Screening for Tuberculosis With Xpert MTB/RIF Assay Versus Fluorescent Microscopy Among Adults Newly Diagnosed With Human Immunodeficiency Virus in Rural Malawi: A Cluster Randomized Trial (Chepetsa)

Abstract

Background: Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV)-infected individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality.

Methods: We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi. Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF assay (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED-FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis.

Results: Prevalent TB was diagnosed in 24 of 1001 (2.4%) individuals enrolled in clinics randomized to Xpert, compared with 10 of 841 (1.2%) in clinics randomized to LED-FM. All-cause mortality was 22% lower in the Xpert arm than in the LED-FM arm (6.7 vs 8.6 per 100 person-years; RR, 0.78 [95% confidence interval {CI}, .58-1.06]). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage 3 or 4) disease had lower mortality in clinics randomized to Xpert than to LED-FM (RR, 0.43 [95% CI, .22-.87]).

Conclusions: In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV.

Clinical trials registration: NCT01450085.

Keywords: HIV; Malawi; diagnosis; randomized controlled trial; tuberculosis.

Figure 1.

Study population. *One clinic stopped offering human immunodeficiency virus services prior to enrolling any participants and was replaced by the next-largest clinic. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IPT, isoniazid preventive therapy; LED, light-emitting diode; TB, tuberculosis.

Figure 2.

Patient flow. Shown are the numbers of patients in each arm who were successfully tested, tested positive, and started on treatment (either treatment for active tuberculosis or isoniazid preventive therapy). Of the 180 patients receiving valid light-emitting diode fluorescence microscopy results within a week, 174 (97%) had 2 smears performed, whereas 6 (3%) had only 1 smear performed. Numbers in the boxes at the bottom represent the total number of patients tested (and testing positive), including the initial baseline assessment and the 1-year follow-up period. Abbreviations: LED-FM, light-emitting diode fluorescence microscopy; TB, tuberculosis.

Figure 3.

All-cause mortality in clinics randomized to Xpert vs light-emitting diode fluorescence microscopy (LED-FM). Shown on the x-axis is the rate ratio for all-cause mortality in clinics randomized to Xpert vs LED-FM for tuberculosis screening among adults recently diagnosed with human immunodeficiency virus in rural Malawi. Diamonds denote point estimates, horizontal lines denote 95% confidence intervals, and the vertical line represents no effect (rate ratio, 1.0). The outcome in the entire population after adjustment for covariates (“Overall”) is shown at the bottom, with subgroup analyses and corresponding P values for interaction shown above. Note that the primary study outcome, adjusted only for clinic (cluster), is not shown in this graph; rather, the covariate-adjusted overall outcome is shown for comparability to the prespecified subgroup analyses, which were adjusted for both clinic and other covariates. Abbreviations: CI, confidence interval; LED-FM, light-emitting diode fluorescence microscopy; PY, person-years; WHO, World Health Organization.

Figure 4.

Kaplan-Meier survival estimates, by study arm and clinical stage. The y-axis shows survival according to study arm (Xpert vs light-emitting diode fluorescence microscopy [LED-FM]) and clinical stage (stage 1/2 [less severe] vs stage 3/4 [more severe]). The upper 2 (dashed) lines correspond to participants with stage 1/2 disease in the Xpert (black) and LED-FM (grey) arms. The lower lines correspond to participants with stage 3/4 disease in the Xpert and LED-FM arms. Time is given in days. The majority of deaths occurred in those participants with stage 3/4 disease, for whom diagnosis at a clinic randomized to Xpert was associated with lower all-cause mortality. Abbreviation: LED-FM, light-emitting diode fluorescence microscopy.