100 person-years. Factors associated with TB incidence included adherence to ART <95% (AHR 2.06; 95% CI, 1.32-3.21). CONCLUSION: Variations in TB screening by clinic and NGO may reflect differing investments in TB screening activities. Future scale-up should target under-performing clinics. Scale-up of TB screening at ART initiation, IPT, and ART adherence interventions could significantly reduce incident TB during ART.

The cost of providing comprehensive HIV treatment in PEPFAR-supported programs.

BACKGROUND: PEPFAR, national governments, and other stakeholders are investing unprecedented resources to provide HIV treatment in developing countries. This study reports empirical data on costs and cost trends in a large sample of HIV treatment sites. DESIGN: In 2006-2007, we conducted cost analyses at 43 PEPFAR-supported outpatient clinics providing free comprehensive HIV treatment in Botswana, Ethiopia, Nigeria, Uganda, and Vietnam. METHODS: We collected data on HIV treatment costs over consecutive 6-month periods starting from scale-up of dedicated HIV treatment services at each site. The study included all patients receiving HIV treatment and care at study sites [62,512 antiretroviral therapy (ART) and 44,394 pre-ART patients]. Outcomes were costs per patient and total program costs, subdivided by major cost categories. RESULTS: Median annual economic costs were US$ 202 (2009 USD) for pre-ART patients and US$ 880 for ART patients. Excluding antiretrovirals, per patient ART costs were US$ 298. Care for newly initiated ART patients cost 15-20% more than for established patients. Per patient costs dropped rapidly as sites matured, with per patient ART costs dropping 46.8% between first and second 6-month periods after the beginning of scale-up, and an additional 29.5% the following year. PEPFAR provided 79.4% of funding for service delivery, and national governments provided 15.2%. CONCLUSION: Treatment costs vary widely between sites, and high early costs drop rapidly as sites mature. Treatment costs vary between countries and respond to changes in antiretroviral regimen costs and the package of services. Whereas cost reductions may allow near-term program growth, programs need to weigh the trade-off between improving services for current patients and expanding coverage to new patients.