Identifying efficient linkage strategies for men (IDEaL): a study protocol for an individually randomised control trial.

INTRODUCTION: Men in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and more likely to have longer cycles of disengagement from ART programmes. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will test the impact of various interventions on 6-month retention in ART programmes among men living with HIV who are not currently engaged in care (never initiated ART and ART clients with treatment interruption). METHODS AND ANALYSIS: We will conduct a programmatic, individually randomised, non-blinded, controlled trial. 'Non-engaged' men will be randomised 1:1:1 to either a low-intensity, high-intensity or stepped arm. The low-intensity intervention includes one-time male-specific counseling+facility navigation only. The high-intensity intervention offers immediate outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. In the stepped arm, intervention activities build in intensity over time for those who do not re-engage in care with the following steps: (1) one-time male-specific counselling+facility navigation→(2) ongoing male mentorship+facility navigation→(3) outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events. The primary analysis will be intention to treat with all eligible men in the denominator and all men retained in care at 6 months in the numerator. The proportions achieving the primary outcome will be compared with a risk ratio, corresponding 95% CI and p value computed using binomial regression accounting for clustering at facility level. ETHICS AND DISSEMINATION: The Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums and in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors. TRIAL REGISTRATION NUMBER: NCT05137210. DATE AND VERSION: 5 May 2023; version 3.

Economic evaluation of facility-based HIV self-testing among adult outpatients in Malawi.

INTRODUCTION: HIV self-testing (HIVST) in outpatient departments (OPD) is a promising strategy for HIV testing in Malawi, given high OPD patient volumes and substantial wait times. To evaluate the relative cost and expected impact of facility-based HIVST (FB-HIVST) at OPDs in Malawi for increasing HIV status awareness, we conducted an economic evaluation of an HIVST cluster-randomized controlled trial. METHODS: A cluster-randomized trial was conducted at 15 sites in Malawi from September 2017 to February 2018 with three arms: 1) Standard provider-initiated-testing-and-counselling (PITC); 2) Optimized PITC (additional provider training and job-aids) and 3) FB-HIVST (HIVST demonstration, distribution and kit use in OPD, private kit interpretation and optional HIV counselling). The total production cost per newly identified positive and per person newly initiated on ART were calculated by study arm. These were calculated as the total cost of testing everyone divided by the number of newly identified positives; and the total cost of testing everyone divided by the number of those initiated on ART. Cost-outcomes were calculated under three cost scenarios: (1) full study costs, (2) routine implementation costs and (3) routine implementation + reduced cost for HIVST kits. RESULTS: The average cost per person newly diagnosed in the full study cost scenario was $101, $156 and $189, and cost per person initiated on ART was $121, $156 and $279 for Standard PITC, Optimized PITC and FB-HIVST respectively. In the routine implementation cost scenario, the average cost per person newly diagnosed was reduced to $83, and $93, and cost per person initiated on ART to $83, and $137 for Optimized PITC and FB-HIVST respectively. In the negotiated HIVST cost scenario, the average cost per person newly diagnosed was reduced to $55 and cost per person newly initiated on ART reduced to $81 in the FB-HIVST arm. CONCLUSIONS: While the cost per new ART initiation through FB-HIVST was higher than Standard PITC, FB-HIVST could become cost-saving compared to PITC if the cost of kits is reduced or if treatment linkage rate were increased in the FB-HIVST arm. For high volume OPDs, HIVST may increase facility capacity and increase the number of newly diagnosed positives.

Multidisciplinary Point-of-Care Testing in South African Primary Health Care Clinics Accelerates HIV ART Initiation but Does Not Alter Retention in Care.

BACKGROUND: Lack of accessible laboratory infrastructure limits HIV antiretroviral therapy (ART) initiation, monitoring, and retention in many resource-limited settings. Point-of-care testing (POCT) is advocated as a mechanism to overcome these limitations. We executed a pragmatic, prospective, randomized, controlled trial comparing the impact of POCT vs. standard of care (SOC) on treatment initiation and retention in care. METHODS: Selected POC technologies were embedded at 3 primary health clinics in South Africa. Confirmed HIV-positive participants were randomized to either SOC or POC: SOC participants were venesected and specimens referred to the laboratory with patient follow-up as per algorithm (∼3 visits); POC participants had phlebotomy and POCT immediately on-site using Pima CD4 to assess ART eligibility followed by hematology, chemistry, and tuberculosis screening with the goal of receiving same-day adherence counseling and treatment initiation. Participant outcomes measured at recruitment 6 and 12 months after initiation. RESULTS: Four hundred thirty-two of 717 treatment eligible participants enrolled between May 2012 and September 2013: 198 (56.7%) SOC; 234 (63.6%) POC. Mean age was 37.4 years; 60.5% were female. Significantly more participants were initiated using POC [adjusted prevalence ratio (aPR) 0.83; 95% confidence interval (CI): 0.74 to 0.93; P < 0.0001], the median time to initiation was 1 day for POC and 26.5 days for SOC. The proportion of patients in care and on ART was similar for both arms at 6 months (47 vs. 50%) (aPR 0.96; 95% CI: 0.79 to 1.16) and 12 months (32 vs. 32%) (aPR 1.05; 95% CI: 0.80 to 1.38), with similar mortality rates. Loss to follow-up at 12 months was higher for POC (36% vs. 51%) (aPR 0.82; 95% CI: 0.65 to 1.04). CONCLUSIONS: Adoption of POCT accelerated ART initiation but once on treatment, there was unexpectedly higher loss to follow-up on POC and no improvement in outcomes at 12 months over SOC.

Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice.

Modulation of purinergic signaling, which is critical for vascular homeostasis and the response to vascular injury, is regulated by hydrolysis of proinflammatory ATP and/or ADP by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) to AMP, which then is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. We report here that compared with littermate controls (wild type), transgenic mice expressing human ENTPDase-1 were resistant to the formation of an occlusive thrombus after FeCl(3)-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S], negated the protection from thrombosis, consistent with a role for ADP in platelet recruitment and thrombus formation. ENTPD-1 expression decreased whole-blood aggregation after stimulation by ADP, an effect negated by adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein α(IIb)/ß(3), in a fully activated state, which is critical for thrombus formation. In vivo treatment with a CD73 antagonist, a nonselective adenosine-receptor antagonist, or a selective A(2A) or A(2B) adenosine-receptor antagonist, negated the resistance to thrombosis in transgenic mice expressing human ENTPD-1, suggesting a role for adenosine generation and engagement of adenosine receptors in conferring in vivo resistance to occlusive thrombosis in this model. In summary, our findings identify ENTPDase-1 modulation of purinergic signaling as a key determinant of the formation of an occlusive thrombus after vascular injury.