TEMPRANO: more evidence for early ART

A trial of early antiretrovirals and isoniazid preventive therapy in Africa.

TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015 Jul 20. [Epub ahead of print]

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 immunodeficieny 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.

Abstract [1]  Full-text [free] access [2]

Editor’s notes: Recommendations and guidelines on the optimal time to start antiretroviral therapy (ART) are evolving rapidly. These are driven by improved ART regimens with better safety profiles, the desire to improve further the survival and health of people living with HIV, and the need to halt HIV transmission. The TEMPRANO study in Côte d’Ivoire is among several randomised trials reporting significant benefits in severe morbidity and mortality from early ART initiation, before serious decline in CD4 count or presentation with clinical disease. Findings are consistent with the multi-site START trial (also discussed in this edition of HIV This Month) and long-term follow-up from HPTN 052 (a trial of early ART among HIV serodiscordant couples), despite the different CD4 count cut-offs, outcome definitions etc. Collectively these findings were a major focus of discussion at the International AIDS Society conference in Vancouver, Canada in July 2015, and they will shape ongoing revision of the WHO treatment guidelines. 

The TEMPRANO study looked at immediate ART (usually tenofovir-emtricitabine + efavirenz) plus or minus six months of isoniazid prophylaxis in people who did not meet the (evolving) WHO criteria for eligibility, in a rigorous, controlled trial with a 2x2 factorial design. The results illustrate significant reductions in risk of a serious event (TB or HIV-associated illness) or death attributable to both programmes over 30 months. Tuberculosis represented 42% of all primary endpoints. It should be noted that the absolute risk of serious events (TB or severe illness or death) was low in the group with higher baseline CD4 counts.

Early ART initiation will be required to meet the UNAIDS target of 90-90-90 (90% of HIV positive individuals knowing their status, 90% of people being on ART and 90% of people on ART being virally suppressed), but may only have an impact on the second of these targets. Observers recognise that the challenge of earlier diagnosis, and retention and adherence on treatment, remain barriers to maximising public health impact of the very promising results of early treatment trials.

In the TEMPRANO study a significant proportion of people screened for this study declined to participate and there was a further loss to follow-up during the study, proportions which may increase in an operational setting. There was a higher rate of short term adverse events in the earlier treatment group, relating to the toxicity of the drugs themselves.

The evidence for earlier ART in terms of individual benefit and reduction of transmission is increasing, particularly in settings with high burdens of tuberculosis and bacterial disease. The challenge will be engaging populations of healthy people and designing treatment systems and strategies to optimise that engagement. Long term follow-up of the cohorts in these trials will be informative as will trials of treatment delivery strategies.   

Avoid TB deaths [4]
Africa [7]
Côte d'Ivoire [8]
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