Trial Information

Benefits and Risks of Early Antiretroviral Therapy in HIV-infected Adults in Abidjan, Côte d'Ivoire: Randomized Controlled Trial (ANRS 12136 TEMPRANO)

- The main individual benefit of very early ART initiation is likely a reduction in early
severe AIDS-defining and non-AIDS-defining morbidity. While the diseases that might
justify earlier initiation in high-income countries are generally non-infectious
(non-AIDS-defining malignancies, renal diseases and cardiovascular diseases), the
leading cause of early severe AIDS-defining morbidity in sub-Saharan Africa is
tuberculosis and the main causes of severe non-AIDS-defining morbidity are non-invasive
bacterial diseases. As a result of poor access to diagnosis and care, some HIV-infected
people die from early infectious diseases before reaching current WHO criteria for
starting ART.

- Although the Côte d'Ivoire National Tuberculosis Program (PNLT) does not authorize the
use of prophylaxis against tuberculosis, it has allowed the Temprano trial to provide
a six-month course of isoniazid (INH) prophylaxis to half of the study subjects. This
will allow us to (i) put early ART in perspective with a early 6-month INH prophylaxis
use, in a setting where tuberculosis is the first cause of severe HIV-associated
morbidity; and (ii) to describe and assess the feasibility of a six-month course of INH
prophylaxis among patients with high CD4 counts.

- Some drug toxicities are immediate but reversible. If early ART is compared to no ART
in the short term, these toxicities may demonstrate erroneously that early ART is
unfavorable. The risks and benefits of early ART initiation should therefore be
evaluated over the long term. In the Temprano trial, we will: (i) follow patients for
at least 30 months and analyze the primary outcome at 30 months; (ii) follow some study
subjects for 80 months and evaluate the evolution of the ART efficacy / toxicity ratio
from month 30 to month 80 as a secondary endpoint, to inform future policies if early
ART is found to be beneficial at 30 months.

Main objective: To assess the benefits and risks of starting ART immediately and/or to
receive a 6-month IPT among HIV-infected adults with CD4 counts <800mm3 and no criteria for
starting ART immediately according to the most recent WHO guidelines.

Location: Abidjan, Côte d'Ivoire.

Methods: randomized 2x2 factorial superiority trial

Main inclusion criteria: (i) HIV-1 or HIV-1+2 infection; (ii) age >18 years; (iii) nadir CD4
count <800/mm3 and no criteria for starting ART immediately according to the most recent WHO
guidelines; and (iv) no active tuberculosis.

Trial arms: Arm I: ART initiation according to WHO criteria, at any time during follow-up;
Arm II: INH prophylaxis (300 mg/day) for six months and ART initiation according to WHO
criteria, at any time during follow-up; Arm III: immediate ART initiation, before reaching
the WHO criteria; Arm IV: INH prophylaxis (300 mg/day) for six months and immediate ART
initiation, before reaching the WHO criteria.

First-line ART regimens

- Tenofovir / emtricitabine + efavirenz for all HIV-1-infected men and all HIV-1-infected
women who meet the following requirements: on effective contraception and no history of
nevirapine use for the prevention of mother-to-child transmission of HIV (PMTCT).

- Tenofovir / emtricitabine + lopinavir / ritonavir for all HIV-1+2-infected patients and
all women who do not use effective contraception or who have a history of nevirapine
use for PMTCT.

Primary endpoint: Death (all-cause), AIDS-defining disease, non-AIDS-defining malignancy, or
non-AIDS-defining invasive bacterial disease.

Main secondary endpoint: Grade 3 or 4 clinical event (including renal and cardiovascular
events) or laboratory test result, as defined by the ANRS classification system of
drug-related adverse events.

Final primary analysis: It will be performed once the last patient has reached 30 months of
follow-up. Time-dependent analyses will compare the primary outcome : (i) among patients
initiating ART immediately (arms III and IV) versus patients initiating ART according to the
WHO criteria (arms I and II); (ii) among patients who were prescribed a 6-months (arms II
and IV) IPT versus those who were not (arms I and III).

Intermediate analysis on safety criteria:

- Toxicity: all-cause mortality. We have not planned to perform any intermediate analyses
for this criterion. If the number of observed deaths is higher than anticipated,
however, the DSMB may decide to carry one out. In this case, we will adjust the alpha
coefficient using the method suggested by Pocock to account for the large variety of
available tests.

- Efficacy: incidence of severe morbidity. Intermediate analysis: We have not planned any
intermediate analyses for this criterion. If the number of severe morbidity evens is
higher than anticipated once all patients have reached 12 months of follow-up, the DSMB
may decide to carry one out. In this case, we will adjust the alpha coefficient using
the method suggested by Haybittle-Peto, to account for the large variety of available
tests.