Timing of antiretroviral therapy initiation in tuberculosis patients with AIDS: a decision analysis (original) (raw)

Tuberculosis (TB) is the leading cause of mortality in people living with HIV infection (PLHIV), 1 with almost 1 in 4 deaths attributed to HIV-associated TB. 1 A crucial question in caring for patients who are co-infected has been the timing of initiation of antiretroviral therapy (ART) after commencing TB therapy. 2 This is particularly pertinent in South Africa, a country with a high HIV-associated disease burden. Many problems are associated with initiation of ART shortly after commencement of TB therapy, including drug interactions, overlapping toxicities, development of the immune reconstitution syndrome (IRIS), and poor adherence to therapy due to a high pill burden. 2,3 These complications must be balanced against the high mortality in PLHIV co-infected with TB and the need to reconstitute their immune systems. In South Africa, before 2010 the decision to initiate or delay ART was based on the CD4 count and World Health Organization (WHO) staging of patients who were co-infected, according to the National ART Guidelines (2004). 4 Only PLHIV with a CD4+ count of <50 cells/µl or WHO stage IV disease were commenced within 1 month of starting TB therapy. Several studies (the CAMELIA study in Cambodia (N=661), the STRIDE study in four continents (N=806) and the SAPiT study in South Africa (N=642)) showed that early initiation of ART decreased mortality for HIV-associated TB with CD4+ counts <50 cells/µl (CAMELIA and STRIDE: 2 weeks post TB therapy, SAPiT: <4 weeks post TB therapy). 5-7 The SAPiT study also showed that ART initiated during TB therapy decreased mortality in higher CD4+ count strata when compared with ART initiated after completion of TB therapy. 3 In all three studies TB IRIS was more common when ART was initiated early, but did not account for any deaths. 3,5,6 The CAMELIA and STRIDE studies reported no significant differences in adverse drug events between any groups. 5,6 However, in the SAPiT study, adverse drug reactions requiring drug switches were more common in patients who initiated ART within 2 weeks of commencing TB therapy across all CD4+ count strata. 7 In addition to late initiation of ART, the CAMELIA study found that a body mass index (BMI) ≤16, extrapulmonary TB (EPTB) plus pulmonary TB (PTB), nontuberculous mycobacterium, and multidrug-resistant (MDR) TB were independent risk factors for mortality. 5 In the SAPiT study, a low CD4+ count was an independent risk factor for mortality. 7 The South African National ART Guidelines were changed in 2010, and now recommend ART initiation as soon as TB therapy is tolerated, usually between 2 and 4 weeks, for all HIV-associated TB in PLHIV with a CD4+ count ≤350 cells/µl. 8 As the outcomes of the above studies are not consistent, it was hoped that this study would contribute to the understanding of when to Background. HIV-associated tuberculosis (TB) is common in South Africa. The optimal time for initiating antiretroviral therapy (ART) in co-infected patients is a clinical challenge. Aim. We aimed to compare clinical outcomes of patients with HIV-associated TB who commenced ART at different stages of TB therapy. Methods. A retrospective chart review was conducted of 458 patients who initiated ART at ≤28 days (immediate), 29-56 days (early) and ≥57 days (delayed) after commencing TB therapy, and clinical outcomes after 6 months of ART were compared. Results. There was a higher mortality in the immediate group, although this was not significant. Renal impairment (hazard ratio (HR) 2.5; 95% confidence interval (CI) 1.3-4.9; p=0.004) and inpatient ART initiation (HR 3.7; 95% CI 1.6-8.2; p=0.001) were risk factors for HIVassociated TB mortality. A baseline haemoglobin concentration ≥10 g/dl (HR 0.2; 95% CI 0.1-0.6; p=0.003), extrapulmonary as opposed to pulmonary TB (PTB) (HR 0.3; 95% CI 0.1-0.7; p=0.005) and extrapulmonary plus PTB as opposed to PTB (HR 0.3, 95% CI 0.1-0.6; p=0.002) were significantly associated with decreased mortality. Conclusion. The timing of initiation of ART after commencing TB therapy was not significantly associated with increased mortality or survival. Patients with more advanced disease were more likely to die. Early HIV testing and ART initiation is recommended to decrease mortality.