Introduction
In resource-limited settings, tuberculosis (TB) is one of the main opportunistic infections and a leading cause of mortality in people living with HIV/AIDS [1–3] [4] [5] [6,7] [6–10]
This study is a retrospective cohort analysis of patients notified as having TB after HAART initiation in five Médecins Sans Frontières (MSF) programmes in low-resource countries with a high TB/HIV burden.
Methods
Settings
By December 2004, MSF was running HIV/AIDS programmes in 24 countries around the world and had approximately 34 000 people enrolled who were followed while taking HAART. Among these programmes, the five included in this study offered HAART for at least 2 years. They are located in Phnom Penh (Cambodia), Surin (Thailand), Homa Bay (Kenya), Chiradzulu (Malawi) and Yaounde (Cameroon). HAART eligibility criteria were similar in all programmes and included patients classified at being at World Health Organization (WHO) clinical stage IV or at stage I, II or III with a CD4 cell count < 200 cells/μl [11]
Diagnosis of tuberculosis
Before HAART initiation, patients were screened for clinical suggestive signs of pulmonary or extra-pulmonary TB. In the Cameroon programme, chest X-ray was systematically performed before starting HAART.
Patients presenting with cough or any respiratory symptoms for 2 weeks or more had three sputum examinations for detection of acid-fast bacilli. Diagnosis of smear-negative cases was based on standard algorithms following WHO guidelines, which include non-response to at least one course of antibiotic targeting pneumonia, chest X-ray suggesting active pulmonary TB and clinician's decision to prescribe a full course of anti-TB therapy [12] Mycobacterium tuberculosis was not available in these programmes.
Inclusions and data collection
All HIV-positive individuals aged 13 years or more and receiving HAART up to December 2003 were included in the analysis. Patients taking TB therapy at the time of HAART initiation were excluded. Data were routinely collected using a standardized monitoring software for HIV patients, called FUCHIA (Follow-UP Care of HIV Infection and AIDS; Epicentre, Paris, France). Demographic data, duration of follow-up, WHO clinical stage, TB and other opportunistic infections, CD4 cell counts and HAART regimen were confidentially recorded. As CD4 cell count was not systematically measured when TB was reported, the most recent available cell count performed 2 months either side of the TB diagnosis was utilized.
Statistical analysis
Incidence rates of notified TB cases were calculated using the numbers of new reported TB cases and were expressed per 100 person-years of follow-up on HAART. The time of follow-up was defined as the interval between HAART initiation and TB diagnosis. For patients on HAART without TB diagnosis, the time of follow-up was defined as the interval between HAART initiation and the last follow-up visit recorded before the date of analysis (April 2004). For patients lost to follow-up or dead, the date of their last recorded visit was utilized. Incidence rates of notified pulmonary and extra-pulmonary TB were measured separately. Simple proportion and 95% confidence intervals were calculated. Analysis was performed using SPSS 11.5 (SPSS, Chicago, Illinois, USA).
Results
A total of 3151 HIV-positive individuals who initiated HAART between December 2001 and December 2003 were included in the analysis. The sex ratio (M/F) ranged from 0.4 in the Cameroon programme to 1.3 in the Cambodia programme. Mean age ranged from 33 years in the Thailand programme to 35 years in the Malawi and Cameroon programmes. Classification as WHO stage 4 also varied, from 26/199 patients (13.1%) in the Cameroon programme to 305/654 (46.6%) in the Kenya programme. Baseline CD4 cell count of < 200 cells/μl ranged between [146/187 (78.1%)] in the Cameroon programme and [621/631 (98.4%)] in the Cambodian programme. The predominant HAART regimen initially prescribed was the fixed drug combination of stavudine, lamuvidine and nevirapine in all programmes (46.3% to 77.8%) except the Cambodia programme, where stavudine, lamuvidine and efavirenz was mostly prescribed (78.0%) (Table 1 ).
Table 1: Baseline characteristics of the 3151 patients included in the analysis from the programmes in Cambodia, Thailand, Kenya, Malawi and Cameroon.
The median durations of follow-up on HAART in Cambodia, Thailand, Kenya, Malawi and Cameroon programmes were 7.3 [interquartile range (IQR) 3.7–12.8], 3.7 (IQR, 1.3–8.3), 3.7 (IQR, 1.4–8.0), 6.7 (IQR, 3.2–15.4) and 11.1 (IQR, 3.2–19.0) months, respectively.
The incidence rates of notified TB are presented for each programme in Table 2 . A total of 320 patients with notified TB was reported, including 209 with pulmonary TB (65.3%) and 111 with extra-pulmonary TB (34.7%).
Table 2: Incidence rate of pulmonary and extrapulmonary tuberculosis in the programmes in Cambodia, Thailand, Kenya, Malawi and Cameroon.
The incidence rate of notified pulmonary TB ranged from 4.8/100 person-years in the Cameroon programme to 17.7/100 person-years in the Kenya programme. Pulmonary TB was reported within the first 3 months after HAART initiation for 29/38 (76.3%), 21/40 (52.5%), 27/52 (51.9%), 46/69 (66.7%) and 8/10 (80.0%) patients with notified pulmonary TB in Cambodia, Thailand, Kenya, Malawi and Cameroon programmes, respectively.
The incidence rate of extra-pulmonary TB ranged from 0/100 person-years in the Cameroon programme to 12.7/100 person-years in the Cambodia programme. Extra-pulmonary TB was reported within the first 3 months after HAART initiation in 34/62 (54.8%), 9/17 (52.9%), 14/21 (66.7%), 4/11 (36.4%) and 0 patients with notified extra-pulmonary TB in the same programmes, respectively.
CD4 cell counts were available at the time of TB diagnosis for only 84/209 (40.2%) patients with pulmonary TB. Among these, 66 (78.6%) had a CD4 cell count < 200 cells/μl and 37 (44.0%) < 50 cells/μl. Similarly, among the 41/111 (36.9%) patients with extra-pulmonary TB and available CD4 cell counts, none had a CD4 cell count > 200 cells/μl and 27 (65.8%) were < 50 cells/μl.
Discussion
Our analysis of open observational cohorts reveals high incidence rates of notified TB among individuals on HAART in five MSF programmes, particularly in the Malawi and Kenya programmes, with pulmonary TB incidence rate of 14.3/100 person-years and 17.6/100 person-years, respectively. These two countries have a very high TB burden, with an overall TB incidence estimated in 2003 of 441/100 000 inhabitants in Malawi and 610/100 000 in Kenya [13] [13] M. tuberculosis culture, presumptive TB instead of confirmed TB was likely to be reported. In addition, the limited availability of diagnostic tools would make it impossible to distinguish between immune reconstitution inflammatory syndrome and undiagnosed prevalent tuberculosis; this is a common problem in such resource-poor settings. Indeed, since 90% of analysed patients had baseline CD4 cell count < 200 cells/μl, it is possible that some of those with notified TB were in fact suffering from immune reconstitution inflammatory syndrome, which is known to be more common in severely immunocompromised patients initiating antiretroviral therapy [14–19] M. tuberculosis culturing and histology and longer follow-up (medians 16.8 and 26 months in South Africa and Ivory Coast, respectively) [14,15]
In spite of this, our data illustrate the limitations of TB diagnosis in HIV/TB-coinfected patients in resource-poor settings and the urgent need to develop more effective and rapid tests. Indeed, direct sputum microscopy only detects up to 50% of pulmonary TB in HIV-positive patients and a recent prospective study evaluating the prevalence of active TB in HIV-infected patients with a CD4 cell count of > 200 cells/μl reported that 29% of those with culture-confirmed pulmonary TB had normal radiography and clinical examination [20,21] [22] M. tuberculosis and reduces laboratory workload significantly, could be used in many settings [23] M. tuberculosis culture, particularly rapid methods, should also be encouraged in some specific settings [24] [25]
A direct consequence of TB diagnosis in HIV-positive patients is the need to switch from a nevirapine-based fixed drug combination to an efavirenz-based regimen according to current WHO recommendations [26]
Another challenge encountered in HIV/AIDS programmes is the difficulties in documenting correctly the notified TB cases, because such cases are diagnosed by, or referred to, existing parallel TB programmes. Indeed, notified TB was difficult to document in our programmes because TB was only reported as ‘any other opportunistic infection’ using our routine monitoring system and detailed TB-related data were only collected under the TB programme conditions. Our results clearly illustrate the urgent need for active integration of TB and HIV/AIDS care, as already stressed strongly by the international community, in order to improve data collection, diagnosis and treatment of TB in HIV-positive patients in resource-poor settings [27]
Our study of observational HIV-positive patient cohorts clearly illustrates the challenges faced by resource-poor countries in TB diagnosis, HIV/TB cotreatment and care integration for TB and HIV. Such challenges will become even more prominent in countries who are scaling up their HAART treatment programmes and adapting their TB protocol from 8 months (with only 2 months rifampicin) to 6 months of a rifampicin-containing regimen [28]
Acknowledgements
The authors are grateful to all the medical officers of the programmes in Phnom Penh, Surin, Homa Bay, Chiradzulu and Yaounde.
Sponsorship: This study was supported by the French, Belgium, Swiss and Holland sections of Médecins Sans Frontières.
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