Influences on Adherence to Antiretroviral Therapy (ART) in Early-Stage HIV Disease: Qualitative Study from Uganda and South Africa.

Realization of optimal treatment and prevention benefits in the era of universal antiretroviral therapy (ART) and "U=U" (undetectable = untransmittable) requires high adherence at all stages of HIV disease. This article draws upon qualitative interview data to characterize two types of influences on ART adherence for 100 Ugandans and South Africans initiating ART during early-stage HIV infection. Positive influences are: (a) behavioral strategies supporting adherence; (b) preserving health through adherence; (c) support from others; and (d) motivating effect of adherence monitoring. "De-stabilizing experiences" (mobility, loss, pregnancy) as barriers are posited to impact adherence indirectly through intervening consequences (e.g. exacerbation of poverty). Positive influences overlap substantially with adherence facilitators described for later-stage adherers in previous research. Adherence support strategies and interventions effective for persons initiating ART later in HIV disease are likely also to be helpful to individuals beginning treatment immediately upon confirmation of infection. De-stabilizing experiences merit additional investigation across varying populations.

Timing of Antiretroviral Therapy and Systemic Inflammation in Sub-Saharan Africa: Results From the META Longitudinal Cohort Study.

Chronic inflammation predicts complications in persons with human immunodeficiency virus infection. We compared D-dimer, soluble CD14, and interleukin 6 levels before and 12 months after antiretroviral therapy (ART) initiation, among individuals starting ART during earlier-stage (CD4 T-cell count >350/µL) or late-stage disease (CD4 T-cell count <200/µL). Female sex, older age, viral load, and late-stage disease were associated with pre-ART biomarkers (n = 661; P < .05). However, there were no differences in biomarkers by disease stage after 12 months of ART (n = 438; P > .05), owing to loss from observation and greater declines in biomarkers in late-stage initiators (P < .001). Earlier initiation of ART is associated with decreased inflammation, but levels seem to converge between earlier and later initiators surviving to 12 months.

Biomarker-Measured Unhealthy Alcohol Use in Relation to CD4 Count Among Individuals Starting ART in Sub-Saharan Africa.

Individuals are initiating antiretroviral therapy (ART) at earlier HIV disease stages. Unhealthy alcohol use is a known barrier to successful HIV treatment outcomes, yet it is unclear whether the problem varies by disease stage. We measured alcohol use with an objective biomarker (phosphatidylethanol [PEth]), comparing individuals (n = 401) with early (CD4 > 350 cells/mL, WHO Stage 1) versus late (CD4 < 200 cells/mL) ART initiation in HIV care in Uganda and South Africa (SA). We examined the association between CD4 count and biomarker results using multivariable regression modeling, and compared PEth results to self-report to assess underreporting. Overall, 32.2% (n = 129) had unhealthy alcohol use (PEth ≥ 50 ng/ml). Early ART initiation was significantly associated with unhealthy alcohol use in Uganda (AOR 2.65; 95% CI: 1.05-6.72), but not SA (AOR 1.00; 95% CI: 0.46-2.17). In Uganda, 23.2% underreported unhealthy alcohol use versus 11.6% in SA (χ2 = 9.30; p < 0.01). Addressing unhealthy alcohol use is important as patients initiate ART earlier, yet challenging due to underreporting.

High retention in care among HIV-infected patients entering care with CD4 levels >350 cells/µL under routine program conditions in Uganda.

BACKGROUND: In Africa, human immunodeficiency virus (HIV)-infected patients who present to care with CD4 levels >350 cells/µL (ie, current antiretroviral treatment thresholds) are often thought to be poorly retained in care, but most estimates do not account for outcomes among patients lost to follow-up. METHODS: We evaluated HIV-infected adults who had made a visit in the last 2.5 years in a program in Uganda. We identified a random sample of patients lost to follow-up (9 months without a visit). Ascertainers sought patients in the community in this sample and outcomes were incorporated into revised survival estimates of mortality and retention for the clinic population using a probability weight. RESULTS: Of 6473 patients, (29% male, median age 29 years, median CD4 count 550 cells/µL), 1294 (20%) became lost to follow-up over 2.5 years. Two hundred seven (16%) randomly selected lost patients were sought, and in 175 (85%) vital status was ascertained. In 19 of 175 (11%), the patient had died. Of the 156 (89%) alive, 74 (47%) were interviewed in person, and 38 of 74 (51%) reported HIV care elsewhere, whereas 36 of 74 (49%) were not in care. Application of weights derived from sampling found that at 2.5 years, retention among patients who enrolled with CD4 levels >350 cells/µL was 88.2% and mortality was 2.5%. Lower income, unemployment, and rural residence were associated with failure to be retained. CONCLUSIONS: Retention in patients entering care with high CD4 counts under routine program conditions in Africa is high in a Ugandan care program and may be systematically underestimated in many other settings.

Factors Associated With Changes in Alcohol Use During Pregnancy and the Postpartum Transition Among People With HIV in South Africa and Uganda.

Identifying factors associated with alcohol use changes during pregnancy is important for developing interventions for people with HIV (PWH). Pregnant PWH (n = 202) initiating antiretroviral therapy in Uganda and South Africa completed two assessments, 6 months apart (T1, T2). Categories were derived based on AUDIT-C scores: "no use" (AUDIT-C = 0 at T1 and T2), "new use" (AUDIT-C = 0 at T1, >0 at T2), "quit" (AUDIT-C > 0 at T1, =0 at T2), and "continued use" (AUDIT-C > 0, T1 and T2). Factors associated with these categories were assessed. Most participants had "no use" (68%), followed by "continued use" (12%), "quit" (11%), and "new use" (9%). Cohabitating with a partner was associated with lower relative risk of "continued use." Borderline significant associations between food insecurity and higher risk of "new use" and between stigma and reduced likelihood of "quitting" also emerged. Alcohol use interventions that address partnership, food security, and stigma could benefit pregnant and postpartum PWH.

Antiretroviral therapy adherence patterns, virological suppression, and emergence of drug resistance: A nested case-control study from Uganda and South Africa.

BACKGROUND: Relationships between distinct antiretroviral therapy (ART) adherence patterns and risk of drug resistance are not well understood. METHODS: We conducted a nested case-control analysis within a longitudinal cohort study of individuals initiating efavirenz-based ART. Primary outcomes of interest, measured at 6 and 12 months after treatment initiation, were: 1) virologic suppression, 2) virologic failure with resistance, and 3) virologic failure without resistance. Our primary exposure of interest was ART adherence, measured over the 6 months before each visit with electronic pill monitors, and categorized in three ways: 1) 6 months average adherence; 2) running adherence, defined as the proportion of days with average adherence over 9 days of less than or equal to 10%, 20%, and 30%; and 3) number of 3-, 7-, and 28-day treatment gaps in the prior 6 months. RESULTS: We analyzed data from 166 individuals (107 had virologic failure during observation and 59 had virologic suppression at 6 and 12 months). Average adherence was higher among those with virologic suppression (median 83%, IQR 58-96%) versus those with virologic failure with resistance (median 35%, IQR 20-77%, pairwise P < 0.01) and those with virologic failure without resistance (median 21%, IQR 2-54%, pairwise P < 0.01). Although treatment gaps generally predicted virologic failure (P < 0.01), they did not differentiate failure with and without drug resistance (P > 0.6). CONCLUSIONS: Average adherence patterns, but not the assessed frequency of treatment gaps, differentiated failure with versus without drug resistance among individuals initiating efavirenz-based ART. Future work should explore adherence-resistance relationships for integrase inhibitor-based regimens.

Brief Report: The Impact of Disease Stage on Early Gaps in ART in the "Treatment for All" Era-A Multisite Cohort Study.

BACKGROUND: Adoption of "Treat All" policies has increased antiretroviral therapy (ART) initiation in sub-Saharan Africa; however, unexplained early losses continue to occur. More information is needed to understand why treatment discontinuation continues at this vulnerable stage in care. METHODS: The Monitoring Early Treatment Adherence Study involved a prospective observational cohort of individuals initiating ART at early-stage versus late-stage disease in South Africa and Uganda. Surveys and HIV-1 RNA levels were performed at baseline, 6, and 12 months, with adherence monitored electronically. This analysis included nonpregnant participants in the first 6 months of follow-up; demographic and clinical factors were compared across groups with χ2, univariable, and multivariable models. RESULTS: Of 669 eligible participants, 91 (14%) showed early gaps of ≥30 days in ART use (22% in South Africa and 6% in Uganda) with the median time to gap of 77 days (interquartile range: 43-101) and 87 days (74, 105), respectively. Although 71 (78%) ultimately resumed care, having an early gap was still significantly associated with detectable viremia at 6 months (P ≤ 0.01). Multivariable modeling, restricted to South Africa, found secondary education and higher physical health score protected against early gaps [adjusted odds ratio (aOR) 0.4, 95% confidence interval (CI): 0.2 to 0.8 and (aOR 0.93, 95% CI: 0.9 to 1.0), respectively]. Participants reporting clinics as "too far" had double the odds of early gaps (aOR 2.2: 95% CI: 1.2 to 4.1). DISCUSSION: Early gaps in ART persist, resulting in higher odds of detectable viremia, particularly in South Africa. Interventions targeting health management and access to care are critical to reducing early gaps.

Adherence to HIV antiretroviral therapy among pregnant and postpartum women during the Option B+ era: 12-month cohort study in urban South Africa and rural Uganda.

INTRODUCTION: We conducted a cohort study to understand patterns of anti-retroviral therapy (ART) adherence during pregnancy, postpartum and non-pregnancy follow-up among women initiating ART in public clinics offering Option B+ in rural Uganda and urban South Africa. METHODS: We collected survey data, continuously monitored ART adherence (Wisepill), HIV-RNA and pregnancy tests at zero, six and twelve months from women initiating ART in Uganda and South Africa, 2015 to 2017. The primary predictor of interest was follow-up time categorized as pregnant (pregnancy diagnosis to pregnancy end), postpartum (pregnancy end to study exit) or non-pregnancy-related (neither pregnant nor postpartum). Fractional regression models included demographics and socio-behavioural factors informed by the Behavioral Model for Vulnerable Populations. We evaluated HIV-RNA at 12 months by ever- versus never-pregnant status. RESULTS: In Uganda, 247 women contributed 676, 900 and 1274 months of pregnancy, postpartum and non-pregnancy-related follow-up. Median ART adherence was consistently ≥90%: pregnancy, 94% (interquartile range [IQR] 78,98); postpartum, 90% (IQR 70,97) and non-pregnancy, 90% (IQR 80,98). Poorer adherence was associated with younger age (0.98% [95% CI 0.33%, 1.62%] average increase per year of age) and higher CD4 cell count (1.01% [0.08%, 1.94%] average decrease per 50 cells/mm3 ). HIV-RNA was suppressed among 91% (N = 135) ever-pregnant and 86% (N = 85) never-pregnant women. In South Africa, 190 women contributed 259, 624 and 1247 months of pregnancy, postpartum and non-pregnancy-related follow-up. Median adherence was low during pregnancy, 74% (IQR 31,96); postpartum, 40% (IQR 4,65) and non-pregnancy, 77% (IQR 47,92). Poorer adherence was associated with postpartum status (22.3% [95%CI 8.6%, 35.4%] average decrease compared to non-pregnancy-related follow-up) and less emotional support (1.4% [0.22%, 2.58%] average increase per unit increase). HIV-RNA was suppressed among 57% (N = 47) ever-pregnant and 86% (N = 93) never-pregnant women. CONCLUSIONS: Women in rural Uganda maintained high adherence with 91% of ever-pregnant and 86% of never-pregnant women suppressing HIV-RNA at 12 months. Women in urban South Africa struggled with adherence, particularly during postpartum follow-up with median adherence of 40% and 57% of women with HIV-RNA suppression at one year, suggesting a crisis for postpartum women with HIV in South Africa. Findings suggest that effective interventions should promote emotional support.

Inflammatory biomarkers prior to antiretroviral therapy as prognostic markers of 12-month mortality in South Africa and Uganda.

OBJECTIVE: The aim of this study was to determine the utility of biomarkers of immune activation, systemic inflammation and coagulopathy prior to antiretroviral therapy to predict mortality during the first year of antiretroviral therapy (ART) in sub-Saharan Africa. DESIGN: A prospective, observational cohort. METHODS: We measured soluble CD14, interleukin-6 and D-dimer in nonpregnant individuals initiating ART in South Africa and Uganda in the Measuring Early Treatment Adherence (META) Study. We used survival analysis methods to estimate their association with 12-month mortality, and fit receiver operator curves (ROC) to assess the prognostic value of each biomarker. RESULTS: Six-hundred and sixty individuals were enrolled and had pretreatment biomarkers measured. Approximately 60% were women, with a median CD4 cell count of 187 cells/µl [interquartile range (IQR) 111-425] and approximately half were enrolled each from South Africa and Uganda. We observed 34 deaths for a crude mortality of 5.3 deaths/100 person-years (py) (95% confidence interval 3.8-7.4), which ranged from 0/100 py to 13.7/100 py in the lowest and highest tertile of pretreatment sCD14, respectively. In Cox models, all three biomarkers were strongly predictive of the hazard of death (adjusted hazard ratio 3-6, all P < 0.01). In multivariable models including biomarkers, both pretreatment CD4 cell count and pretreatment viral load became borderline or nonsignificantly associated with mortality. The c-statistic for area under ROC was higher for all three biomarkers than for CD4 cell count (P < 0.01). CONCLUSION: Biomarkers of immune activation, systemic inflammation and coagulopathy prior to ART initiation are strongly predictive of early death on treatment after adjustment for CD4 cell count. Such biomarkers might serve as important prognostic indicators for patient triage in this population.

High Rates of Biomarker-Confirmed Alcohol Use Among Pregnant Women Living With HIV in South Africa and Uganda.

BACKGROUND: Alcohol use is common among people living with HIV and particularly harmful during pregnancy. However, objective data on alcohol use in pregnant women living with HIV (WLWH) are lacking. In areas with high levels of alcohol use generally, such as South Africa and Uganda, these data are needed to inform interventions. METHODS: Pregnant and nonpregnant, antiretroviral therapy-naive WLWH were recruited from outpatient clinics in South Africa and Uganda. Women provided self-report data on previous three-month alcohol use and potential mental health correlates of alcohol use (depression and stigma). Blood samples were used to measure phosphatidylethanol (PEth), an objective biomarker of recent alcohol intake. We analyzed any alcohol use (ie, any self-reported use or PEth-positive [≥8 ng/mL]) and under-reporting of alcohol use (ie, no self-reported use with concurrent PEth-positive). RESULTS: Among pregnant WLWH (n = 163, median age was 26 [interquartile range: 23-29], median gestational age was 20 weeks [interquartile range: 16-26]), 40% were using alcohol and 16% under-reported alcohol use. Neither any alcohol use nor under-reporting of alcohol use differed significantly between pregnant and nonpregnant women or by country (P > 0.05). Greater depression (but not greater stigma) was significantly associated with any alcohol use (adjusted odds ratio = 1.41, 95% confidence interval: [1.01 to 1.99]; P = 0.045). CONCLUSIONS: Alcohol use was prevalent and under-reported among pregnant WLWH in South Africa and Uganda, similar to nonpregnant participants, and associated with depression. General health care and antenatal clinic settings present opportunities to provide integrated alcohol-based counseling and depression treatment.

Closing the gap: A novel metric of change in performance.

BACKGROUND: Interventions to improve performance of global programs in the HIV cascade of care are widespread and increasing the focus of implementation science. At present, however, there is no clear consensus on how to conceptualize their improvement at the program level. The commonly used measures of association, based on ratios of probabilities (or odds), have well-known defects in public health applications. They yield large effect sizes even when the absolute effects, and therefore the public health impact, are small. On the other hand, risk differences create problems because settings with higher baseline values are penalized. We aim to examine ways of quantifying improvement in each health center of a cluster-randomized trial in Uganda to accelerate antiretroviral therapy initiation among HIV-infected adults. METHODS: We formalize the concept of the 'improvement index,' defined as the fraction of gaps closed as a metric of improvement, and suggest that it has unique features and strengths when compared to risk ratios and risk differences. RESULTS: Overall agreement between the different indices was not high, especially among health centers that were among the top 5 or 10. However, all ranking showed broad similarities at the far ends of the spectrum. On scatter plots, there was a positive linear relationship between the metrics, and the Bland Altman (B-A) plots were in agreement. CONCLUSION: The improvement index can be used as an alternative measure of association in implementation science interventions. It can be useful for public health purposes as it demonstrates how much can be covered from the baseline.

ART adherence and viral suppression are high among most non-pregnant individuals with early-stage, asymptomatic HIV infection: an observational study from Uganda and South Africa.

INTRODUCTION: The success of universal antiretroviral therapy (ART) access and aspirations for an AIDS-free generation depend on high adherence in individuals initiating ART during early-stage HIV infection; however, adherence may be difficult in the absence of illness and associated support. METHODS: From March 2015 to October 2017, we prospectively observed three groups initiating ART in routine care in Uganda and South Africa: men and non-pregnant women with early-stage HIV infection (CD4 > 350 cells/µL), pregnant women with early-stage HIV infection and men and non-pregnant women with late-stage HIV infection (CD4 < 200 cells/µL). Socio-behavioural questionnaires were administered and viral loads were performed at 0, 6 and 12 months. Adherence was monitored electronically. RESULTS: Adherence data were available for 869 participants: 322 (37%) early/non-pregnant, 199 (23%) early/pregnant and 348 (40%) late/non-pregnant participants. In Uganda, median adherence was 89% (interquartile range 74 to 96) and viral suppression was 90% at 12 months; neither differed among groups (p > 0.72). In South Africa, median adherence was higher in early/non-pregnant versus early/pregnant or late/non-pregnant participants (76%, 37%, 52%; p < 0.001), with similar trends in viral suppression (86%, 51%, 79%; p < 0.001). Among early/non-pregnant individuals in Uganda, adherence was higher with increasing age and lower with structural barriers; whereas in South Africa, adherence was higher with regular income, higher perceived stigma and use of other medications, but lower with maladaptive coping and cigarette smoking. DISCUSSION: ART adherence among non-pregnant individuals with early-stage infection is as high or higher than with late-stage initiation, supporting universal access to ART. Challenges remain for some pregnant women and individuals with late-stage infection in South Africa and highlight the need for differentiated care delivery.

Acceptability of routine HIV counselling and testing, and HIV seroprevalence in Ugandan hospitals.

OBJECTIVE: Mulago and Mbarara hospitals are large tertiary hospitals in Uganda with a high HIV/AIDS burden. Until recently, HIV testing was available only upon request and payment. From November 2004, routine free HIV testing and counselling has been offered to improve testing coverage and the clinical management of patients. All patients in participating units who had not previously tested HIV-positive were offered HIV testing. Family members of patients seen at the hospitals were also offered testing. METHODS: Data collected at the 25 participating wards and clinics between 1 November 2004 and 28 February 2006 were analysed to determine the uptake rate of testing and the HIV seroprevalence among patients and their family members. FINDINGS: Of the 51,642 patients offered HIV testing, 50,649 (98%) accepted. In those who had not previously tested HIV-positive, the overall HIV prevalence was 25%, with 81% being tested for the first time. The highest prevalence was found in medical inpatients (35%) and the lowest, in surgical inpatients (12%). The prevalence of HIV was 28% in the 39,037 patients who had never been tested before and 9% in those who had previously tested negative. Of the 10,439 family members offered testing, 9720 (93%) accepted. The prevalence in family members was 20%. Among 1213 couples tested, 224 (19%) had a discordant HIV status. CONCLUSION: In two large Ugandan hospitals, routine HIV testing and counselling was highly acceptable and identified many previously undiagnosed HIV infections and HIV-discordant partnerships among patients and their family members.

Association between HIV and blood pressure in adults and role of body weight as a mediator: Cross-sectional study in Uganda.

The authors sought to describe the association between human immunodeficiency virus (HIV) and blood pressure (BP) levels, and determined the extent to which this relationship is mediated by body weight in a cross-sectional study of HIV-infected and HIV-uninfected controls matched by age, sex, and neighborhood. Mixed-effects models were fit to determine the association between HIV and BP and amount of effect of HIV on BP mediated through body mass index. Data were analyzed from 577 HIV-infected and 538 matched HIV-uninfected participants. HIV infection was associated with 3.3 mm Hg lower systolic BP (1.2-5.3 mm Hg), 1.5 mm Hg lower diastolic BP (0.2-2.9 mm Hg), 0.3 m/s lower pulse wave velocity (0.1-0.4 mm Hg), and 30% lower odds of hypertension (10%-50%). Body mass index mediated 25% of the association between HIV and systolic BP. HIV infection was inversely associated with systolic BP, diastolic BP, and pulse wave velocity. Comprehensive community-based programs to routinely screen for cardiovascular risk factors irrespective of HIV status should be operationalized in HIV-endemic countries.

Understanding uptake of an intervention to accelerate antiretroviral therapy initiation in Uganda via qualitative inquiry.

INTRODUCTION: The Streamlined Antiretroviral Therapy Initiation Strategy (START-ART) study found that a theory-based intervention using opinion leaders to inform and coach health care providers about the risks of treatment delay, provision of point of care (POC) CD4 testing machines (PIMA) and reputational incentives, led to rapid rise in ART initiation. We used qualitative research methods to explore mechanisms of provider behaviour change. METHODS: We conducted in-depth interviews (IDIs) with 24 health care providers and nine study staff to understand perceptions, attitudes and the context of changes in ART initiation practices. Analyses were informed by the Theoretical Domains Framework. RESULTS: Rapid dissemination of new practices was enabled in the environmental context of an existing relationship based on communication, implementation and accountability between Makerere University Joint AIDS Program (MJAP), a Ugandan University-affiliated organization that provided technical oversight for HIV service delivery at the health facilities where the intervention was implemented, and a network of health facilities operated by the Uganda Ministry of Health. Coaching carried out by field coordinators from MJAP strengthened influence and informal accountability for carrying out the intervention. Frontline health workers held a pre-existing strong sense of professional identity. They were proud of attainment of new knowledge and skills and gratified by providing what they perceived to be higher quality care. Peer counsellors, who were not explicitly targeted in the intervention design, effectively substituted some functions of health care providers; as role models for successful ART uptake, they played a crucial role in creating demand for rapid ART initiation through interactions with patients. Point of care (POC) CD4 testing enabled immediate action and relieved providers from frustrations of lost or delayed laboratory results, and led to higher patient satisfaction (due to reduced costs because of ability to initiate ART right away, requiring fewer return trips to clinic). CONCLUSIONS: Qualitative data revealed that a multicomponent intervention to change provider behaviour succeeded in the context of strong institutional and individual relationships between a University-affiliated organization, government facilities, and peer health workers (who acted as a crucial link between stakeholders) and the community. Fostering stable institutional relationships between institutional actors (non-governmental organization (NGOs) and ministry-operated facilities) as well as between facilities and the community (through peer health workers) can enhance uptake of innovations targeting the HIV cascade in similar clinical settings.

Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial.

BACKGROUND: In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation. METHODS: In this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289. FINDINGS: Between April 11, 2013, and Feb 2, 2015, 12 024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per µL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41·9%, 95% CI 40·1-43·8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group. INTERPRETATION: A multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale. FUNDING: National Institute of Allergy and Infectious Diseases (NIAID) and the President's Emergency Fund for AIDS Relief (PEPFAR).

Estimated Costs for Delivery of HIV Antiretroviral Therapy to Individuals with CD4+ T-Cell Counts >350 cells/uL in Rural Uganda.

BACKGROUND: Evidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4>350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4>350 in Sub-Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up. METHODS: Within a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts >350 cells/uL (EARLI Study: NCT01479634) in Mbarara, Uganda, we performed a micro-costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing. FINDINGS: Among 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451-716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100-200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals. CONCLUSIONS: In a Ugandan HIV clinic, ART delivery costs--including VL testing--for individuals with CD4>350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions.

Successful antiretroviral therapy delivery and retention in care among asymptomatic individuals with high CD4+ T-cell counts above 350 cells/µl in rural Uganda.

BACKGROUND: HIV antiretroviral therapy (ART) is being rapidly scaled up in sub-Saharan Africa, including recently patients with CD4 T-cell counts above 350 cells/µl. However, concerns persist about adherence and virologic suppression among these asymptomatic, high CD4 cell count individuals. OBJECTIVE: To determine the virologic efficacy and safety of ART among asymptomatic HIV-positive Ugandan adults with high CD4 cell counts above 350 cells/µl via a streamlined model of care. DESIGN: Prospective nonrandomized clinical study (EARLI Study: clinicaltrials.gov NCT#01479634). SETTING: Prototypic rural Ugandan HIV clinic. PATIENTS/PARTICIPANTS: Asymptomatic, ART-naive adults (aged >18 years, N = 197) with CD4 at least 350 cells/µl, without pregnancy or WHO stage 3/4 illness. INTERVENTIONS: ART included tenofovir/emtricitabine/efavirenz, with ritonavir/lopinavir substitution for efavirenz available. Streamlined ART model included nurse-driven visits with physician back-up, basic safety laboratory monitoring with HIV viral load, clinician telephone contact, and defaulter tracking. No incentives were provided. OUTCOMES: Undetectable viral load (≤400 copies/ml) at 24 and 48 weeks [intention to treat (ITT); missing = detectable), self-reported ART adherence, retention in care, and laboratory/clinical ART toxicities. RESULTS: Of the 197 patients with CD4 above 350 cells/µl, median CD4 cell count was 569 cells/µl (interquartile range 451-716). Undetectable viral load was achieved in 189 of 197 (95.9%, ITT) and 189 of 195 (96.9%, ITT) of participants at weeks 24 and 48, respectively. Self-reported adherence was 98% and 192 of 197 (97%) of the patients were retained at week 48. Laboratory adverse events and hospitalizations were rare. CONCLUSIONS: We demonstrate high virologic suppression, retention, and safety among asymptomatic individuals with CD4 above 350 cells/µl in a prototypic Ugandan clinic. Our results challenge current concerns that individuals with high CD4 cell count lack motivation for ART, and may not achieve sustained virologic suppression.

Changes in population HIV RNA levels in Mbarara, Uganda, during scale-up of HIV antiretroviral therapy access.

OBJECTIVE: In a rural Ugandan community scaling up antiretroviral therapy (ART), we sought to determine if population-based HIV RNA levels [population viral load (VL)] decreased from 2011 to 2012. DESIGN: Serial cross-sectional analyses (May 2011 and May 2012) of a defined study community of 6300 persons in a district with HIV prevalence of 8%. METHODS: We measured HIV-1 RNA (VL) levels on all individuals testing positive for HIV during a 5-day high-throughput multidisease community health campaign in May 2012 that recruited two-thirds of the population. We aggregated individual-level VL results into population VL metrics including the proportion of individuals with an undetectable VL and compared these VL metrics to those we previously reported for this geographic region in 2011. RESULTS: In 2012, 223 of 2179 adults were HIV-seropositive adults (10%). Overall, among 208 of 223 HIV-seropositive adults in whom VL was tested, 53% had an undetectable VL [95% confidence interval (CI): 46 to 60], up from 37% (95% CI: 30 to 45; P = 0.02) in 2011. Seven (3%) individuals had a VL of >100,000 copies/mL in 2012, down from 21 (13%) in 2011 (P = 0.0007). Mean log (VL) (geometric mean) was 3.18 log (95% CI: 3.06 to 3.29 log) in 2012, down from 3.62 log (95% CI: 3.46 to 3.78 log) in 2011 (P < 0.0001). Similar reductions in population VL were seen among men and women. CONCLUSIONS: Reductions in population VL metrics and a substantial increase in the proportion of persons with an undetectable VL were observed in a rural Ugandan community from 2011 to 2012. These findings from a resource-limited setting experiencing rapid ART scale-up may reflect a population-level effectiveness of expanding ART access.

Evaluation of the efficiency of patient flow at three HIV clinics in Uganda.

With dramatic increases in antiretroviral therapy (ART) provision, many clinics in sub-Saharan Africa are congested, but little attention has focused on the efficiency of clinics. Between April and June 2008, we conducted a time-and-motion study to assess patient flow at three HIV clinics in Uganda. Mulago HIV Clinic had 6,700 active patients, compared with 2,700 at Mbarara Municipal Council Clinic (MMC) and 2,800 at Reachout Mbuya (ROM). Mulago had six doctors and eight nurses; MMC had two doctors and two nurses, and ROM had two doctors and 12 nurses. Mulago and MMC used a doctor-led model, whereas ROM used a nurse-led model. Randomly selected patients were tracked, with data collected on time waiting and time spent with providers. Patients were categorized as new, preparing for ART, early ART, stable ART, or non-ART. Doctors indicated whether the patients they saw warranted their consultation. Data were collected on 689 patients (230 at Mulago, 229 at MMC, and 230 at ROM). Overall waiting time was longest at ROM (274 min; 209-346) and Mulago ISS (270 min; 230-336) compared with MMC (183 min; 148-233). Nurse-clinicians at ROM spent twice the time with patients compared with the doctors at Mulago. At Mulago, doctors indicated that 27% of the patients they reviewed did not need to see a doctor, compared with 45% at MMC. Task-shifting may not be efficient in terms of time. More-effective triage and longer visit intervals could improve patient flow and capacity for cost-effective scale-up.