Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa

Abstract

Objective To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART). Design Observational community-based ART cohort in South Africa. Methods TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models. Results Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 cells/µl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0–200 cells/µl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk. Conclusion Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/µl, the excess adjusted risk of TB during early ART was consistent with ‘unmasking’ of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200–500 cells/µl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/µl.

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa

“…On the one hand, tuberculosis and bacterial diseases are common diseases that act as opportunistic infections in people living with HIV, and we suspect that there is no higher CD4+ threshold that could identify a sharp decrease in risk. [39][40][41][42] On the other hand, patients with slow progression of HIV infection, who represent a small minority of patients, may not have the same benefitrisk ratio from earlier ART as other patients.…”

The HIV-associated tuberculosis epidemic—when will we act?

“…Although use of ART results in major reductions in rates of tuberculosis in HIV treatment cohorts, [29][30][31][32] the eff ect on tuberculosis control in the community is limited by the fact that so many patients, particularly in sub-Saharan Africa, are diagnosed with HIV and start ART at low CD4 cell counts of 100-150 cells per μL. 33 A large proportion of people with HIV infection fi rst presents with active tuberculosis and a CD4 cell count of less than 200 cells per μL.…”

“…33 A large proportion of people with HIV infection fi rst presents with active tuberculosis and a CD4 cell count of less than 200 cells per μL. 22,23,[29][30][31][32]34 HIV diagnosis and start of ART are therefore too late with regard to tuberculosis prevention. Furthermore, in patients who start ART and have not yet developed tuberculosis, the risk of tuberculosis is high for CD4 cell counts of less than 500 cells per μL.…”

“…Furthermore, in patients who start ART and have not yet developed tuberculosis, the risk of tuberculosis is high for CD4 cell counts of less than 500 cells per μL. 29 An important fi rst step that requires immediate implementation is the promotion of earlier HIV diagnosis (ie, before clinical presentation with tuberculosis) and earlier start of ART within existing guidelines. WHO guidelines published in 2006 recommended start of HIV treatment at CD4 cell counts of less than 200 cells per μL.…”

“…63 Preventive treatment with isoniazid could then be considered later when the diagnosis of tuberculosis is easier to confi rm or exclude as a result of immune recovery. 29,64 …”