HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial.

BACKGROUND: Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released extracellularly by infected cells also under cART and in this form induces immune dysregulation, and promotes virus reactivation, entry and spreading. Of note, anti-Tat antibodies are rare in natural infection and, when present, correlate with asymptomatic state and reduced disease progression. This suggested that induction of anti-Tat antibodies represents a pathogenesis-driven intervention to block progression and to intensify cART. Indeed Tat-based vaccination was safe, immunogenic and capable of immune restoration in an open-label, randomized phase II clinical trial conducted in 168 cART-treated volunteers in Italy. To assess whether B-clade Tat immunization would be effective also in patients with different genetic background and infecting virus, a phase II trial was conducted in South Africa. METHODS: The ISS T-003 was a 48-week randomised, double-blinded, placebo-controlled trial to evaluate immunogenicity (primary endpoint) and safety (secondary endpoint) of B-clade Tat (30 µg) given intradermally, three times at 4-week intervals, in 200 HIV-infected adults on effective cART (randomised 1:1) with CD4(+) T-cell counts ≥200 cells/µL. Study outcomes also included cross-clade anti-Tat antibodies, neutralization, CD4(+) T-cell counts and therapy compliance. RESULTS: Immunization was safe and well-tolerated and induced durable, high titers anti-Tat B-clade antibodies in 97 % vaccinees. Anti-Tat antibodies were cross-clade (all vaccinees tested) and neutralized Tat-mediated entry of oligomeric B-clade and C-clade envelope in dendritic cells (24 participants tested). Anti-Tat antibody titers correlated positively with neutralization. Tat vaccination increased CD4(+) T-cell numbers (all participants tested), particularly when baseline levels were still low after years of therapy, and this had a positive correlation with HIV neutralization. Finally, in cART non-compliant patients (24 participants), vaccination contained viral load rebound and maintained CD4(+) T-cell numbers over study entry levels as compared to placebo. CONCLUSIONS: The data indicate that Tat vaccination can restore the immune system and induces cross-clade neutralizing anti-Tat antibodies in patients with different genetic backgrounds and infecting viruses, supporting the conduct of phase III studies in South Africa. Trial registration ClinicalTrials.gov NCT01513135, 01/23/2012.

Strengthening health policy development and management systems in low- and middle- income countries: South Africa's approach.

The development and management of health policies, strategies and guidelines (collectively, policies) in many low- and middle-income countries (LMICs) are often ad hoc and fragmented due to resource constraints a variety of other reasons within ministries of health. The ad hoc nature of these policy processes can undermine the quality of health policy analysis, decision-making and ultimately public health program implementation. To identify potential areas for policy system strengthening, we reviewed the literature to identify potential best practices for ministries and departments of health in LMICs regarding the development and management of health policies. This review led us to identify 34 potential best practices for health policy systems categorized across all five stages of the health policy process. While our review focused on best practices for ministries of health in LMICs, many of these proposed best practices may be applicable to policy processes in high income countries. After presenting these 34 potential best practices, we discuss the potential of operationalizing these potential best practices at ministries of health through the adoption of policy development and management manuals and policy information management systems using the South Africa National Department of Health's experience as an example.