Immunological recovery in tuberculosis/HIV co-infected patients on antiretroviral therapy: implication for tuberculosis preventive therapy

Abstract

BackgroundUnderstanding the immune response to combination antiretroviral therapy (cART) is essential for a clear approach to tuberculosis (TB) preventive therapy. We investigated the immunological recovery in cART-treated HIV-infected patients developing TB compared to those who remained free of TB.MethodsWe extracted data of HIV-infected patients from a multicenter cohort for the HIV clinical surveillance in Germany. No patients included in our study had TB at the beginning of the observation. Using a longitudinal mixed model, we assessed the differences in the mean change of biomarkers (CD4+ cell count, CD8+ cell count, CD4:CD8 ratio and viral load) since cART initiation in patients who remained free of TB vs. those developing TB. To detect the best-fit trajectories of the immunological biomarkers, we applied a multivariable fractional polynomials model.ResultsWe analyzed a total of 10,671 HIV-infected patients including 139 patients who developed TB during follow-up. The highest TB incidences were observed during the first two years since cART initiation (0.32 and 0.50 per 100 person-years). In an adjusted multivariable mixed model, we found that the average change in CD4+ cell count recovery was significantly greater by 33 cells/μl in patients who remained free of TB compared with those developing TB. After the initial three months of cART, 65.6% of patients who remaining free of TB achieved CD4+ count of ≥400 cells/μl, while only 11.3% of patients developing TB reached this immunological status after the three months of cART. We found no differences in the average change of CD8+ cell count, CD4:CD8 ratio or viral load between the two-patient groups.ConclusionAll HIV-infected patients responded to cART. However, patients developing TB showed reduced recovery in CD4+ cell count and this might partly explain the incident TB in HIV-infected patients receiving cART. These findings reinforce the importance of adjunctive TB preventive therapy for patients with reduced recovery in CD4+ cell count.

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+

“…Few studies have reported long-term trends in post-ART CD8 + cell counts. Two years post-ART, two studies reported similar findings to ours, of continued declines in CD8 + cell counts [ 18 , 21 ], whereas three studies reported stabilized CD8 + cell counts at elevated levels (approximately 600–900 cells/μl) [ 12 , 17 , 19 ]. However, sample sizes in these studies were small compared with ours (≤1253), and the patient population was heterogenous, consisting of late presenters or a mixture of treatment naïve and treatment experienced patients.…”

“…The benefits of ART for recovery of CD4 + cell counts are well documented [ 14 – 16 ]. However, few studies have investigated long-term trends in CD8 + cell counts [ 17 – 21 ] and in CD4 + : CD8 + ratio [ 17 – 24 ] after starting ART, with almost all based on small (<150) or moderate (<2000) sample sizes. Given the potential health implications of elevated CD8 + cell counts and CD4 + : CD8 + ratios below 1 [ 19 , 20 , 25 ], more information is needed about their long-term trends in treated patients.…”

Role of CD4/CD8 ratio on the incidence of tuberculosis in HIV-infected patients on antiretroviral therapy followed up for more than a decade

“…Median CD4/CD8 ratio at time of ART initiation in patients who developed incident TB in our cohort was similar to recent reports [18,44]. However, no significant difference in the average change of ratio over time on ART was seen in patients developing TB compared to patients remaining free of TB [44].…”

Increased Prevalence of Liver Fibrosis and HIV Viremia among Patients with HIV, HBV, and Tuberculosis in Botswana

“…In light of this, cHIV/HBV was previously shown to result in slow CD4+ T-cell recovery in these patients compared to PLWHIV only [ 9 , 42 ]. TB also results in slow CD4+ T-cell recovery even after ART initiation [ 43 , 44 , 45 ]. In one South Africa cohort of 15,646 adults, there was no difference in immune restoration between participants with cHIV/TB and those without TB after ART initiation [ 46 ].…”