HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide.
Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services.
Most sites reported serving urban (61%; region range (rr): 33–100%) and both adult and paediatric populations (77%; rr: 29–96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services – nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother-to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) – were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services.
This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care.
HIV/AIDS; HIV care capacity; clinic characteristics; comprehensive care; resource-limited settings
To generate maps reflecting the intersection of community-based Voluntary Counseling and Testing (VCT) delivery points with facility-based HIV program demographic information collected at the district level in three districts (Ile, Maganja da Costa and Chinde) of Zambézia Province, Mozambique; in order to guide planning decisions about antiretroviral therapy (ART) program expansion.
Program information was harvested from two separate open source databases maintained for community-based VCT and facility-based HIV care and treatment monitoring from October 2011 to September 2012. Maps were created using ArcGIS 10.1. Travel distance by foot within a 10 km radius is generally considered a tolerable distance in Mozambique for purposes of adherence and retention planning.
Community-based VCT activities in each of three districts were clustered within geographic proximity to clinics providing ART, within communities with easier transportation access, and/or near the homes of VCT volunteers. Community HIV testing results yielded HIV seropositivity rates in some regions that were incongruent with the Ministry of Health’s estimates for the entire district (2–13% vs. 2% in Ile, 2–54% vs. 11.5% in Maganja da Costa, and 23–43% vs. 14.4% in Chinde). All 3 districts revealed gaps in regional disbursement of community-based VCT activities as well as access to clinics offering ART.
Use of geospatial mapping in the context of program planning and monitoring allowed for characterizing the location and size of each district’s HIV population. In extremely resource limited and logistically challenging settings, maps are valuable tools for informing evidence-based decisions in planning program expansion, including ART.
The Tshepo study was the first clinical trial to evaluate outcomes of adults receiving nevirapine (NVP)-based versus efavirenz (EFV)-based combination antiretroviral therapy (cART) in Botswana. This was a 3 year study (n=650) comparing the efficacy and tolerability of various first-line cART regimens, stratified by baseline CD4+: <200 (low) vs. 201-350 (high). Using targeted maximum likelihood estimation (TMLE), we retrospectively evaluated the causal effect of assigned NNRTI on time to virologic failure or death [intent-to-treat (ITT)] and time to minimum of virologic failure, death, or treatment modifying toxicity [time to loss of virological response (TLOVR)] by sex and baseline CD4+. Sex did significantly modify the effect of EFV versus NVP for both the ITT and TLOVR outcomes with risk differences in the probability of survival of males versus the females of approximately 6% (p=0.015) and 12% (p=0.001), respectively. Baseline CD4+ also modified the effect of EFV versus NVP for the TLOVR outcome, with a mean difference in survival probability of approximately 12% (p=0.023) in the high versus low CD4+ cell count group. TMLE appears to be an efficient technique that allows for the clinically meaningful delineation and interpretation of the causal effect of NNRTI treatment and effect modification by sex and baseline CD4+ cell count strata in this study. EFV-treated women and NVP-treated men had more favorable cART outcomes. In addition, adults initiating EFV-based cART at higher baseline CD4+ cell count values had more favorable outcomes compared to those initiating NVP-based cART.
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08–1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1–1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03–3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring.
More HIV-infected women in need of services for the prevention of mother-to-child transmission of HIV (PMTCT) give birth in Nigeria than in any other nation in the world. To meet the UNAIDS/WHO goal of eliminating mother-to-child HIV transmission by 2015, multiple interventions will be required to scale up PMTCT services, especially to lower-level, rural health facilities. To address this, we are conducting a cluster-randomized controlled study to evaluate the impact and cost-effectiveness of a novel, family-focused integrated package of services for PMTCT. A systematic reassignment of patient care responsibilities coupled with the adoption of point-of-care CD4+ cell count testing could facilitate the ability of lower-cadre health providers to manage PMTCT care, including the provision and scale-up of antiretroviral therapy to pregnant women in rural settings. Additionally, as influential community members, male partners could support their partners’ uptake of and adherence to PMTCT care. We describe an innovative approach to scaling up PMTCT service provision that incorporates considerations of where and from whom women can access services (task-shifting), ease of obtaining a CD4 result (point-of-care testing), the degree of HIV service integration for HIV-infected women and their infants, and the level of family and community involvement (specifically male partner involvement). This systematic approach, if proven feasible and effective, could be scaled up in Nigeria and similar resource-limited settings as a means to accelerate progress toward eliminating mother-to-child transmission of HIV and help women with HIV infection live long, healthy lives (Trial registration: NCT01805752).
prevention of mother-to-child HIV transmission; task shifting; male participation; point-of-care diagnostics; Nigeria; antiretroviral therapy uptake
Despite seven years of investment from the President's Emergency Plan For AIDS Relief (PEPFAR), the expansion of human immunodeficiency virus (HIV)-related services continues to challenge Mozambique’s health-care infrastructure, especially in the country’s rural regions.
In 2012, as part of a national acceleration plan for HIV care and treatment, Namacurra district employed a mobile clinic strategy to provide temporary manpower and physical space to expand services at four rural peripheral clinics. This paper describes the strategy deployed, the uptake of services and the key lessons learnt in the first 18 months of implementation.
In 2012, Namacurra´s adult population was estimated to be 125 425, and of those 15 803 were estimated to be HIV infected. Although there is consistent government support of antiretroviral therapy (ART) programmes, national coverage remains low, with less than 15% of those eligible having received ART by December 2012.
Between April 2012 and September 2013, Namacurra district enrolled 4832 new patients into HIV care and treatment. By using the mobile clinic strategy for ART expansion, the district was able to expand provision of ART from two to six (of a desired seven) clinics by September 2013.
Mobile clinic strategies could rapidly expand HIV care and treatment in under-funded settings in ways that both build local capacity and are sustainable for local health systems. The clinics best serve as a transition to improved capacity at fixed-site services.
Elevated serum levels of inflammatory biomarkers have been associated with increased mortality and morbidity among HIV-infected individuals receiving combination antiretroviral therapy (cART) in European and U.S. cohorts. Few similar data are available from sub-Saharan Africa, where most cART-treated adults reside and the prevalence of advanced immunosuppression and opportunistic infections (OIs) at cART initiation is higher. This was a retrospective nested case-control analysis of clinical trial data from the completed Adult Antiretroviral Treatment and Drug Resistance (“Tshepo”) study, 2002–2007, Gaborone, Botswana. We measured pretreatment serum levels of interleukin-6 (IL-6), high sensitivity C-reactive protein, and D-dimer in stored plasma samples from 32 deceased participants (cases) and 64 survivors (controls), matched for age, sex, baseline CD4+ cell count, and plasma HIV-1 RNA. Multivariate conditional logistic regression analyses were used to compare inflammatory biomarker levels, adjusting for pretreatment body mass index (BMI) and the presence of OIs. A total of 37 (5.7%) of 650 patients died on study, for a crude mortality rate of 20.6/1,000 person-years. Of 37 (86%) study participants who died on study 32 were included in this analysis. Causes of death (n=32) included non-AIDS-defining events (31.3%), HIV-related OIs (28.1%), cART/toxicity-related (21.9%), other infectious etiologies (15.6%), and unknown (3.1%). Median time to death was 31 weeks [interquartile range (IQR) 14–64]. Median baseline levels of all three biomarkers were higher in cases compared to matched controls. After adjusting for BMI and the presence of OIs, only baseline and most recent (near time of event) levels of IL-6 remained as significant predictors of all-cause mortality [adjusted OR (aOR)=1.25, 95% CI (1.05–1.48); p=0.012; and aOR=1.48 (1.05–2.09); p=0.027, respectively]. Serum IL-6 levels are important predictors of all-cause mortality in this adult urban sub-Saharan African cART-treated population. Future translational studies are warranted to better elucidate pathophysiology and inform the design of novel interventions to ameliorate the risk of death among these “at-risk” individuals.
Studies suggest that mitochondrial DNA (mtDNA) haplogroups are associated with antiretroviral therapy (ART)-related metabolic complications and distal sensory polyneuropathy (DSP), but there have been few studies in persons of African descent. We explored such associations in South African adults. Clinical and laboratory data and DNA specimens from a cross-sectional study were used. Sequencing and Phylotree determined African mtDNA subhaplogroups. Wilcoxon and regression analyses determined associations between mtDNA subhaplogroups and ART-related complications. The 171 participants represented six major haplogroups: L0 (n=78), L1 (n=3), L2 (n=30), L3 (n=53), L4 (n=1), and L5 (n=6). Analyses were restricted to 161 participants representing L0, L2, and L3: 78% were female; the median age was 36 years. All had been exposed to thymidine analogues, 42% were on lopinavir/ritonavir (lopinavir/r), and 58% were on either efavirenz or nevirapine. Median (IQR) ART duration was 22 (14–36) months. Median fasting triglycerides were 1.60 (1.13–1.75) and 1.04 (0.83–1.45) mmol/liter among L3e1 (n=22) and other subhaplogroups, respectively (p=0.003). Subhaplogroup L3e1 [adjusted OR (aOR) 3.16 (95% CI: 1.11–8.96); p=0.03] and exposure to lopinavir/r [aOR 2.98 (95% CI: 1.02–8.96); p=0.05] were independently associated with hypertriglyceridemia, after adjusting for age, sex, and ART duration. There were no significant associations between mtDNA haplogroups and cholesterol, dysglycemia, hyperlactatemia, or lipoatrophy, or DSP. Subhaplogroup L3e1 and lopinavir/r exposure were independently associated with hypertriglyceridemia in black South Africans on ART. This is the first report to link an African mtDNA variant with hypertriglyceridemia. If replicated, these findings may provide new insights into host factors affecting metabolic complications.
Greater adipose tissue is associated with increased circulating high-sensitivity C-reactive protein (hsCRP) levels in HIV-infected adults on antiretroviral therapy (ART), but the relationship between adiposity and other inflammation biomarkers is not well characterized.
We measured total and regional adipose tissue deposits using dual energy X-ray absorptiometry (DXA) and serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) receptor 1 & 2, macrophage inflammatory protein-1α (MIP-1α), macrophage chemotactic protein-1 (MCP-1), soluble CD14, and hsCRP in a cohort of adults on long-term ART. Regression models were adjusted for age, sex, CD4+ count, smoking status, PI use, and daily use of either NSAIDs or aspirin.
The majority (77%) of the 85 study participants were male, median CD4+ cell count was 500 cells/µl (IQR 315, 734) and median BMI was 25.1 kg/m2 (IQR 22.7, 28.1). DXA measurements of total fat mass were positively associated with serum hsCRP (β=1.82, p<0.01) and MIP-1α (β=1.36, p<0.01), but negatively associated with soluble CD14 (β=0.90, p<0.01). Results were similar for trunk fat, limb fat, and serum leptin level. The positive relationship between DXA measurements and TNF-α receptor 1 approached significance (p≤0.07 for all). There was no consistent relationship between adiposity and serum IL-6, TNF-α receptor 2, or MCP-1 levels.
Total and regional adiposity was associated with serum hsCRP, but not other inflammatory cytokines shown to predict morbidity and mortality in treated HIV. Greater adiposity is associated with higher MIP-1α and lower soluble CD14 levels possibly reflecting an important role for cells of the monocyte/macrophage lineage.
HIV; antiretroviral therapy; inflammation; obesity; adipose tissue; nutrition
Timely initiation of combination antiretroviral therapy (ART) in eligible HIV-infected patients is associated with substantial reductions in mortality and morbidity. Nigeria has the second largest number of persons living with HIV/AIDS in the world. We examined patient characteristics, time to ART initiation, retention and mortality at five rural facilities in Kwara and Niger states of Nigeria.
We analyzed program-level cohort data for HIV-infected, ART-naïve clients (≥15 years) enrolled from June 2009-February 2011. We modeled the probability of ART initiation among clients meeting national ART eligibility criteria using logistic regression with splines.
We enrolled 1,948 ART-naïve adults/adolescents into care, of whom 1174 were ART eligible (62% female). Only 74% of eligible patients (n=869) initiated ART within 90 days post-enrollment. The median CD4+ count for eligible clients was 156 cells/μL [IQR: 81–257], with 67% in WHO stage III/IV disease. Adjusting for CD4+ count, WHO stage, functional status, hemoglobin, body mass index, sex, age, education, marital status, employment, clinic of attendance, and month of enrollment, we found that immunosuppression (CD4 350 vs. 200, odds ratio (OR)=2.10 [95%CI: 1.31, 3.35], functional status (bedridden vs. working, OR=4.17 [95%CI: 1.63–10.67]), clinic of attendance (Kuta hospital vs. referent: OR=5.70 [95%CI:2.99–10.89]), and date of enrollment (December 2010 vs. June 2009: OR=2.13 [95%CI:1.19–3.81]) were associated with delayed ART initiation.
Delayed initiation of ART was associated with higher CD4+ counts, lower functional status, clinic of attendance, and later dates of enrollment among ART-eligible clients. Our findings provide targets for quality improvement efforts that may help reduce attrition and improve ART uptake in similar settings.
HIV/AIDS; Nigeria; antiretroviral therapy; implementation science; outcomes; PEPFAR; retention; mortality
As increasing numbers of persons are placed on potentially life-saving combination antiretroviral therapy (cART) in sub-Saharan Africa, it is imperative to identify the psychosocial and social factors that may influence antiretroviral (ARV) medication adherence. Using an 87 question survey, the following data were collected from patients on cART in Botswana: demographics, performance (Karnofsky) score, perceived stigma and level of HIV disclosure, attitudes and beliefs concerning HIV/AIDS, substance and/or drug use, depression, and pharmacy and healthcare provider-related factors. Overall adherence rates were determined by patient self-report, institutional adherence, and a culturally modified Morisky scale. Three hundred adult patients were recruited between April and May 2005. The overall cART adherence rate was 81.3% based on 4 day and 1 month patient recall and on clinic attendance for ARV medication refills during the previous 3 months. Adults receiving cART for 1–6 months were the least adherent (77%) followed by those receiving cART for greater than 12 months (79%). Alcohol use, depression, and nondisclosure of positive HIV status to their partner were predictive of poor adherence rates (p value <0.02). A significant proportion (81.3%) of cART-treated adults were adherent to their prescribed treatment, with rates superior to those reported in resource-rich settings. Adherence rates were poorest among those just starting cART, most likely due to the presence of ARV-related toxicity. Adherence was lower among those who have been treated for longer periods of time (greater than 1 year), suggesting complacency, which may become a significant problem, especially among these long-term cART-treated patients who return to improved physical and mental functioning and may be less motivated to adhere to their ARV medications. Healthcare providers should encourage HIV disclosure to “at-risk” partners and provide ongoing counseling and education to help patients recognize and overcome HIV-associated stigma, alcohol abuse, and depression.
Students at the University of Botswana, an at-risk group, have previously been shown to have high levels of risky sexual behavior despite widespread knowledge that these behaviors might lead to HIV-1 infection. As there have recently been considerable efforts focused on HIV-1 prevention in Botswana through nationwide media education campaigns and the opening of voluntary counselling and testing centers, re-evaluation of HIV-related knowledge, attitudes, and practices among students is needed. A cross-sectional survey was administered to 393 students chosen via a random cluster method. Respondents were 50% junior and 50% senior students with 42% males. Half (52%) were “single”, 44% were “in a relationship”, and 4% were “married”. The mean percentage of knowledge questions answered correctly was 96%. 98% agreed that all sexually active adults should know their status and that condom use is important, but only 56% believed getting tested was common and 66% believed that it was common for students to always use a condom. As with the previous survey, we again found that students had excellent knowledge yet perceived use of testing services and condoms remain lower than might be predicted based on knowledge scores.
HIV/AIDS; health knowledge; attitudes; practice; Africa; southern; university students; University of Botswana
Mortality rates within the first year of combination antiretroviral therapy (cART) initiation are several-fold higher in resource-limited countries than in resource-replete settings. However studies in western countries examining virologic, immunologic and clinical responses after cART initiation in indigenous versus non-indigenous populations have shown mixed results. This study aimed to determine whether there is a difference in these outcomes in a United States setting between foreign-born and US-born patients.
This retrospective observational cohort study of HIV-1 infected adults in one urban clinic in the United States compared virologic suppression, immune recovery and rates of AIDS defining events (ADEs) within the first year of cART using linear mixed effect models, log rank tests and Cox proportional hazard models. Data were analyzed for 94 foreign-born and 1242 US-born patients.
Foreign-born patients were younger (31.7 years versus 38.5 years), more often female (38.3% versus 27.1%), less often injection drug users (3.2% versus 9.5%) or men who have sex with men (19.0% versus 54.5%), and had higher loss to follow-up rates (14.9% versus 6.2%). No significant differences were detected between the groups in suppression of plasma HIV-1 RNA, CD4+ cell recovery or development of ADEs.
During the first year on cART, virologic suppression, immune recovery and development of ADEs were comparable between foreign-born and US-born patients in care in a US clinic. Differential rates of loss to follow-up warrant further investigation in the foreign-born population.
Nucleoside reverse-transcriptase inhibitors (NRTIs) are a major component of combination antiretroviral therapy (cART) worldwide but they have been associated with mitochondrial toxicities, with one of the most significant being lactic acidosis. In southern Africa, being female and overweight (BMI > 25) as well as receiving d4T and/or ddI-based cART are risk factors for the development of this potentially life-threatening complication. It is challenging in many resource-limited settings to obtain reliable serum lactate measurements while screening for the presence of lactic acidosis. Point-of-care devices, however, are now available that provide simple, accurate measurements of serum lactate levels at relatively low cost. The objective of this study was to assess the agreement of the portable (Accutrend™ handheld) lactate analyzer to the conventional laboratory system for obtaining serum lactate.
Eighty two “at-risk” cART-treated adults were evaluated, having their lactate levels tested in parallel using both modalities.
The mean (range) lactate level for the portable device was 2.28 (0.9-5.0) compared to 1.96 (0.7-5.4) using the conventional method. There was a strong correlation (p<0.05) between the portable device and the conventional means with a Pearson correlation coefficient of 0.92 [95% CI: 0.88-0.95]. The mean bias was 0.33 [95% CI: -0.39-1.04], with the portable device having slightly higher values.
The use of a portable lactate device provides an accurate and user-friendly means of screening at-risk patients for the presence of lactic acidosis in resource-limited settings with limited laboratory capacity.
HIV/AIDS; lactic acidosis; Botswana; Point-of-care devices; Complications of combination antiretroviral therapy (cART)
Gastrointestinal histoplasmosis (GIH) is common in patients with disseminated disease but only rarely comes to clinical attention due to the lack of specific signs and symptoms. We report the unusual case of a 33-year-old Caucasian male with advanced AIDS who presented with upper GI bleeding from diffuse erosions throughout the duodenum. Biopsy of the lesions revealed small bowel mucosa with granulomatous inflammation and macrophages with small intracellular yeasts consistent with disseminated histoplasmosis. The patient demonstrated significant clinical improvement following a two-week course of liposomal amphotericin B. To our knowledge, this is the first case report of duodenal histoplasmosis leading to clinically significant bleeding, manifesting with worsening anemia and melanotic stools. Given our findings, we maintain that GIH should be considered on the differential diagnosis for GI bleeding in AIDS patients at risk, specifically those with advanced immunosuppression (i.e., CD4+ cell counts <100 cells/mm3) who reside in endemic areas (Ohio or Mississippi river valleys) and/or have a prior history of histoplasmosis. For diagnostic evaluation, we recommend checking a urine Histoplasma quantitative antigen EIA as well as upper and/or lower endoscopy with biopsy. We recommend treatment with a two-week course of liposomal amphotericin B followed by indefinite itraconazole.
The Cox proportional hazards model or its discrete time analogue, the logistic failure time model, posit highly restrictive parametric models and attempt to estimate parameters which are specific to the model proposed. These methods are typically implemented when assessing effect modification in survival analyses despite their flaws. The targeted maximum likelihood estimation (TMLE) methodology is more robust than the methods typically implemented and allows practitioners to estimate parameters that directly answer the question of interest. TMLE will be used in this paper to estimate two newly proposed parameters of interest that quantify effect modification in the time to event setting. These methods are then applied to the Tshepo study to assess if either gender or baseline CD4 level modify the effect of two cART therapies of interest, efavirenz (EFV) and nevirapine (NVP), on the progression of HIV. The results show that women tend to have more favorable outcomes using EFV while males tend to have more favorable outcomes with NVP. Furthermore, EFV tends to be favorable compared to NVP for individuals at high CD4 levels.
causal effect; semi-parametric; censored longitudinal data; double robust; efficient influence curve; influence curve; G-computation; Targeted Maximum Likelihood Estimation; Cox-proportional hazards; survival analysis
To compare incidence and distribution of non-AIDS-defining events (NADEs) among HIV-1-infected adults receiving combination antiretroviral therapy (cART) in urban sub-Saharan African versus United States settings.
Retrospective cohort analysis of clinical trial and observational data.
Compared crude and standardized (to US cohort by age and sex) NADE rates from two urban adult HIV-infected cART-initiating populations: a clinical trial cohort in Gaborone, Botswana (Botswana) and an observational cohort in Nashville, Tennessee (USA).
Crude NADE incidence rates were similar: 10.0 [95% confidence interval 6.3–15.9] per 1000 person-years in Botswana versus 12.4 [8.4–18.4] per 1000 person-years in the United States. However, after standardizing to an older, predominantly male US population, the overall NADE incidence rates were higher in Botswana [18.7 (8.3–33.1) per 1000 person-years]. Standardized rates differed most for cardiovascular events (8.4 versus 5.0 per 1000 person-years) and non-AIDS-defining malignancies (8.0 versus 0.5 per 1000 person-years) – both higher in Botswana. Conversely, hepatic NADE rates were higher in the United States (4.0 versus 0.0 per 1000 person-years), whereas renal NADE rates [3.0 per 1000 person-years (United States) versus 2.4 per 1000 person-years (Botswana)] were comparable.
Crude NADE incidence rates were similar between cART-treated patients in a US observational cohort and a sub-Saharan African clinical trial. However, when standardized to the US cohort, overall NADE rates were higher in Botswana. NADEs appear to be a significant problem in our sub-Saharan African setting, and the monitoring, prevention, and treatment of NADEs should be a critical component of care in resource-limited settings.
combination antiretroviral therapy; HIV/AIDS; non-AIDS-defining events; urban sub-Saharan Africa; urban United States
To evaluate the relationship between early CD4+ lymphocyte recovery on antiretroviral therapy (ART) and subsequent survival among low body mass index (BMI) HIV-1 infected adults.
Retrospective analysis of a large programmatic cohort in Lusaka, Zambia.
We evaluated ART treated adults enrolled in care >6 months. We stratified this study population according to WHO malnutrition criteria: normal (BMI ≥18.5 kg/m2), mild (17.00-18.49), moderate (16.00-16.99), and severe (<16.0). We used Cox proportional hazards regression to estimate the subsequent risk of death associated with absolute CD4+ count change over the first 6 months on ART. To account for effect modification associated with baseline CD4+ count, a weighted summary measure was calculated.
From May 2004 to February 2009, 56,612 patients initiated ART at Lusaka district clinics; of these, 33,097 (58%) were included in this analysis. The median change in 0-6 month CD4+ count in each baseline BMI strata varied from 127 to 131 cells/μL. There was a statistically significant, inverse association between baseline BMI and the post-6 month hazard for mortality only among those patients with <100 cells/μL increase in the first 6 months of ART. A CD4+ count increase of ≥100 cells/μL over the first 6 months of ART was not associated with a higher hazard for mortality, regardless of baseline BMI.
Low baseline BMI and attenuated CD4+ count response at 6 months had a compounding, negative impact on post-6 month survival. Specific guidelines for monitoring ART response using immunologic criteria may be warranted for low BMI patients.
HIV; Nutrition; CD4 lymphocyte count; Antiretroviral therapy, highly active; Body mass index; Zambia; Africa
National initiatives offering NNRTI-based combination antiretroviral therapy (cART) have expanded in sub-Saharan Africa (SSA). The Tshepo study is the first clinical trial evaluating the long-term efficacy and tolerability of EFV- vs. NVP-based cART among adults in Botswana.
Three year randomized study (n = 650) using a 3×2×2 factorial design comparing efficacy and tolerability among: A: ZDV/3TC vs. ZDV/ddI vs. d4T/3TC; B: EFV vs. NVP, and C: Com-DOT vs. standard adherence strategies. This manuscript focuses on comparison B.
There was no significant difference by assigned NNRTI in time to virologic failure with resistance (log-rank p = 0.14), NVP vs. EFV risk ratio (RR) = 1.54 [0.86-2.70]. Rates of virologic failure with resistance were 9.6% NVP-treated [6.8-13.5] vs. 6.6% EFV-treated [4.2-10.0] at 3 years. Women receiving NVP-based cART trended towards higher virological failure rates when compared to EFV-treated women, Holm-corrected log-rank p = 0.072, NVP vs. EFV RR = 2.22 [0.94-5.00]. 139 patients had 176 treatment modifying toxicities, with shorter time to event in NVP-treated vs. EFV-treated, RR = 1.85 [1.20-2.86], log-rank p = 0.0002.
Tshepo-treated patients had excellent overall immunologic and virologic outcomes, and no significant differences were observed by randomized NNRTI comparison. NVP-treated women trended towards higher virologic failure with resistance compared to EFV-treated women. NVP-treated adults had higher treatment modifying toxicity rates when compared to those receiving EFV. NVP-based cART can continue to be offered to women in SSA if routine safety monitoring chemistries are done and the potential risk of EFV-related teratogenicity is considered.
HIV/AIDS; HAART; non-nucleoside reverse transcriptase inhibitors (NNRTI’s); nevirapine versus efavirenz; sub-Saharan Africa; randomized clinical trial
A low body mass index (BMI) at antiretroviral therapy (ART) initiation is a strong predictor of mortality among HIV-infected adults in resource-constrained settings. The relationship between nutrition and inflammation-related serum biomarkers and early treatment outcomes (e.g., less than 90 days) in this population is not well described.
An observational cohort of 142 HIV-infected adults in Lusaka, Zambia, with BMI under 16 kg/m2 or CD4+ lymphocyte counts of less than 50 cells/mm3, or both, was followed prospectively during the first 12 weeks of ART. Baseline and serial post-treatment phosphate, albumin, ferritin and highly sensitive C-reactive protein (hsCRP) serum levels were measured. The primary outcome was mortality.
Lower baseline phosphate and albumin serum levels, and higher ferritin and hsCRP, were significantly associated with mortality prior to 12 weeks (p < 0.05 for all comparisons), independent of known risk factors for early ART-associated mortality in sub-Saharan Africa. The time-dependent interval change in albumin was associated with mortality after adjusting for the baseline value (AHR 0.62 [0.43, 0.89] per 5 g/L increase), but changes in the other biomarkers were not.
The predictive value of serum biomarkers for early mortality in a cohort of adults with malnutrition and advanced HIV in a resource-constrained setting was primarily driven by pre-treatment values, rather than post-ART changes. Interventions to promote earlier HIV diagnosis and treatment, address nutritional deficiencies, and identify the etiologies of increased systemic inflammation may improve ART outcomes in this vulnerable population.
Numerous national antiretroviral (ARV) treatment initiatives offering protease-inhibitor (PI)-sparing combination antiretroviral therapy (cART) have recently commenced in southern Africa, the first of which began in Botswana in January 2002. Evaluation of the efficacy and tolerability of various PI-sparing cART regimens requires intensive study in the region, as does investigation of the development of drug resistance and the optimal means of sustaining adherence. The Tshepo Study is the first large-scale randomized clinical trial which addresses these important issues among HIV-1 subtype C infected, ARV-treatment naïve adults in southern Africa.
The Tshepo Study is a completed open-labeled randomized study that enrolled 650 ARV-naïve adults between December 2002 and December 2004. The study is a 3 × 2 × 2 factorial design comparing the efficacy and tolerability among factors: (i) three combinations of nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (ZDV) + lamivudine (3TC); ZDV + didanosine (ddI); and stavudine (d4T) + 3TC; (ii) two different Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): nevirapine (NVP) and efavirenz (EFV); and (iii) two different adherence strategies: the current national “Standard of Care (SOC)” versus an “intensified adherence strategy”, incorporating “community-based Directly Observed Therapy (Com-DOT)”. Study patients were stratified into two balanced CD4+ T cell count groups: less than 201 cells/mm3 versus 201-350 cells/mm3 with viral load greater than 55,000 copies/mL. Following DSMB recommendations in April 2006, ZDV/ddI-containing arms were discontinued due to inferiority in primary endpoint, namely, virologic failure with resistance. We report both overall data and pooled data from patients receiving ZDV/ddI- versus ZDV/3TC- and d4T/3TC-containing cART through 1 April 2006.
Four hundred fifty-one (69.4%) females and 199 males with a median age of 33.3 years were enrolled into the study. The median follow-up as of 1 April 2006 was 104 weeks, and loss to follow-up rate at two years was 4.1%. The median baseline CD4+ T cell count was 199 cells/mm3 [IQR 136-252] and the median plasma HIV-1 RNA level was 193,500 copies/mL [IQR 69-250, 472-500]. The proportion of participants with virologic failure and genotypic resistance mutations was 11% in those receiving ZDV/ddI-based cART versus 2% in those receiving either ZDV/3TC- or d4T/3TC-based cART (p=0.002). The median CD4+ T cell count increase at one year was 137cells/mm3 [IQR 74-223] and 199 cells/mm3 [IQR 112-322] at two years with significantly lower gain in the ZDV/ddI arm. At one and two years, respectively, 92.0% and 88.8% of patients had an undetectable plasma HIV-1 RNA level (≤400 copies/mL). Kaplan-Meier survival estimates at one and two years were 96.6% and 95.4%. One hundred twenty (18.2%) patients had treatment modifying toxicities, of which the most common were lipodystrophy, anemia, neutropenia, and Stevens-Johnson syndrome. There was a trend towards difference in time to treatment modifying toxicity by pooled dual NRTI combination, and no difference in death rates.
The preliminary study results show overall excellent efficacy and tolerability of NNRTI-based cART among HIV-1 subtype C infected adults. ZDV/ddI-containing cART, however, is inferior to the dual NRTIs d4T/3TC or ZDV/3TC when used with an NNRTI for first-line cART.
HIV/AIDS; cART; Africa; Randomized clinical trial
Numerous national public initiatives offering first-line combination antiretroviral therapy (cART) for HIV infection have commenced in sub-Saharan Africa since 2002. Presently, 2.1 million of an estimated seven million Africans in need of cART are receiving treatment. Analyses from the region report favorable clinical/treatment outcomes and impressive declines in AIDS-related mortality among HIV-1-infected adults and children receiving cART. While immunologic recovery, virologic suppression and cART adherence rates are on par with resource-rich settings, loss to follow-up and high mortality rates, especially within the first 6 months of treatment, remain a significant problem. Over the next decade, cART coverage rates are expected to improve across the region, with attendant increases in healthcare utilization for HIV- and non-HIV-related complications and the need for expanded laboratory and clinical services. Planned and in-progress trials will evaluate the use of cART to prevent primary HIV-1 infection with so-called ‘test and treat’ expansions of coverage and treatment. Education and training programs as well as patient-retention strategies will need to be strengthened as national cART programs are expanded and more people require lifelong monitoring and care.
adherence; cART; combination antiretroviral therapy; efficacy; HIV/AIDS; mortality/survival; sub-Saharan Africa; tolerability/toxicity
Antiretroviral treatment (ART) initiatives have now been established in many sub-Saharan African countries showing early benefits. To date, few results are available concerning long-term clinical outcomes in these treatment programs.
Response to ART is described in the first HIV–1C infected adults enrolled in the Botswana ART program in 2002. Data analysis was conducted on available longitudinal data up to April 1st, 2007.
633 severely immunodeficient patients with a median CD4+ cell count of 67 cells/mm3 were initiated on NNRTI-based combination ART and followed for a median of 41.9 months. The median CD4+ increases were 169 cells/mm3, 302 cells/mm3, and 337 cells/mm3 at 1, 3, and 5 years, respectively. The percentages of patients with a viral load of less than 400 copies/mL at 1, 3, and 5 years were 91.3%, 90.1%, and 98.3%, respectively. 75% of patients did not miss a single, or missed only one, monthly ART pick-up per year with a mean pick-up rate of 92.5%. The Kaplan-Meier survival estimates (95% CI) at 1, 3, and 5 years were 82.7% (81.2%, 84.3%), 79.3% (77.6%, 81.0%), and 79.0% (77.3%, 80.7%), respectively. At six months, the risk of treatment modification for anemia was 6.94% (5.9%, 8.0%) for cutaneous hypersensitivity reactions, 1.3% (0.8%, 1.7%), and 1.1% (0.7%, 1.6%) for hepatotoxicity.
This initial group of adults on ART in Botswana had excellent sustained immunologic, virologic, and clinical outcomes for up to five years of follow-up with low mortality among those surviving into the second year of antiretroviral treatment.
HIV/AIDS; Africa; antiretroviral therapy; Botswana; public sector
The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1–4.2 log10) and cART-initiating cohorts (5.1–5.3 log10) by about one log10. The proportion of individuals with high (≥50,000 (4.7 log10) copies/ml) HIV-1 RNA levels ranged from 24%–28% in the general HIV-positive population cohorts to 65%–83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%–50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load ≥50,000 (4.7 log10) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%–82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified “test-and-treat” strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities.
In parallel with the rollout of Botswana’s national antiretroviral therapy (ART) program, the Botswana Ministry of Health established the KITSO AIDS Training Program by entering into long-term partnerships with the Botswana–Harvard AIDS Institute Partnership for HIV Research and Education and others to provide standardized, country-specific training in HIV/AIDS care. The KITSO training model has strengthened human capacity within Botswana’s health sector and been indispensable to successful ART rollout. Through core and advanced training courses and clinical mentoring, different cadres of health care workers have been trained to provide high-quality HIV/AIDS care at all ART sites in the country. Continuous and standardized clinical education will be crucial to sustain the present level of care and successfully address future treatment challenges.