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La chimioprophylaxie antituberculeuse primaire par isoniazide à l’ère des traitements antirétroviraux

Abstract : Tuberculosis (TB) has been a worldwide scourge for millennia. It has regressed in the second half of the 20th century before resurging in the 1980s because of the HIV pandemic. Both diseases potentiate each other and form a "cursed duet". In Africa, TB is the leading cause of mortality among HIV-infected adults, regardless of their level of immunity. One of the measures to fight HIV-associated TB is chemoprophylaxis, which consists in treating latent TB infection to prevent the progression to TB disease. The most evaluated chemoprophylaxis, referred to as "Isoniazid Preventive Therapy" (IPT), consists in prescribing 6 to 12 months of isoniazid monotherapy. Since 1993, WHO recommends the prescription of 6 months of IPT in all HIV-infected persons who do not have evidence of active TB. Despite strong scientific evidence to support this recommendation, the use of IPT has remained low. Before our work, there were three reasons for this:(i) people feared that chemoprophylaxis might favor the emergence of resistance to TB drug; (ii) the IPT trials demonstrated the effectiveness of IPT in reducing TB incidence, not in reducing mortality; (iii) most IPT trials took place before the antiretroviral treatment (ART) era, in highly immunocompromised individuals. As ART also reduces the risk of TB by decreasing immunosuppression, some people considered that IPT had become useless. In this work, we first go over the basic knowledge about HIV infection, TB, the combination of the two diseases, and the concept of antituberculous chemoprophylaxis. Then we present the results of the long-term follow-up of the Temprano ANRS 12136 randomized trial, which took place between 2008 and 2015. This trial followed 2056 HIV infected adults in 9 care centers in Abidjan. Participants with high CD4 counts (mean: 477 cells/mm3) were randomized into 4 arms to study two interventions: 6 months of IPT (received vs. not received) and early ART (immediate initiation vs. delayed initiation). Participants were followed for an average of 4.9 years. Eighty nine percent of participants received ART. During follow-up, there were 86 deaths, 34 in patients randomized to IPT (6-year probability: 4.1%, 95% CI 2.9-5.7) and 52 in those randomized to no-IPT (6-year probability: 6.9%, 5.1-9.2). The Hazard ratio of deaths among those randomized to IPT compared to others was 0.63 (95% CI 0.41-0.97). There was no interaction between IPT and early ART, nor between IPT and time. These results were published in The Lancet Global Health. Finally, we discuss these results with those of previous IPT trials, after reviewing all available randomized-controlled evidence on efficacy, safety, efficacy determinants and risks of resistance. We show that the Temprano trial complements and widens the spectrum of evidence accumulated since 1993 and that ART modifies some key parameters of IPT previously thought to be strongly established. Prior to the ART era, evidence suggested that the efficacy of IPT was high in people with positive Tuberculin Skin Test (TST) but very low in those with negative TST; that there was a loss of IPT efficacy over time; and that IPT had no effect on mortality. With ART, IPT appears to be effective regardless of TST results, have prolonged efficacy, and reduce not only TB but also mortality. IPT remains a very topical intervention in the ART era. These results should convince IPT-reluctant countries to implement WHO recommendations.
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Anani Dodzi Badje. La chimioprophylaxie antituberculeuse primaire par isoniazide à l’ère des traitements antirétroviraux. Médecine humaine et pathologie. Université de Bordeaux, 2017. Français. ⟨NNT : 2017BORD0853⟩. ⟨tel-02441628⟩

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