Universal Testing, Expanded Treatment, and Incidence of HIV Infection in Botswana.

BACKGROUND: The feasibility of reducing the population-level incidence of human immunodeficiency virus (HIV) infection by increasing community coverage of antiretroviral therapy (ART) and male circumcision is unknown. METHODS: We conducted a pair-matched, community-randomized trial in 30 rural or periurban communities in Botswana from 2013 to 2018. Participants in 15 villages in the intervention group received HIV testing and counseling, linkage to care, ART (started at a higher CD4 count than in standard care), and increased access to male circumcision services. The standard-care group also consisted of 15 villages. Universal ART became available in both groups in mid-2016. We enrolled a random sample of participants from approximately 20% of households in each community and measured the incidence of HIV infection through testing performed approximately once per year. The prespecified primary analysis was a permutation test of HIV incidence ratios. Pair-stratified Cox models were used to calculate 95% confidence intervals. RESULTS: Of 12,610 enrollees (81% of eligible household members), 29% were HIV-positive. Of the 8974 HIV-negative persons (4487 per group), 95% were retested for HIV infection over a median of 29 months. A total of 57 participants in the intervention group and 90 participants in the standard-care group acquired HIV infection (annualized HIV incidence, 0.59% and 0.92%, respectively). The unadjusted HIV incidence ratio in the intervention group as compared with the standard-care group was 0.69 (P = 0.09) by permutation test (95% confidence interval [CI], 0.46 to 0.90 by pair-stratified Cox model). An end-of-trial survey in six communities (three per group) showed a significantly greater increase in the percentage of HIV-positive participants with an HIV-1 RNA level of 400 copies per milliliter or less in the intervention group (18 percentage points, from 70% to 88%) than in the standard-care group (8 percentage points, from 75% to 83%) (relative risk, 1.12; 95% CI, 1.09 to 1.16). The percentage of men who underwent circumcision increased by 10 percentage points in the intervention group and 2 percentage points in the standard-care group (relative risk, 1.26; 95% CI, 1.17 to 1.35). CONCLUSIONS: Expanded HIV testing, linkage to care, and ART coverage were associated with increased population viral suppression. (Funded by the President's Emergency Plan for AIDS Relief and others; Ya Tsie ClinicalTrials.gov number, NCT01965470.).

Comparing the Diagnostics Accuracy of CD4+ T-Lymphocyte Count and Percent as a Surrogate Markers of Pediatric HIV Disease.

The percentage CD4+ T-lymphocytes is used to monitor pediatric HIV disease. However, in resource-limited settings, enumerating the percentage of CD4+ T-lymphocytes is hampered by the lack of laboratory infrastructure and trained technicians. In this paper, we investigated the performances of the percentage and absolute CD4+ T-lymphocytes as markers of pediatric HIV disease progression using data from HIV-infected children enrolled through the Yale Prospective Longitudinal Pediatric Cohort study. A Lehmann family of Receiver Operating Characteristic (ROC) curves were used to estimate and compare the performance of the two biomarkers in monitoring pediatric HIV disease progression. The area under the ROC (AUC) curve and its empirical estimator have previously been used to assess the performance of biomarkers for a cross-sectional data. However, there is a paucity of literature on the AUC for correlated longitudinal biomarkers. Previous works on the estimation and inference of the AUC for longitudinal biomarkers have largely focused on independent biomarkers or failed to consider the effect of covariates. The Lehmann approach allowed us to estimate the AUC of the aforementioned correlated longitudinal biomarkers as functions of explanatory variables. We found that the overall performance of the two biomarkers was comparable. The area under the ROC curves for CD4+ T cell count and percentage were 0.681 [SE = 0.029; 95% CI: 0.624-0.737] and 0.678 [SE = 0.024; 95% CI:0.630-0.725], respectively. Our results suggest that absolute CD4+ T-lymphocyte counts could be used as a proxy for percentage of CD4+ T-lymphocytes in monitoring pediatric HIV in resource-limited settings.

The ROC curve for regularly measured longitudinal biomarkers.

The receiver operating characteristic (ROC) curve is a commonly used graphical summary of the discriminative capacity of a thresholded continuous scoring system for a binary outcome. Estimation and inference procedures for the ROC curve are well-studied in the cross-sectional setting. However, there is a paucity of research when both biomarker measurements and disease status are observed longitudinally. In a motivating example, we are interested in characterizing the value of longitudinally measured CD4 counts for predicting the presence or absence of a transient spike in HIV viral load, also time-dependent. The existing method neither appropriately characterizes the diagnostic value of observed CD4 counts nor efficiently uses status history in predicting the current spike status. We propose to jointly model the binary status as a Markov chain and the biomarkers levels, conditional on the binary status, as an autoregressive process, yielding a dynamic scoring procedure for predicting the occurrence of a spike. Based on the resulting prediction rule, we propose several natural extensions of the ROC curve to the longitudinal setting and describe procedures for statistical inference. Lastly, extensive simulations have been conducted to examine the small sample operational characteristics of the proposed methods.

Exact inference on the random-effects model for meta-analyses with few studies.

We describe an exact, unconditional, non-randomized procedure for producing confidence intervals for the grand mean in a normal-normal random effects meta-analysis. The procedure targets meta-analyses based on too few primary studies, ≤7 , say, to allow for the conventional asymptotic estimators, e.g., DerSimonian and Laird (1986), or non-parametric resampling-based procedures, e.g., Liu et al. (2017). Meta-analyses with such few studies are common, with one recent sample of 22,453 heath-related meta-analyses finding a median of 3 primary studies per meta-analysis (Davey et al., 2011). Reliable and efficient inference procedures are therefore needed to address this setting. The coverage level of the resulting CI is guaranteed to be above the nominal level, up to Monte Carlo error, provided the meta-analysis contains more than 1 study and the model assumptions are met. After employing several techniques to accelerate computation, the new CI can be easily constructed on a personal computer. Simulations suggest that the proposed CI typically is not overly conservative. We illustrate the approach on several contrasting examples of meta-analyses investigating the effect of calcium intake on bone mineral density.

The effect of multimedia interventions on the informed consent process for cataract surgery in rural South India.

CONTEXT: The provision of ocular surgical interventions for poorer, less educated populations is increasing as a result of increased globalization and outreach. However, these populations still have trouble understanding surgical concepts and are not always fully informed decision makers. AIMS: We aimed to test the effect that a multimedia addition to a traditional verbal informed consent would have on patient comprehension of relatively difficult cataract surgical concepts. SETTINGS AND DESIGN: We conducted a randomized controlled trial with relatively uneducated patients reporting to a private surgical hospital in Chennai, India. 47 patients were placed into the intervention group and 50 patients were placed into the control group. MATERIALS AND METHODS: The intervention group was presented with a scripted verbal informed consent as well as a 3-fold pamphlet and a presentation with a 3-dimensional model of the eye. The control group was only presented with a scripted verbal informed consent. The two groups were tested using an 11 item "True/False/I don't know" quiz directly before the informed consent, directly after the informed consent, and one-day postoperatively. STATISTICAL ANALYSIS USED: Scores on the quiz were compared across groups and time-points using paired t-tests. RESULTS: Patients in the both groups showed a significant improvement in scores between pre- and post-informed consent quizzes (P value on the order of 10(-6)) and the improvement in scores was significantly greater in the intervention group than the control group (P value on the order of 10(-16)). There was no significant difference observed in either group with regards to the change in scores between post-informed consent and post-operative quizzes. CONCLUSION: Multimedia aids in addition to a standard informed consent process are effective in improving patient comprehension even for patients with low literacy and limited knowledge of surgical interventions.