HIV patients initiating ART who were prescribed empirical tuberculosis therapy demonstrated similar mortality rates compared with those who received preventive isoniazid alone, according to a study recently published in The Lancet.
“Providers often have concerns about using isoniazid as preventive therapy in patients with HIV, and particularly in patients with very advanced HIV disease, because they worry that they may be giving patients with active TB a single drug,” Gregory P. Bisson, MD, MSCE, assistant professor of infectious disease and senior scholar at the Perelman School of Medicine, University of Pennsylvania, told Infectious Disease News. “As a result, they don’t screen, and they don’t use isoniazid to prevent TB.”
Gregory P. Bisson
Reduced AIDS progression among patients receiving isoniazid
From Oct. 31, 2011 to June 9, 2014, Bisson and colleagues enrolled 850 HIV patients with no exposure to ART into an open-label randomized controlled trial. Eligible participants were aged 13 years or older, demonstrated CD4 cell counts of less than 50 cells/μL, did not have evidence of active TB and were eligible for either preventive isoniazid therapy or empirical TB treatment. Patients were randomly assigned to receive one of these treatments alongside ART and TB screening, and received care relevant to any diagnoses received throughout the study. The primary endpoint was survival at 24 weeks, with secondary outcomes including time to death, AIDS progression, TB status, clinical symptoms and lab abnormalities.
The baseline characteristics of patients in both groups were similar, and a median CD4 count of 18 cells/μL. Each had 22 recorded deaths or unknown vital outcomes at 24 weeks, equivalent to a 5.2% mortality rate (isoniazid 95% CI, 3.4-7.8 empirical 95% CI, 3.5-7.8) and an absolute risk difference of –0.06% (95% CI, –3.05% to 2.94). These rates were similar among patients regardless of enrollment country. Time until the primary endpoint also was comparable, and the leading cause of patient death was HIV-associated infection. When compiling the death or AIDS progression outcomes, the empirical treatment group more frequently demonstrated unfavorable outcomes than the isoniazid group (17% vs. 13%; P = .06) and did so at a quicker pace. The rate of safety-related outcomes, such as grade three or four symptoms or laboratory abnormalities, also were similar in each group.
Taken together, the researchers wrote that these findings suggest isoniazid preventive therapy is safe and no less effective than empiric TB treatment among patients with advanced HIV initiating ART.
“No previous study has compared, in a randomized trial, use of isoniazid vs. multidrug TB therapy in patients with such advanced HIV,” Bisson said. “The study results suggest that screening and use of isoniazid can be safely done in even the most advanced HIV-infected patients. Indeed, the very low mortality rate in the study suggests that routine screening and provision of isoniazid may improve mortality rates in those at highest risk for near-term death on ART.”
Nurse-led empiric TB treatment for HIV patients ineffective
Similar findings were presented in February at CROI 2016 by Alison Grant, MBBS, PhD, DTM&H, professor of international health at the London School of Hygiene & Tropical Medicine.
In her study, Grant and colleagues randomly assigned 24 South African primary care clinics to either conduct a risk-based TB management strategy, or act as a control. When engaging HIV patients with CD4 counts of 150 cells/μL or fewer who were not already taking ART or TB treatment, nurses at the intervention clinics were asked to categorize the patient as high probability (hemoglobin < 10 g/dL, BMI ≤ 18.5 or positive lateral flow assay for urinary lipoarabinomannan), medium probability (any TB symptom and no high probability criteria) or low probability (no TB symptoms or high probability criteria). Patients determined to be at high risk by nurses were immediately given TB treatment and received ART after 2 weeks. Those classified as medium risk underwent additional investigation for TB.
Among the 1,507 patients enrolled within the intervention arm, 46% were categorized as high probability, 32% as medium and 23% as low. However, analysis of patients with known vital status revealed a mortality rate of 19 per 100 person-years among those receiving the intervention, an insignificant decrease over the 21.6 per 100 person-years reported among controls (adjusted RR = 0.87; 95% CI, 0.61-1.24). No difference was seen between the intervention and control arms for hospitalization at 6 months (13.3% vs. 10.4%; aRR = 1.11; 95% CI, 0.88-1.38), as was the case when examining the proportion who had started ART by 30 days (66.4% vs. 72.8%; aRR = 0.91; 95% CI, 0.79-1.05).
“Just increasing the number of people treated for TB alone is not enough to make a big difference on early mortality,” Grant said. “What we need is more refined care for these very high-risk people with advanced HIV disease.” – by Dave Muoio
Grant A, et al. Abstract 155. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 22-25, 2016; Boston.
Hosseinipour MC, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)00546-8.
Disclosure: The researchers report no relevant financial disclosures.