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Background: There are limited data on adverse effects of tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART) on pregnant women and their infants., Methods: We conducted a systematic review of studies published between January 1980 and January 2017 that compared adverse outcomes in HIV-infected women receiving TDF- vs. non-TDF-based ART during pregnancy. The risk ratio (RR) for associations was pooled using a fixed-effects model., Results: Seventeen studies met the study inclusion criteria. We found that the rate of preterm (<37 weeks gestation) delivery (RR = 0.90, 95% confidence interval [CI]: 0.81 to 0.99, I = 59%) and stillbirth (RR = 0.60, 95% CI: 0.43 to 0.84, I = 72.0%) were significantly lower in women exposed (vs. not) to TDF-based ART regimen. We found no increased risk in maternal severe (grade 3) or potentially life-threatening (grade 4) adverse events (RR = 0.62; 95% CI: 0.30 to 1.29), miscarriage (RR = 1.09; 95% CI: 0.80 to 1.48), very preterm (<34 weeks gestation) delivery (RR = 1.08, 95% CI: 0.72 to 1.62), small for gestational age (RR = 0.87, 95% CI: 0.67 to 1.13), low birth weight (RR = 0.91; 95% CI: 0.80 to 1.04), very low birth weight (RR = 3.18; 95% CI: 0.65 to 15.63), congenital anomalies (RR = 1.03; 95% CI: 0.83 to 1.28), infant adverse outcomes or infant mortality (age >14 days) (RR = 0.65; 95% CI: 0.23 to 1.85), but increased neonatal mortality (age <14 days) risk (RR = 5.64, 95% CI: 1.70 to 18.79) with TDR-based ART exposure. No differences were found for anthropomorphic parameters at birth; one study reported minor differences in z-scores for length and head circumference at age 1 year., Conclusions: TDF-based ART in pregnancy seems generally safe for women and their infants. However, data remain limited and further studies are needed, particularly to assess neonatal mortality and infant growth/bone effects.

Background: Raising the guidelines for the initiation of antiretroviral therapy in resource-limited settings at CD4 T-cell counts of 350 cells per microliter raises concerns about feasibility and cost. We examined costs of this shift using data from Uganda for almost 10 years., Methods: We projected total costs of earlier initiation with combined antiretroviral therapy, including inpatient and outpatient services, antiretroviral treatment and treatment for limited HIV-related opportunistic diseases, and benefits expressed in years-of-life-saved over 5- and 30-year time horizons using a deterministic economic model to examine the incremental cost-effectiveness ratio (ICER), expressed in cost per year-of-life-saved (YLS)., Results: The model generated ICERs for 5- and 30-year time horizons. Discounting both costs and benefits at 3% annually, for the 5-year analysis, the ICER was $695/YLS and $769 in the 30-year analysis. The results were most sensitive to program cost and the discount rate applied, but they were less sensitive to opportunistic infection treatment costs or the relative-risk reduction from earlier initiation. Program costs varied from 25% to 125%, and the ICER for the lower bound decreased to $491/YLS at 5-years and $574/YLS at 30 years. For the upper bound, the ICER increased to $899 for 5-years and $964 at 30-years. The budget impact of adoption, assuming the same level of program penetration in the community, is $261,651,942 for 5 years and $872,685,561 for 30 years., Conclusions: Our model showed that earlier initiation of combined antiretroviral therapy in Uganda is associated with improved long-term survival and is highly cost-effective, as defined by WHO-CHOICE.

Background: Currently, boosted protease inhibitor-containing regimens are the only option after first-line regimen failure available for patients in most resource-limited settings, yet little is known about long-term adherence and outcomes., Methods: We enrolled patients with virologic failure (VF) who initiated lopinavir/ritonavir-containing second-line antiretroviral therapy (ART). Medication possession ratios were calculated using pharmacy refill dates. Factors associated with 12-month second-line virologic suppression [viral load (VL) <50 copies/mL] and adherence were determined., Results: One hundred six patients (median CD4 count and VL at failure: 153 cells/mm(3) and 28,548 copies/mL, respectively) were enrolled. Adherence improved after second-line ART switch (median adherence 6 months prior, 67%; median adherence during initial 6 months of second-line ART, 100%; P = 0.001). Higher levels of adherence during second-line ART was associated with virologic suppression at month 12 of ART (odds ratio 2.5 per 10% adherence increase, 95% CI 1.3 to 4.8, P = 0.01). Time to virologic suppression was most rapid among patients with 91%-100% adherence compared with patients with 80%-90% and <80% adherence (log rank test, P = 0.01). VF during 24 months of second-line ART was moderate (month 12: 25%, n = 32/126; month 18: 21%, n = 23/112; and month 24: 25%, n = 25/99)., Conclusions: The switch to second-line ART in South Africa was associated with an improvement in adherence, however, a moderate ongoing rate of VF--among approximately 25% of patients receiving second-line ART patients at each follow-up interval--was a cause for concern. Adherence level was associated with second-line ART virologic outcome, helping explain why some patients achieved virologic suppression after switch and others did not.

Background: In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure., Methods: We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study., Results: Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 µg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair., Conclusions: Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.

Objective: To determine adherence to and effectiveness of antiretroviral therapy (ART) in adolescents vs. adults in southern Africa., Design: Observational cohort study., Setting: Aid for AIDS, a private sector disease management program in southern Africa., Subjects: Adolescents (age 11-19 years; n = 154) and adults (n = 7622) initiating ART between 1999 and 2006 and having a viral load measurement within 1 year after ART initiation., Main Outcome Measures: Primary: virologic suppression (HIV viral load < or = 400 copies/mL), viral rebound, and CD4 T-cell count at 6, 12, 18, and 24 months after ART initiation. Secondary: adherence assessed by pharmacy refills at 6, 12, and 24 months. Multivariate analyses: loglinear regression and Cox proportional hazards., Results: A significantly smaller proportion of adolescents achieved 100% adherence at each time point (adolescents: 20.7% at 6 months, 14.3% at 12 months, and 6.6% at 24 months; adults: 40.5%, 27.9%, and 20.6% at each time point, respectively; P < 0.01). Patients achieving 100% 12-month adherence were significantly more likely to exhibit virologic suppression at 12 months, regardless of age. However, adolescents achieving virologic suppression had significantly shorter time to viral rebound (adjusted hazard ratio 2.03; 95% confidence interval: 1.31 to 3.13; P < 0.003). Adolescents were less likely to experience long-term immunologic recovery despite initial CD4 T-cell counts comparable to adults., Conclusions: Compared with adults, adolescents in southern Africa are less adherent to ART and have lower rates of virologic suppression and immunologic recovery and a higher rate of virologic rebound after initial suppression. Studies must determine specific barriers to adherence in this population and develop appropriate interventions.

Little is known about the patient characteristics, social support networks, and relationship factors associated with excellent adherence in resource-limited settings, even though these can be important clues that inform the identification of targets and the approaches of individual- and community-based antiretroviral therapy adherence interventions. In this study, we aimed to understand how patient-selected treatment supports might affect antiretroviral treatment outcomes and to identify key components of support, including the social and material resources necessary for promoting high adherence in South Africa. Data were collected from the proceedings of 2 focus groups with 6 HIV-infected adults each and from 7 in-depth interviews with health care providers in the Western Cape Province of South Africa. The patients and health care workers identified individuals-usually a mother, daughter, sister, brother, or partner-who were confidantes and had moral authority with them. These individuals command respect, and patients allow them to influence health-related decision making, both of which are necessary if they are to be effective treatment supporters. Barriers to adherence identified by study participants include alcohol abuse, stigma related to disclosure of HIV status, and lack of financial resources and food. These are critically important challenges to address if high adherence is to be achieved in this setting. In addition, our results suggest that interventions tailored to treatment supporter characteristics and relationship factors may be effective in influencing patients' antiretroviral therapy adherence.

It is unclear how adherence to highly active antiretroviral therapy (HAART) may best be monitored in large HIV programs in sub-Saharan Africa where it is being scaled up. We aimed to evaluate the association between HAART adherence, as estimated by pharmacy claims, and survival in HIV-1-infected South African adults enrolled in a private-sector AIDS management program. Of the 6288 patients who began HAART between January 1999 and August 2004, 3805 (61%) were female and 6094 (97%) were black African. HAART adherence was >or=80% for 3298 patients (52%) and 100% for 1916 patients (30%). Women were significantly more likely to have adherence>or=80% than men (54% vs 49%, P<0.001). The median (interquartile range) follow-up time was 1.8 (1.37-2.5) years. As of 1 September 2004, 222 patients had died-a crude mortality rate of 3.5%. In a multivariate Cox regression model, adherence<80% was associated with lower survival (relative hazard 3.23; 95% confidence interval: 2.37-4.39). When medication adherence was divided into 5 strata with a width of 20% each, each stratum had lower survival rates than the adjacent, higher-adherence stratum. Among other variables tested, only baseline CD4+ T-cell count was significantly associated with decreased survival in multivariate analysis (relative hazard 5.13; 95% confidence interval: 3.42-7.72, for CD4+ T-cell count200 cells/microL). Pharmacy-based records may be a simple and effective population-level tool for monitoring adherence as HAART programs in Africa are scaled up.

A cross-sectional study of knowledge, attitudes, beliefs, and practices (KABPs) toward HIV and antiretroviral therapy (ART) was conducted in Soweto, South Africa, using a standardized validated questionnaire. Of 105 HIV clinic patients evaluated, 70% of whom were not on ART, 89% had good knowledge about the cause of HIV infection and 83% knew about modes of transmission. Fifty-nine percent reported they were not worried about ART side effects. Sixty-five percent agreed that missing ART doses can lead to disease progression. Ninety percent had disclosed their HIV serostatus to 1 or more persons, but only 62% of those with a current sexual partner reported having told that partner. Approximately 80% reported that if they were taking ART, they would not be worried about family or friends finding out. Forty-nine percent believed that ART can cure HIV, a belief that was associated with a low level of education (P<0.001). Overall, knowledge of the cause of HIV/AIDS, modes of transmission, and importance of ART adherence was good in our study population. Further research is warranted to assess the extent to which this knowledge and attendant attitudes predict ART adherence levels. The low rate of HIV serostatus disclosure to sexual partners calls for multidimensional interventions to reduce HIV-related stigma.