Incidence of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome and Impact on Patient Outcome

Abstract

Objectives and DesignWe used data from a randomized trial of HIV-tuberculosis co-infected patients in Mozambique to determine the incidence and predictors of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) occurring within 12 weeks of starting antiretroviral therapy, and to evaluate its association with patient outcome at 48 weeks. MethodsHIV-tuberculosis co-infected and antiretroviral therapy-naïve adults with less than 250 CD4/mm3 were randomized to a nevirapine or efavirenz-based antiretroviral therapy initiated 4 to 6 weeks after starting tuberculosis treatment, and were then followed for 48 weeks. Tuberculosis cases were diagnosed using WHO guidelines, and tuberculosis-IRIS by case definitions of the International Network for the Study of HIV-associated IRIS.ResultsThe 573 HIV-tuberculosis co-infected patients who initiated antiretroviral therapy had a median CD4 count of 92 cells/mm3 and HIV-1 RNA of 5.6 log10 copies/mL. Mortality at week 48 was 6.1% (35/573). Fifty-three (9.2%) patients presented a tuberculosis-IRIS within 12 weeks of starting antiretroviral therapy. Being female and having a low CD4 count, high HIV-1 RNA load, low body mass index and smear-positive pulmonary tuberculosis were independently associated with tuberculosis-IRIS. After adjustment for baseline body mass index, CD4 count and hemoglobin, occurrence of tuberculosis-IRIS was independently associated with 48-week mortality (aOR 2.72 95%CI 1.14-6.54). Immunological and HIV-1 virological responses and tuberculosis treatment outcomes were not different between patients with and without tuberculosis-IRIS.ConclusionIn this large prospective cohort, tuberculosis-IRIS occurrence within 12 weeks of starting antiretroviral therapy was independently associated with the mortality of HIV-tuberculosis co-infected patients at 48 weeks post antiretroviral therapy initiation.

Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis

“…25,26,33 Additionally, higher bacillary/antigen loads have been measured directly in patients who go on to develop PR/IRIS compared to those who do not. In the lung, baseline sputum smear positivity was independently associated with paradoxical TB-IRIS in one study, 34 and a trend towards a similar association has been observed in patients with PR. 3 MTB culture-positive cerebrospinal fluid at the time of diagnosis of TB meningitis (TBM) is a more common finding in patients with subsequent paradoxical TBM-IRIS.…”

“…In HIV-seronegative individuals, low baseline lymphocyte counts at the time of TB diagnosis are associated with an increased risk of developing PR, 2,8 whilst in HIV-seropositive individuals, low CD4+ T cell counts have been related to subsequent IRIS in a range of studies. 13,18,23,24,34 Advanced HIV disease has also been identified as a risk factor for IRIS, consequent on high pre-HAART HIV-1 viral loads. 34 Given that a relationship between active TB and lymphopenia has been reported, 42 and it is suggested that active TB is associated with a degree of immunodeficiency, 43 one could hypothesize that a baseline immunodeficient phenotype in both HIV seronegative and seropositive individuals is implicated in the development of both PR and IRIS.…”

“…13,18,23,24,34 Advanced HIV disease has also been identified as a risk factor for IRIS, consequent on high pre-HAART HIV-1 viral loads. 34 Given that a relationship between active TB and lymphopenia has been reported, 42 and it is suggested that active TB is associated with a degree of immunodeficiency, 43 one could hypothesize that a baseline immunodeficient phenotype in both HIV seronegative and seropositive individuals is implicated in the development of both PR and IRIS. A mouse model of MAC-IRIS has been utilized to explore mechanisms underlying this, and has suggested that it is immune reconstitution occurring in a lymphopenic setting that is the causative factor, rather than specific cellular functions or phenotypes generated during immunodeficiency.…”

Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis

“…Kumarasamy [25] [25] Pedral-Sampaio et al [35] Tansuphasawadikul et al [53] Naidoo et al in South Africa [59] and CARINEMO in Mozambique [58]), two in Asia, TIME in Thailand [53] and CAMELIA in Cambodia [20] and STRIDE [21] was conducted across four continents as described above. Four of the five RCTs (SAPiT, STRIDE, CAMELIA and TIME) investigated different strategies with respect to the timing of ART initiation among TB patients.…”

“…The primary end point in these trials was either death or death and AIDS progression, and paradoxical TB-IRIS was a secondary end point. The CARINEMO trial compared the efficacy and safety of efavirenz versus nevirapine-based ART during rifampicin-based TB therapy with ART started 4-6 weeks after TB treatment [58]. Four of the trials have published secondary papers focused specifically on the TB-IRIS end point [15,24,55,58].…”