Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings

Abstract

Trials of isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretroviral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to posttherapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0-30.9%)]. The proportion cured for 3-mo regimens containing rifampicin or rifapentine was 19-100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit.

Post-treatment effect of isoniazid preventive therapy on tuberculosis incidence in HIV-infected individuals on antiretroviral therapy

“…In contrast, in a previous analysis of trial data from the pre-antiretroviral therapy (ART) era, we found that the high rates of TB following completion of 6-12 months IPT in PLHIV were consistent with an almost complete lack of 'cure' of latent Mycobacterium tuberculosis infection (LTBI) [8]. Mathematical modelling of a trial of community-wide INH in South African gold mines reached similar conclusions about the effectiveness of IPT in PLHIV [9].…”

“…The model is based on a previously published model [8] and is similar in structure to a number of other TB models [16,17]. It describes the TB dynamics in a preventive therapy trial cohort of HIV-infected individuals on ART after the cessation of IPTor placebo.…”

“…In this article, we use an extension of the approach presented in [8] to analyze data from the Khayelitsha trial [15] and estimate the proportion of HIV-infected individuals on ART that were 'cured' by IPT.…”

Human ULK1 Variation and Susceptibility toMycobacterium tuberculosisInfection

“…With few exceptions [9], studies of LTBI susceptibility and genetic variation occurred in tuberculosisendemic regions (geographic differences may affect responses to tuberculosis treatments) [28,29] and did not adjust for epidemiologic risk factors, potentially leading to loss of study power. We enrolled close contacts of tuberculosis cases through a US tuberculosis program to examine whether variation in autophagy genes is associated with susceptibility to M. tuberculosis infection.…”

Aktuelle Aspekte zur Epidemiologie, Diagnose und Therapie der Tuberkulose bei HIV-infizierten Patienten

“…B. auf 36 Monate) die Wirksamkeit erhöht, allerdings erlischt die protektive Wirkung oft, sobald die Gabe von INH abgebrochen wird[57]. In einer Modellanalyse ist dargestellt worden, dass INH bei koinfizierten Personen die LTBI nicht ausheilen kann und auch aufgrund des Risikos einer Reinfektion eine kontinuierliche Gabe nötig ist[58]. Die subklinische TB-Erkrankung und die Häufigkeit einer Reinfektion als Ursache für ein TB-Rezidiv fordern dazu auf, die Konzepte der LTBI-Behandlung zu überdenken[50].…”