Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis Against Tuberculosis in HIV-infected Adults (ANRS 12136 TEMPRANO)
Information source: French National Agency for Research on AIDS and Viral Hepatitis
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infections; Tuberculosis
Intervention: Antiretroviral medications (Drug); Antiretroviral medications+Isoniazid prophylaxis (Drug); Antiretroviral medications (Drug); Antiretroviral medications+Isoniazid prophylaxis (Drug)
Phase: Phase 3
Sponsored by: French National Agency for Research on AIDS and Viral Hepatitis
Official(s) and/or principal investigator(s):
Xavier Anglaret, MD, PhD, Principal Investigator, Affiliation: Universit茅 Bordeaux 2
Serge Eholi茅, MD, MSc, Pr, Principal Investigator, Affiliation: CHU de Treichville, Abidjan
Christine Danel, MD, PHD, Phone: +225 21 75 59 63, Email: Christine.Danel@pacci.ci
Objective: To compare the benefits and risks of initiating ART according to the WHO
guidelines to the benefits and risks of initiating ART immediately among HIV-infected adults
with CD4 counts >350mm3 in C魌e d'Ivoire, West Africa
Official title: Benefits and Risks of Early Antiretroviral Therapy in HIV-infected Adults in Abidjan, C魌e d'Ivoire: Randomized Controlled Trial (ANRS 12136 TEMPRANO)
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Death (all-cause), or severe HIV-related disease (AIDS-defining diseases, non-AIDS-defining malignancies, and non-AIDS-defining invasive bacterial diseases)
prevalence of HIV resistance (ANRS12253 associated study)
Grade 3 or 4 clinical events (including cardiovascular, renal and bone disease) and laboratory test results, as defined by the ANRS classification system of drug-related adverse events
Tuberculosis disease or tuberculosis-related death
Changes in CD4 counts
Resistance to antiretroviral medications
Adherence to treatment
Individual socio-economic factors
Quality of life
Conversions and reversions of repeated QuantiFERON庐 TB Gold tests between inclusion and month 12 (M12)(ANRS12224 associated study)
Cost-effectiveness of each trial arm in the short- and long-term
- The Temprano trial, began on March 18, 2008 in Abidjan, C魌e d'Ivoire. From March 2008
to November 2009, the trial was carried out according to versions 3. 0 (March 2008-March
2009) and 4. 0 (March 2009-November 2009) of the protocol. During this phase, patients
were eligible for enrolment at CD4 counts 250-350/mm3 and World Health Organization
(WHO) clinical stage 1, or at CD4 counts 350-600/mm3 and WHO stage 1, 2 or 3. They
could be randomized to start antiretroviral therapy (ART) immediately or according to
the 2006 WHO criteria (see protocol versions 3. 0 and 4. 0 for details).
- When the WHO working group on ART for HIV-infected adults and adolescents met in Geneva
on October 14-16, 2009, it revised the 2006 WHO recommendations. Specifically, the
universal CD4 count threshold for initiating ART was increased to 350/mm3. The
Scientific Advisory Board of the Temprano trial met on October 26, 2009 to consider the
implications of this revision and added a second amendment to the Temprano trial
protocol. This amendment was endorsed by the Data Safety Monitoring Board (DSMB) on
January 4, 2010, approved by the funder and authorized by the C么te d'Ivoire National
Ethics Committee for Life Sciences and Health on February 25, 2010. The objective of
this amendment was: (i) to discontinue the trial among subjects who were included with
CD4 counts <350/mm3 and to start them on ART if they were not already receiving
treatment; and (ii) to continue the study among subjects with CD4 counts >350/mm3.
- The current version of the protocol (version 5. 0) only discusses the Temprano trial
among subjects with baseline CD4 counts >350/mm3 . Patients with baseline CD4 counts
<350/mm3 will continue to be followed in accordance with the previous version of the
protocol (version 4. 0)
- As of December 1, 2009, the WHO recommends initiating ART in adults with CD4 counts
<350/mm3, regardless of clinical stage. The Temprano trial evaluates the individual
risks and benefits of starting ART at CD4 counts >350/mm3 in C么te d'Ivoire.
- 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 CD4 counts <350/mm3.
- The main individual risks of very early ART initiation are likely ART-related adverse
events and the development of resistance to antiretroviral drugs.
- Some of the diseases that earlier ART initiation could reduce in sub-Saharan Africa are
infectious and preventable. In C么te d'Ivoire:
- Cotrimoxazole prophylaxis, which prevents bacterial diseases among others, is
recommended for all patients with CD4 counts <500/mm3. All patients in the
Temprano trial whose CD4 counts are <500/mm3 receive cotrimoxazole
- Although the 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) adjust the results of the primary analysis by INH
prophylaxis use; 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 60 months and evaluate the evolution of the ART efficacy / toxicity ratio
from month 30 to month 60 as a secondary endpoint, to inform future policies if early
ART is found to be beneficial at 30 months.
Main objective: To compare the efficacy of initiating ART according to the WHO guidelines to
the efficacy of initiating ART immediately among HIV-infected adults with CD4 counts >350mm3
who are followed for at least 30 months.
Location: Abidjan, C么te d'Ivoire.
Methods: (i) Unblinded multicenter randomized controlled superiority trial evaluating early
ART; (ii) niche cohort within the trial evaluating outcomes in patients exposed to a
six-month course of INH prophylaxis.
Main inclusion criteria: (i) HIV-1 or HIV-1+2 infection; (ii) age >18 years; (iii) nadir CD4
count 350-800/mm3 and WHO clinical stage 1, 2 or 3; 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 among patients
initiating ART immediately (arms III and IV) with patients initiating ART according to the
WHO criteria (arms I and II), after adjusting for INH prophylaxis use.
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
- Efficacy: incidence of severe morbidity
- Description: Data on the incidence of severe morbidity (AIDS-defining diseases,
non-AIDS-defining diseases and non-AIDS-defining bacterial diseases) in
sub-Saharan African adults with CD4 counts >350/mm3 are rare. We will monitor
morbidity events to verify the hypotheses used to calculate the number of patients
needed, and thus to ensure the study's optimal sample size and power, as well as
minimal follow- up time. The DSMB will evaluate morbidity events once the first
400 patients (all arms combined) reach 18 months of follow-up. If the number of
events is higher than anticipated (according to the hypotheses described in
Section 11. 2 of the protocol), the DSMB may suggest an adjustment of the sample
- 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 O'Brien and Flemming, to account for the large variety of available tests.
Minimum age: 18 Years.
Maximum age: N/A.
- HIV-1 or HIV-1 + HIV-2 infection
- Age >18 years
- No ongoing active tuberculosis
- Home address in any district of the greater Abidjan area
- Written informed consent before any clinic visit or laboratory test
- Clinical and immunologic status: CD4 counts 350-800/mm3 and WHO stage 1,2,or 3
- Pregnant or breastfeeding women
- HIV-2 infection alone
- Clinical signs suggesting a severe disease (including tuberculosis) that has not yet
been diagnosed, such as fever, wasting, diarrhea or unexplained cough (partial list)
- Previous ART initiation
- Known severe renal, cardiac or hepatic disease
Locations and Contacts
Christine Danel, MD, PHD, Phone: +225 21 75 59 63, Email: Christine.Danel@pacci.ci
Centre de Prise en Charge et de Formation ACONDA, Abidjan, C么te D'Ivoire; Recruiting
Eug猫ne Messou, MD, PHD, Email: email@example.com
Phone: +225 23 46 25 51
Eugene Messou, MD, PHD, Principal Investigator
Centre de Suivi des donneurs de sang, Centre National de Transfusion Sanguine, Abidjan, C么te D'Ivoire; Recruiting
Albert Minga, MD,MPH, Email: firstname.lastname@example.org
Phone: +225 21 35 52 78
Albert Minga, MD, MPH, Principal Investigator
Centre Int茅gr茅 de Recherches Biocliniques d'Abidjan, Abidjan, C么te D'Ivoire; Recruiting
Henri Chenal, MD, Email: email@example.com
Phone: +225 21 24 09 24
Henri Chenal, MD, Principal Investigator
Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, C么te D'Ivoire; Recruiting
Emmanuel Bissagnene, MD, Pr, Email: firstname.lastname@example.org
Phone: +225 21 24 91 22
Emmanuel Bisagnene, MD, Pr, Principal Investigator
Formation Sanitaire Urbaine Anonkoua Kout茅, Abidjan, C么te D'Ivoire; Recruiting
Makaila Oweyole, MD, Phone: +225 01 51 06 03, Email: email@example.com
Makaila Oweyole, MD, Principal Investigator
Centre de prise en charge de personnes vivant avec le VIH la pierre angulaire, Abidjan, C么te D'Ivoire; Recruiting
Madeleine Sassan Morokro, MD, Phone: +225 21 35 09 68, Email: firstname.lastname@example.org
Madeleine Sassan Morokro, MD, Principal Investigator
Hopital G茅n茅ral Felix Houphouet Boigny, Abidjan, C么te D'Ivoire; Recruiting
Emmanuel Kouam茅, MD, Phone: +225 07 07 31 64, Email: email@example.com
Emmanuel Kouame, MD, Principal Investigator
Unit茅 de Soins Ambulatoires et de Conseil, CHU de Treichville, Abidjan, C么te D'Ivoire; Recruiting
Serge Koul茅, MD, Email: firstname.lastname@example.org
Phone: +225 21 25 94 13
Serge Koule, MD, Principal Investigator
Starting date: March 2008
Last updated: December 2, 2011