Background:  Immune activation from secondary infections is proposed as a prominent stimulus of HIV disease progression. We considered whether acute invasive bacterial infections, Streptococcus pneumoniae and Salmonella, common complications of HIV disease in Africa (> 1.5%/year), are markers for clinical, immunologic, and virologic progression or drive the process.

Methods:  In a prospective cohort of HIV-infected patients in Uganda in a pneumococcal vaccine efficacy trial 1996–1998, we characterized mortality among patients who developed acute S. pneumoniae (n = 30) and Salmonella (n = 30) infections during the trial and control subjects who did not (n = 1279) with Cox regression survival models and likelihood ratio tests. We determined death rates and CD4⁺ T cells/µL in the cohort over time, and plasma HIV-1 in cases and 2 controls matched for age, sex, CD4.

Results:  At enrollment, mean CD4⁺ T cells/µL were lower in cases who subsequently developed S. pneumoniae (232; p = 0.09) and Salmonella (149; p < 0.0001) vs non-case controls (330). HIV-1 RNA (log virions/mL) was higher in both S. pneumoniae (5.3; p < 0.02) and Salmonella (5.4; p < 0.001) vs matched controls (5.7). Overall mortality (deaths/1000 person-years) was 67% in S. pneumoniae (451), 70% in Salmonella (552), and 34% in controls (286), and was CD4-dependent. Covariate-adjusted hazard ratios (HR; 95% CI) for death were 2.1 (1.3 to 3.5) for S. pneumoniae and 2.4 (1.5 to 4.0) for Salmonella vs controls (both p < 0.002), especially among cases with 200 to 500 CD4⁺ cells/µL (HR 4.2 and 3.7). HIV RNA did not change significantly in the pre- and post- 6-month bridging S. pneumoniae or Salmonella nor in matched controls. However, CD4⁺ T cells declined (266 to 143/µL) and HIV RNA increased significantly (5.6 to 6.1 log virions/mL) in the 6 months preceding invasive S. pneumoniae (n = 14), but neither changed in the period bridging S. pneumoniae infection nor among 48 controls.

Conclusions:  The development of invasive bacterial infections is associated with increased long-term mortality among HIV-infected patients in Uganda. However, both S. pneumoniae and Salmonella occur among a relatively more advanced subset of HIV-infected patients in Uganda with lower CD4⁺ T cells and higher HIV RNA than among non-case controls. Moreover, although the incidence of these infections is associated with more advanced disease, no persistent changes in either CD4⁺ T cells or HIV RNA are directly related to the acute infection. Thus, acute invasive bacterial infections may reflect more advanced HIV disease, but these infections do not appear to appreciably drive the disease progression.

Keywords: bacteremia; Africa; mortality