title: The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial.
abstract: BACKGROUND
  Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients.
  
  
  OBJECTIVE
  To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis.
  
  
  METHODS
  Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996)
  
  
  METHODS
  An outpatient clinic in Durban, South Africa.
  
  
  METHODS
  642 patients co-infected with HIV and tuberculosis.
  
  
  METHODS
  In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored.
  
  
  RESULTS
  Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups.
  
  
  CONCLUSIONS
  It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis.
  
  
  CONCLUSIONS
  Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 109 cells/L, given the increased survival benefit of early ART initiation in this group.
  
  
  BACKGROUND
  Comprehensive International Program of Research on AIDS.
authors.affiliation: Doris Duke Medical Research Institute, 2nd Floor, University of KwaZulu-Natal, 719 Umbilo Road, Private Bag X7, Congella, 4013, Durban, South Africa.
authors.forename: Kogieleum
authors.initials: K
authors.lastname: Naidoo
authors.forename: Nonhlanhla
authors.initials: N
authors.lastname: Yende-Zuma
authors.forename: Nesri
authors.initials: N
authors.lastname: Padayatchi
authors.forename: Kasavan
authors.initials: K
authors.lastname: Naidoo
authors.forename: Niraksha
authors.initials: N
authors.lastname: Jithoo
authors.forename: Gonasagrie
authors.initials: G
authors.lastname: Nair
authors.forename: Sheila
authors.initials: S
authors.lastname: Bamber
authors.forename: Santhana
authors.initials: S
authors.lastname: Gengiah
authors.forename: Wafaa M
authors.initials: WM
authors.lastname: El-Sadr
authors.forename: Gerald
authors.initials: G
authors.lastname: Friedland
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool Karim
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000150:complications / Q000188:drug therapy*; D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects*; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000453:epidemiology / Q000209:etiology*; D016867:Immunocompromised Host; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D011446:Prospective Studies; D012293:Rifampin / Q000627:therapeutic use; D012307:Risk Factors; D012720:Severity of Illness Index; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*
chemical_list: D044966:Anti-Retroviral Agents; D000904:Antibiotics, Antitubercular; D012293:Rifampin