TEMPRANO

TEMPRANO
Name	TEMPRANO
Acronym	TEMPRANO
Phase	Randomized controlled trial
Population	HIV-positive adults with high CD4 counts
Interventions	Early antiretroviral therapy; isoniazid preventive therapy
Locations	Côte d'Ivoire; West Africa
Enrollment	~2,000 participants
Primary outcome	Mortality and severe morbidity
Start date	2006
Completion date	2015
Principal investigator	François Dabis; Jean-François Delfraissy
Sponsor	ANRS; Agence Nationale de Recherches sur le Sida et les hépatites virales

TEMPRANO TEMPRANO was a randomized, open-label clinical trial evaluating early initiation of antiretroviral therapy (ART) and short-course isoniazid preventive therapy (IPT) among HIV-positive adults in West Africa. The study tested whether starting ART at higher CD4 counts and providing six months of IPT reduced mortality and serious morbidity compared with standard care, informing policy debates involving World Health Organization guidelines, national programs in Côte d'Ivoire, and international funders like the Global Fund.

Background and Rationale

TEMPRANO was motivated by contemporaneous trials and policy discussions including SMART (HIV trial), HPTN 052, and evolving WHO recommendations on timing of ART initiation. Researchers considered evidence from trials such as START (Strategic Timing of Antiretroviral Treatment) and observational cohorts from South Africa, Kenya, and Uganda that suggested benefits to early ART. Concurrent public health concerns like high tuberculosis incidence in cohorts from Mali and Burkina Faso plus WHO guidance on TB preventive therapy prompted incorporation of isoniazid arms. Funders and implementers—including ANRS, INSERM, and ministries of health—sought rigorous local data to guide programs in settings similar to Côte d'Ivoire and Cameroon.

Trial Design and Methods

TEMPRANO employed a 2x2 factorial randomized design enrolling adults with asymptomatic or mildly symptomatic HIV and CD4 counts above thresholds then used by national programs. Randomization allocated participants to immediate ART versus deferred ART per prevailing national criteria, and separately to six months of IPT versus no IPT. The protocol drew on trial methods from HIV Prevention Trials Network strategies and monitoring approaches used in DREAM program evaluations. Primary endpoints mirrored those in START and HPTN 052—composite measures of mortality, AIDS-defining illnesses, and severe non-AIDS events—with case definitions aligned to standards from CDC clinical categories and WHO stage criteria. Clinical sites integrated laboratory monitoring using platforms promoted by PEPFAR and diagnostic algorithms similar to those validated in studies by MSF and IDRC collaborators. Data safety oversight involved independent committees with charters influenced by practices at NIH-funded trials and ethical review by institutional review boards linked to Inserm and local ministries.

Outcomes and Results

TEMPRANO reported that immediate ART reduced the incidence of severe morbidity and death compared with deferred ART, consistent with results from START and reinforcing HPTN 052 findings regarding individual clinical benefit. The IPT intervention lowered the risk of active tuberculosis, echoing results from trials such as Thibela TB and preventive therapy analyses in Botswana and South Africa. Subgroup analyses stratified by baseline CD4 count, viral load, age, and coinfections revealed heterogeneity similar to that observed in cohorts from Ghana and Senegal. Results influenced WHO policy deliberations and were cited in guideline updates alongside data from INSIGHT networks and region-specific modeling from groups like Imperial College London and Johns Hopkins Bloomberg School of Public Health.

Safety and Adverse Events

Safety monitoring documented adverse events attributable to ART and isoniazid consistent with preexisting literature from trials in India, Brazil, and Thailand. Hepatotoxicity, peripheral neuropathy, and drug interactions—concerns highlighted in pharmacovigilance reports from EMA and FDA—were tracked, with rates comparable to contemporaneous ART cohorts in West Africa and pharmacokinetic substudy findings reported in partnership with laboratories at ANRS and INSERM. Serious adverse events triggered data safety monitoring board reviews modeled on procedures used by NIH and Wellcome Trust-funded trials. Programmatic implications for screening and monitoring mirrored recommendations from WHO and national TB programs.

Interpretation and Impact

TEMPRANO provided randomized evidence supporting earlier ART initiation and short-course IPT in high-burden settings, contributing to shifts in global policy championed by WHO and informing national guideline revisions in Côte d'Ivoire, Mali, and neighboring countries. Its findings fed into advocacy and technical guidance by UNAIDS, influenced funding priorities at the Global Fund and PEPFAR, and were incorporated in systematic reviews by groups at Cochrane and modeling exercises by Imperial College London. The trial also strengthened clinical networks and research capacity through collaborations with ANRS, regional universities, and public health institutions.

Criticisms and Limitations

Critiques of TEMPRANO echoed concerns raised in discussions around START and HPTN 052—including generalizability to populations with different comorbidity profiles, operational challenges for scale-up in resource-limited programs like those overseen by Ministry of Health (Côte d'Ivoire), and evolving drug regimens since trial initiation (e.g., shifts toward integrase inhibitor–based ART popularized by studies at DHHS and FDA-approved labels). Limitations included open-label design susceptible to ascertainment bias, sample size constraints for mortality endpoints compared with large international consortia such as INSIGHT, and the need for longer-term follow-up to assess durability of IPT effects against recurrent tuberculosis observed in cohort studies from Zimbabwe and Zambia.

Category:Clinical trials in HIV