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

• Death (all-cause), or severe HIV-related disease (AIDS-defining diseases, non-AIDS-defining malignancies, and non-AIDS-defining invasive bacterial diseases) [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
  • Severe HIV-related disease are defined as AIDS-defining diseases, non-AIDS- defining malignancies, and non-AIDS-defining invasive bacterial diseases
  • Invasive bacterial diseases are defined as: bacteremia, or bacterial infection of any solid organ or aseptic cavity (eg: pneumonia, pleurisy, meningitis,pyomyositis, pyelonephritis, prostatitis, orchitis, epididymitis, salpingitis, endometritis, endocarditis, cholecystitis, visceral abscesses).
• prevalence of HIV resistance (ANRS12253 associated study) [ Time Frame: 30 month after ARV initiation ] [ Designated as safety issue: No ]

• 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 [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
• Tuberculosis disease or tuberculosis-related death [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
• Changes in CD4 counts [ Time Frame: 30 months ] [ Designated as safety issue: No ]
• Resistance to antiretroviral medications [ Time Frame: 30 months ] [ Designated as safety issue: No ]
• Adherence to treatment [ Time Frame: 30 months ] [ Designated as safety issue: No ]
• Individual socio-economic factors [ Time Frame: 30 months ] [ Designated as safety issue: No ]
• Quality of life [ Time Frame: 30 months ] [ Designated as safety issue: No ]
• Conversions and reversions of repeated QuantiFERON® TB Gold tests between inclusion and month 12 (M12)(ANRS12224 associated study) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Cost-effectiveness of each trial arm in the short- and long-term [ Time Frame: 30 months ] [ Designated as safety issue: No ]
• Death [ Time Frame: 60 months ] [ Designated as safety issue: Yes ]

• probability of first grade 3-4 drug-related side effect [ Time Frame: 30-months ]
• probability of first WHO clinical stage 3-4 defining morbidity event [ Time Frame: 30-months ]

The Temprano trial is based on the following assumptions:

• ART initiation at CD4 counts <800/mm3 could significantly reduce the probability of severe HIV-related morbidity or death in the medium term.
• Tuberculosis and tuberculosis-related deaths are likely to represent a considerable proportion of morbidity and mortality among HIV-infected patients with high CD4 counts in sub-Saharan Africa. Therefore, 6-month Isoniazide Prophylaxis for Tuberculosis (IPT) and early ART could enhance each others efficacy.

• 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.

• HIV Infections
• Tuberculosis

• Drug: Antiretroviral medications
  Antiretroviral medications initiation at any time during the trial if at least one WHO-recommended criterion for starting ART is observed.
• Drug: Antiretroviral medications+Isoniazid prophylaxis
  • Antiretroviral initiation at any time during the trial if at least one 2009 WHO-recommended criterion for starting ART is observed.
  • Isoniazid prophylaxis:300 mg of INH once a day before breakfast for six months, starting one month after study inclusion
• Drug: Antiretroviral medications
  Early ART initiation on the day of inclusion, before reaching the current WHO criteria
• Drug: Antiretroviral medications+Isoniazid prophylaxis
  • Early Antiretroviral medications initiation on the day of inclusion, before reaching the current WHO criteria
  • Isoniazid prophylaxis: 300 mg of INH once a day before breakfast for six months, starting one month after study inclusion

• Active Comparator: I
  Standard of care
  Intervention: Drug: Antiretroviral medications
• Experimental: II
  Standard of care+Isoniazid Prophylaxis:
  Intervention: Drug: Antiretroviral medications+Isoniazid prophylaxis
• Experimental: III
  Early Antiretroviral therapy
  Intervention: Drug: Antiretroviral medications
• Experimental: IV
  Early Antiretroviral therapy + Isoniazid prophylaxis
  Intervention: Drug: Antiretroviral medications+Isoniazid prophylaxis

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 <800/mm3 and no criteria for starting ART according to the most recent WHO guidelines

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

• Gilead Sciences
• Merck