Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis Against Tuberculosis in HIV-infected Adults (ANRS 12136 TEMPRANO)

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

Status: Recruiting

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: Université Bordeaux 2
Serge Eholié, MD, MSc, Pr, Principal Investigator, Affiliation: CHU de Treichville, Abidjan

Overall contact:
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 Côte d'Ivoire, West Africa

Official title: Benefits and Risks of Early Antiretroviral Therapy in HIV-infected Adults in Abidjan, Côte 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

Primary outcome:

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)

Secondary outcome:

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® TB Gold tests between inclusion and month 12 (M12)(ANRS12224 associated study)

Cost-effectiveness of each trial arm in the short- and long-term

Detailed description: Historical Background

- The Temprano trial, began on March 18, 2008 in Abidjan, Côte 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 Côte 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)

Scientific Background

- 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 Côte 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.

Specific issues

- Some of the diseases that earlier ART initiation could reduce in sub-Saharan Africa are

infectious and preventable. In Côte 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 chemoprophylaxis.

- 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, Côte 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 available tests.

- 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 size.

- 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. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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

Exclusion Criteria:

- 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

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, Côte D'Ivoire; Recruiting
Eugène Messou, MD, PHD, Email: messou_eugene@yahoo.fr
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, Côte D'Ivoire; Recruiting
Albert Minga, MD,MPH, Email: minga.albert@yahoo.fr
Phone: +225 21 35 52 78
Albert Minga, MD, MPH, Principal Investigator

Centre Intégré de Recherches Biocliniques d'Abidjan, Abidjan, Côte D'Ivoire; Recruiting
Henri Chenal, MD, Email: chenal@aviso.ci
Phone: +225 21 24 09 24
Henri Chenal, MD, Principal Investigator

Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Côte D'Ivoire; Recruiting
Emmanuel Bissagnene, MD, Pr, Email: bissagnene@yahoo.fr
Phone: +225 21 24 91 22
Emmanuel Bisagnene, MD, Pr, Principal Investigator

Formation Sanitaire Urbaine Anonkoua Kouté, Abidjan, Côte D'Ivoire; Recruiting
Makaila Oweyole, MD, Phone: +225 01 51 06 03, Email: omakaila@yahoo.fr
Makaila Oweyole, MD, Principal Investigator

Centre de prise en charge de personnes vivant avec le VIH la pierre angulaire, Abidjan, Côte D'Ivoire; Recruiting
Madeleine Sassan Morokro, MD, Phone: +225 21 35 09 68, Email: sassan@aviso.ci
Madeleine Sassan Morokro, MD, Principal Investigator

Hopital Général Felix Houphouet Boigny, Abidjan, Côte D'Ivoire; Recruiting
Emmanuel Kouamé, MD, Phone: +225 07 07 31 64, Email: kenkouamem@yahoo.fr
Emmanuel Kouame, MD, Principal Investigator

Unité de Soins Ambulatoires et de Conseil, CHU de Treichville, Abidjan, Côte D'Ivoire; Recruiting
Serge Koulé, MD, Email: kooleyso@yahoo.fr
Phone: +225 21 25 94 13
Serge Koule, MD, Principal Investigator

Starting date: March 2008
Last updated: December 2, 2011