A total of 7 patients with a median CD4 lymphocyte count of 15 cells per microliter (IQR: 3-37) had a positive serum CrAG at enrollment. All started fluconazole 400 mg daily and 4 were able to start ART. Four of the patients who had a positive serum CrAG died: 1 from cryptococcal meningitis, 1 from gastroenteritis with severe dehydration, 1 from intestinal obstruction, and 1 from progressive TB disease. The patient who developed cryptococcal meningitis was on fluconazole but not yet on ART. Of the remaining 3 patients, 2 completed follow-up, and 1 was lost to follow-up after requesting transfer to another clinic.
In this cohort of HIV-TB-coinfected patients eligible for ART, we documented high rates of early mortality. Two-thirds of the deaths occurred within the first 6 months after TB diagnosis. This is similar to what has been reported previously.6,7,22
No ART use was the main risk factor for increased mortality. Several retrospective studies and clinical trials have reported the benefit of ART in reducing HIV-associated mortality.13,23,24 This led to the revision of the World Health Organization guidelines for initiation of ART in all TB-HIV-coinfected patients regardless of their CD4 lymphocyte count.25 Unfortunately, in Africa, still many patients present late for TB treatment, with advanced immune deficiency and without prior knowledge of their HIV status. This is illustrated in our cohort where the median nadir CD4 lymphocyte count was 53 cells per microliter. This low CD4 count may also reflect delayed referral for ART by the physicians in charge of TB treatment. In most hospitalized patients, ART could only be started after discharge and referral to the TB/HIV clinic. Many patients consequently deteriorate although on TB treatment because they miss an early opportunity for concurrent HIV care. In primary care clinics in Kampala, there is a low uptake of HIV testing among patients diagnosed with TB except where an “opt-out” approach is used.26 In our clinic, an "opt-out" approach was used, and all patients with TB were routinely offered HIV testing, and previous studies in this and other hospitals indicate HIV testing acceptance rates of 95%-98%.27,28
Male participants were almost 3 times more likely to die than females. In a community-based surveillance study, Zwang et al3 found higher PTB-HIV death rates in males and in older age groups. A study by Cornell et al29 in a South African ART program found that male patients presented late and with advanced disease compared with women. This was associated with higher early mortality. Thus higher mortality in males coinfected with TB-HIV may likely be attributed to differences in health-seeking behavior, although biological differences cannot be ruled out.
In our study among patients who started ART, 10% of the patients who developed TB-IRIS died, and in most cases, there were other non-IRIS-related contributing causes of death. This is consistent with previous reports that indicate life-threatening TB-IRIS is uncommon.8,10,30-32 A systematic review by Muller et al33 concerning the incidence and outcome of IRIS which included information on 54 cohorts, of which 23 had data available on deaths, reported a mortality of only 3% in patients with TB-IRIS.
Cryptococcal antigenemia was associated with a 4-fold increase in the risk of dying. This is consistent with the 7-fold increase in the risk of early mortality reported in a rural Ugandan cohort of patients with HIV infection and asymptomatic cryptococcal antigenemia commencing ART.34 In another Ugandan urban cohort of patients where serum CrAG was systematically measured before ART, fluconazole treatment in patients with a positive serum CrAG and a CD4 lymphocyte count ≤100 cells per microliter was reported as being cost-effective.35 The cost to test and treat to prevent 1 death from cryptococcal meningitis was $299.35
Our study had some limitations. First, 20% of eligible patients with TB-HIV coinfections were not enrolled. Of patients enrolled, 20 (7%) were lost to follow-up; some of whom may have died. Second, in most patients, the cause of death was unknown because postmortem examination was done in only 1 patient.
In conclusion, despite the availability of ART, many of our TB-HIV-infected patients presented with advanced HIV disease. High mortality occurs as patients wait to access ART. Male gender and cryptococcal antigenemia were recognized as additional independent risk factors for early death. Early initiation of ART in patients coinfected with TB-HIV, routine screening for cryptococcal antigenemia in patients with a CD4 count < 250 cells per microliter, and antifungal treatment for those identified to be positive may reduce the risk of death.
We thank all the study clinical staff Proscovia Lwanga, Margaret Nakuya, Carol Olive Namujju, Cynthia Ahimbisibwe, Jane Namganda, Alfred Andama, and Edward Bazze; Nadine Pakker and the data monitoring and management staff of INTERACT; Danstan Bagenda (School of Public Health-Makerere University, Kampala, Uganda) and Olivier Koole (Institute of Tropical Medicine, Antwerp, Belgium); for their expert statistical input. We also thank the leadership of Mulago Hospital administration and the National TB and Leprosy Unit; and the Director Mulago Mbarara Hospital Joint AIDS Program TB-HIV services for the support to patient care in this study.
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APPENDIX I: TB-IRIS STUDY GROUP
Institute of Tropical Medicine, Antwerp, Belgium: Luc Kestens, Robert Colebunders, Pascale Ondoa, Marguerite Massinga Loemb´e; Infectious Disease Institute, Kampala, Uganda: Harriet Mayanja, William Worodria; Joint Clinical Research Centre: Harriet Mayanja; Universite Libre de Bruxelles, Belgium: Francoise Mascart; VIB, Brussels, Belgium and Vrije Universiteit Brussel, Brussels, Belgium: Rafael van den Bergh; Institut Pasteur de Lille, France: Camille Locht; AcademicMedical Centre, Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands: Peter Reiss, Frank Cobelens, Pascale Ondoa, Nadine Pakker; INTERACT, Kampala, Uganda: Roy Mugerwa, Harriet Mayanja, Nadine Pakker, William Worodria.