6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial

Samandari, Taraz; Agizew, Tefera; Nyirenda, Samba; Tedla, Zegabriel; Sibanda, Thabisa; Shang, Nong; Mosimaneotsile, Barudi; Motsamai, Oaitse I.; Bozeman, Lorna; Davis, Margarett; Talbot, Elizabeth A.; Moeti, Themba; Moffat, Howard; Kilmarx, Peter H.; Castro, Kenneth G.; Wells, Charles D.

doi:10.1016/s0140-6736(11)60204-3

Cited by 314 publications

(331 citation statements)

References 33 publications

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“…22,[28][29][30][31] Evidence for the added value of IPT in patients receiving ART was mostly from patients with CD4+ counts of less than 500 cells per cubic millimeter. [32][33][34][35][36][37][38] Our data are consistent with these previous studies that showed that IPT and ART have additive efficacy with respect to the prevention of tuberculosis and that suggested that the two therapies should be given concomitantly. They also highlight for countries that are reluctant to recommend IPT that isoniazid can be prescribed safely when given early in the course of HIV disease.…”

Section: Discussionsupporting

confidence: 91%

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa

2015

N Engl J Med

1,021

447

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BACKGROUND: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast. METHODS: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies. RESULTS: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies. CONCLUSIONS: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.)

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Section: Discussionsupporting

confidence: 91%

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa

2015

N Engl J Med

1,021

447

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“…Concerns also exist on the need and feasibility of monitoring IPT in terms of toxicity and occurrence of TB disease [27]. Recent data from more than 24,000 South African patients showed, however, very low rates of IPT-related adverse events (particularly clinical hepato-toxicity: 0.07%), and suggested that monitoring based on clinical symptoms was sufficient [28].…”

Section: Key Areas Of Operational Researchmentioning

confidence: 99%

Improving the prevention, diagnosis and treatment of TB among people living with HIV: the role of operational research

Sculier

Getahun

Lienhardt

2011

Journal of the International AIDS Society

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Operational research is necessary to improve the access to and delivery of tuberculosis prevention, diagnosis and treatment interventions for people living with HIV. We conducted an extensive review of the literature and reports from recent expert consultations and research-related meetings organized by the World Health Organization and the Stop TB Partnership to identify a TB/HIV operational research agenda. We present critical operational research questions in a series of key areas: optimizing TB prevention by enhancing the uptake of isoniazid preventive therapy and the implementation of infection control measures; assessing the effectiveness of existing diagnostic tools and scaling up new technologies; improving service delivery models; and reducing risk factors for mortality among TB patients living with HIV. We discuss the potential impact that addressing the operational research questions may have on improving programmes’ performance, assessing new strategies or interventions for TB control, or informing global or national policy formulation. Financial resources to implement these operational research questions should be mobilized from existing and new funding mechanisms. National TB and HIV/AIDS programmes should develop their operational research agendas based on these questions, and conduct the research that they consider crucial for improving TB and HIV control in their settings in collaboration with research stakeholders.

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“…The effect is most clearly seen in individuals with presumed Mycobacterium tuberculosis infection, as indicated by a positive tuberculin skin test (TST) (2,3). However, long-term follow-up of TB-preventive therapy trials set in sub-Saharan Africa have shown high rates of TB post IPT (2,(4)(5)(6)(7)(8), and the results of the recently published Thibela study (9) showed a rapid loss of protection following completion of IPT. It is unclear what drives this lack of durable protection from TB disease.…”

mentioning

confidence: 99%

“…If preventive therapy does not cure, all noncured patients will immediately be at risk for developing TB disease through reactivation of their M. tuberculosis infection in addition to the risk of disease following reinfection. The latter scenario, where IPT does not cure latent M. tuberculosis infections (LTBI) in this population, could explain the high TB rates observed immediately post IPT (2,(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

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

Houben¹,

Sumner²,

Grant

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.

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6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial

Cited by 314 publications

References 33 publications

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa

Improving the prevention, diagnosis and treatment of TB among people living with HIV: the role of operational research

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

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