The SAPiT trial showed that initiation of ART during tuberculosis treatment in patients with sputum AFB smear positive tuberculosis and HIV-infection with CD4+ counts <500 cells/mm3
reduced mortality by 56% (95% CI, 21% to 75%). The mortality rate rose from 5.4 per 100 person-years to 12.1 per 100 person-years when initiation of ART was delayed until completion of tuberculosis treatment. The period between completion of tuberculosis treatment and ART initiation is important; a considerable number of the deaths in the sequential arm occurred during this time (). Once initiated, however, ART was associated with comparable high levels of viral suppression in both treatment arms, which are similar to those observed in other AIDS treatment programmes in South Africa17
Mortality in HIV-tuberculosis co-infected patients is known to be high despite effective tuberculosis treatment5
. Observational studies among HIV-tuberculosis co-infected patients, have indicated that ART initiation during tuberculosis treatment improves treatment outcomes. A meta-analysis of 6,934 patients from five hospitals in Madrid, showed a significant 63% improvement in survival in patients initiated on ART during tuberculosis therapy18
. In Thailand, an analysis of 1003 patients demonstrated a 20-fold higher mortality rate in patients not receiving ART with tuberculosis treatment.19
Another Thai review of 626 patients found a HR of 0.17 for death in patients who commenced ART during tuberculosis treatment20
. Although these studies show a consistent association between ART and survival in co-infected patients, the SAPiT trial is the first randomized controlled trial to corroborate these retrospective observational data.
Mortality was 46% lower (p=0.04) in the integrated treatment arm participants with CD4+ counts <200 cells/mm3
. While the number of deaths is small in the sub-group with CD4+ counts between 200 and 500, the trend of lower mortality in the integrated treatment arm was present. This finding has treatment guideline and policy implications. Current WHO guidelines on treatment of HIV-tuberculosis co-infection recommends deferment of ART initiation until completion of tuberculosis treatment in WHO stage 3 patients with CD4+ counts >200 cells/mm3 10
. Our findings suggest that this guideline be expanded to include co-treatment of HIV and tuberculosis in patients with CD4+ counts <500 cells/mm3
There is increasing evidence to suggest that earlier ART initiation in HIV-infected patients even without tuberculosis is associated with improved outcomes21–23
. In an analysis of 8,362 asymptomatic patients with HIV infection in the United States and Canada22
, mortality was 69% lower in patients who initiated ART at CD4+ counts between 350 and 500 cells/mm3
. Similarly, data from 18 prospective cohort studies have shown that deferring ART was associated with higher rates of AIDS and death than starting therapy when the CD4+ count was >350 cells/mm3 23
However, major concerns regarding the early initiation of ART during tuberculosis treatment are the potential mitigating effects of the increased risk of IRIS, additive toxicities and potential adverse effect on tuberculosis treatment outcomes. The study found similar rates of grade 3 and 4 adverse events in the two treatment arms and similar tuberculosis outcomes. Since many of the deaths occurred after tuberculosis treatment completion, the tuberculosis treatment providers were unaware of the benefits of tuberculosis and HIV co-treatment. Although the IRIS incidence rate was significantly higher in the integrated treatment arm, this was not unexpected. IRIS has been associated with earlier ART initiation in co-infected patients24, 25
. The IRIS incidence rate in the integrated treatment arm was similar to that observed in other developing country cohorts24, 26
including a retrospective analysis of hospitalised Thai patients receiving both ART and tuberculosis treatment that found that 12.6% (21/167) experienced an IRIS event26
. However, none of the deaths in the SAPiT trial, where information on cause of death was available, were considered attributable to IRIS. It is reassuring that recent studies of tuberculosis-associated IRIS indicate that this complication is rarely fatal and that severe episodes can be successfully managed with prednisone27
. Thus, the concern about increasing the likelihood of IRIS must be tempered by the survival benefit shown in our study. Nevertheless, the paradoxical deterioration in the clinical status is sufficiently common to warrant close clinical monitoring in the first few months of ART initiation in patients co-infected with tuberculosis.
We acknowledge several limitations of our study. Using all-cause mortality as the primary endpoint might underestimate the potential impact of integrated HIV-tuberculosis treatment on tuberculosis and HIV-specific mortality. Since we were not able to obtain reliable information on the causes of all deaths in the trial, we were not able to estimate the impact on deaths related only to tuberculosis and HIV. As our trial only included patients who had AFB smear positive disease and were diagnosed and treated in an ambulatory tuberculosis clinic setting, results may not be directly generalizable to all forms and severity of tuberculosis. Since a retrospective analysis of 549 AIDS patients with extra-pulmonary tuberculosis showed that the introduction of HAART significantly improved survival28
, early ART initiation may have similar benefits in extra-pulmonary tuberculosis patients. While we have no reason to believe that our findings do not apply to sputum smear negative tuberculosis this needs empiric confirmation. Another limitation was the delay in ART initiation after tuberculosis treatment completion in the sequential treatment arm due to clinical grounds (often due to raised liver enzymes) or missed visits. Further, the question of when during the course of tuberculosis treatment, ART should be initiated awaits completion of the study.
In summary, the findings from this study provide compelling evidence of the benefit of initiation of ART during tuberculosis treatment in patients with HIV disease. They support recommendations by the WHO and others for the integration of tuberculosis and HIV care. Health care providers within countries and funders should consider monitoring the proportion of HIV-tuberculosis co-infected patients who are initiated on ART. Such a metric could serve as an impetus for HIV-tuberculosis integration and serve as a key indicator of the success of such programs. This would require that all newly diagnosed tuberculosis patients be offered an HIV test; those who are HIV positive be offered a CD4+ count and those with a CD4+ count <500 cells/mm3 be initiated on ART during tuberculosis treatment. If implemented in South Africa alone, it is estimated that such a strategy could lead to approximately 150,000 more HIV-tuberculosis co-infected patients initiating ART during tuberculosis treatment annually and an estimated 10,000 deaths averted each year.