The global HIV pandemic has a dramatic impact on the epidemiology of tuberculosis (TB).1-3 It has been estimated that global prevalence of active TB was greater than one third of the estimated 36 million patients infected with HIV.4 The risk of TB is dramatically increased in HIV-infected patients as a result of a higher probability of either primary progression or reactivation of latent infection.5 The annual risk of TB among HIV/TB-coinfected patients can exceed 10%, compared with 10% to 20% lifetime risk among non-HIV-infected patients.6,7 The HIV and TB epidemics overlap to a great degree in Southeast Asian countries, including Thailand.8 Tuberculosis is the most frequent major opportunistic infection (OI) in HIV-infected patients,8-10 and TB is still the leading cause of mortality among HIV-infected patients. This accounts for one third of deaths due to AIDS worldwide.11-15
The number of HIV/TB-coinfected patients is declining in the developed countries. This is due to improved infection-control practices along with better diagnosis and treatment of both HIV infection and TB. In the era of effective combined antiretroviral therapy (ART) in developed countries, HIV-related morbidity and mortality rate has dramatically declined.16-18 Nevertheless, most HIV-infected patients in many developing countries still cannot access to ART, and this is primarily due to economic barriers.
In patients with advanced AIDS and active TB, highly active antiretroviral therapy (HAART) may be administered concurrently with the TB treatment because-if ART is deferred-another OI may superimpose and accelerate HIV disease progression.19,20 A small study showed that therapy with antiretroviral drugs can reduce the short-term risk of death for an HIV-infected patient diagnosed with TB.21 Currently, the optimal timing of such therapy is still unknown because adherence, adverse events, and paradoxical reactions are important problems in concurrent treatment of TB and HIV.22
To date, there have been limited clinical data regarding survival rates among HIV/TB-coinfected patients and the impact of ART on clinical outcomes in developing countries. We therefore conducted the present study to compare the survival rate among HIV/TB-coinfected patients who received and did not receive ART. This study also aimed to determine possible risk factors that related to death among these patients and the appropriate timing for initiating ART after TB diagnosis.
A retrospective cohort study was conducted among HIV-infected patients who were diagnosed with active TB between January 2000 and December 2004 at Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand. The patients' identification numbers were identified from annual database of the institute. The data were extracted from the medical records. Inclusion criteria were as follows: (1) HIV-infected patients older than 15 years; (2) diagnosed with active TB by clinical features, positive acid-fast stain and/or positive culture for Mycobacterium tuberculosis; (3) receiving antituberculous therapy. Isoniazid, rifampicin, pyrazinamide, and ethambutol were initiated for the first 2 months followed by isoniazid and rirampicin for the subsequent 4 months. If there is evidence of slow response, prolongation of the continuation phase to 7 months was administered. Direct-observed therapies program was not adopted at the time of study period. Lowenstein-Jansen medium was used for culture and susceptibility. All patients were followed until April 2005. The patients were excluded if the culture results yielded nontuberculous mycobacteria and initiated ART before the patient was diagnosed with TB. Each patient was classified into 2 groups during follow-up period: received ART (ART+ group) and did not receive ART (ART− group). A patient who was eligible to ART+ group defined as a patient who received ART at least 2 visits.
The primary outcome of interest was time from TB diagnosis to death, which was calculated by subtracting the date of the death from the date on which the patient was diagnosed with TB. Patients were censored at the date of last visit if they were lost to follow-up or censored at the date of referral. To obtain the vital status of the patients who were lost to follow-up, we searched the National Registration Database System and the Central Population Database of the Ministry of the Interior in July 2005. The secondary objectives were to determine the possible risk factors related to death and to compare the frequency of death among patients who received ART at different time points after TB diagnosis. Possible risk factors along with other data collected were studied and compared between the 2 groups. This included patients' demographics, previous OIs, site of TB, baseline CD4 cell counts, baseline plasma HIV RNA, and susceptibility of M. tuberculosis to anti-TB drugs. Extrapulmonary TB included TB that involved lymph node, pleura, gastrointestinal tract, central nervous system, skeletal tissue, genitourinary tract, and skin. Disseminated TB defined as military TB or TB that involved greater than 2 organs. Medical records of all deaths that have occurred in the institute were reviewed by the same physician. Cause of death was defined as the last event responsible for the patients' death, whatever the underlying condition is.
Mean (±SD), median (interquartile range, IQR), and frequencies (%) were used to describe patients' characteristics in each group. χ2 test and Mann-Whitney U test were used to compare categorical and continuous variables between the 2 groups, respectively. The Kaplan-Meier test was used to estimate the probability of death and the median time to death after TB diagnosis. The log-rank test was used to compare the median time to death between the 2 groups. The Cox proportional hazard model was used to determine the chance of death after TB diagnosis by adjusting for confounding factors, that is, ART, site of TB, multidrug resistant TB (MDR-TB), and weight. The hazard ratio (HR) and its 95% confidence interval (CI) were estimated. All analyses were performed using SPSS version 11.5. A P value less than 0.05 was considered statistically significant. The study was reviewed and approved from the institute review board.
A total of 1087 patients who met the inclusion criteria were identified from the database. Eighty-four patients needed to be excluded because they initiated ART before they were diagnosed with TB. Mean (± SD) age of 1003 patients was 35.6 (± 8.1) years, and median (IQR) CD4 cell count of 197 patients was 53 (20-129) cells/mm3. Median (IQR) time of follow-up was 14.3 (7.4-26.7) months. Of the 1003 patients, 411 were categorized in ART+ group and 592 were in ART− group. The median (IQR) time from TB diagnosis to initiating ART was 4.7 (1.1-10.6) months.
The patients' characteristics were described and compared between the 2 groups as shown in Table 1. The patients in ART+ group had a higher body weight than the patients in ART− group (P < 0.05). The patients in ART− group had a higher proportion of isolated pulmonary TB, cervical tuberculous lymphadenitis, isoniazid (INH) resistance, and MDR-TB (P < 0.05). The distribution of antiretroviral regimens in ART+ group was as follows: nevirapine-based ART, 397 (80.2%) patients; efavirenz-based ART, 79 (16.0%) patients; protease inhibitors-based ART, 13 (2.6%) patients; and abacavir-based triple nucleoside reverse transcriptase inhibitor ART, 6 (1.2%) patients. The combined backbone nucleoside reverse transcriptase inhibitors were stavudine plus lamivudine (86.3%), zidovudine plus lamivudine (8.7%), stavudine plus didanosine (3.8%), zidovudine plus didanosine (1.0%), and didanosine plus lamivudine (0.2%). The overall mortality rate was 7.7% in ART+ group and 67.7% in ART− group (P < 0.001).
The probability of survival after TB diagnosis estimated by the Kaplan-Meier method is shown in Figure 1. Survival rates at 1, 2, and 3 years were 96.1%, 94.0%, and 87.7% in ART+ group and 44.4%, 19.2%, and 9.3% in ART− group (log-rank test, P < 0.001). Fifty percent of patients in ART− group died within 10.7 months after TB diagnosis. The Cox proportional hazard model was used to compare the chance of death between the patients in ART+ group and ART− group. The factors in this model included weight, pulmonary TB, gastrointestinal TB, CNS TB, MDR-TB, and receiving ART (Table 2). We found that "not receiving ART" was associated with a higher probability of death (HR = 20.0, 95% CI = 8.62-45.45, P < 0.001); that is, patients who did not received ART were 20 times as likely to die compared with patients who received ART. The other risk factors associated with a higher probability of death were gastrointestinal TB (HR = 9.2, 95% CI = 1.10-78.02, P = 0.042) and MDR-TB (HR = 2.0, 95% CI = 1.04-3.78, P = 0.038).
The mortality rate among 411 patients who initiated ART at different time points after TB diagnosis are shown in Table 3. At a median follow-up duration of 14.3 months, patients who initiated ART after 6 months of TB diagnosis were 2.6 times as likely to die compared with those who initiated ART within 6 months after TB diagnosis (P = 0.018).
Among 440 patients who died in both groups, 68 patients died in the hospital and 27 of these (39.7%) patients died of TB-related conditions. The others died of non-TB-related conditions including Mycobacterium avium complex infection, cryptococcal meningitis, bacterial pneumonia with sepsis, Pneumocystis jiroveci pneumonia, wasting syndrome, and lymphoma.
In the present study, most patients with HIV and TB coinfection presented late with very low CD4 cell counts. Most of CD4 cell counts were performed while the patients attended at TB clinic. This finding corresponds with the previous reports from the developed countries.19,23 A number of patients did not receive ART despite low CD4 cell count. The reason is that the national universal coverage ART program was not implemented at that period. Thus, the low-income patients could not afford to initiate ART. Approximately half of our patients presented with either extrapulmonary TB or disseminated TB. Extrapulmonary involvement or disseminated infection of TB had been reported to be more common in patients with advanced immunodeficiency.5 In addition to the treatment of TB, treatment of HIV disease is also required.
To date, combined ART has been widely used for the treatment for HIV-infected patients. A plenty of studies precisely demonstrate the impact of ART on the survival outcomes among HIV-infected patients with successful immune restoration and reductions in morbidity and mortality.16-18 However, the data regarding clinical safety and outcomes of concurrent treatment of HIV and TB are still limited.23,24 A previous study could not demonstrate the survival benefit of ART among HIV/TB-coinfected patients.24 This might be explained by the small sample size and by the fact that study was conducted in the early period of HAART. From the MEDLINE database, the present study is the largest cohort study to date documenting survival rate and risk factors of death among HIV/TB-coinfected patients. The study also included the patients in the era of HAART, although access to ART was an obstacle for a substantial number of HIV-infected patients in Thailand. Herein, we can demonstrate the marked difference of survival rate between HIV/TB-coinfected patients who received and did not receive ART. For HIV/TB-coinfected patients who did not receive ART, approximately half of them died within 1 year after TB diagnosis. This duration is considered to be very short. The results from the present study point out that ART is crucial to improve survival in this population.
It is of interest that the present study also demonstrated gastrointestinal TB as a risk factor of death. Whalen et al24 have shown that survival time was shorter in HIV-infected patients with extrapulmonary TB. This finding may be explained by the fact that patients with extrapulmonary TB have a higher bacterial load of M. tuberculosis and much more severe immunodeficiency status.5
Normally, MDR-TB confers a high risk of mortality rate for both HIV-seropositive and seronegative patients.25-27 Among HIV-infected patients, the prognosis is poor even when the organisms are still susceptible to first-line antituberculous drugs. Our results indicate that HIV-infected patients who were infected with MDR-M. tuberculosis were 2 times as likely to die when compared with those who were infected with non-MDR-M. tuberculosis. Tuberculosis caused by MDR-bacilli in HIV-infected patients is associated with widely disseminated disease, poor treatment response with an inability to eradicate the organism, and substantial mortality.28
Regarding the causes of death, most patients in the present study died of non-TB-related conditions. The previous studies have demonstrated that death within the first few months of TB treatment may be related to TB, whereas late deaths are attributable to HIV disease progression.29,30
For the concurrent treatment of HIV and TB, multiple major concerns should be considered, including the optimal timing to initiating ART after TB treatment, overlapping drug toxicities, drug-drug interactions between rifamycin and antiretroviral drugs, and immune reconstitution syndrome of TB after ART. A previous retrospective study has shown that initiating ART early in severely immunosuppressed HIV-infected patients presenting with TB is associated with decreased mortality.19 Another study demonstrated favorable outcomes of both HIV and TB treatment when ART was initiated at 2 to 4 months of TB treatment.31 Nevertheless, the optimal time to initiate ART in HIV/TB-coinfected patients is still not known. To date, there has not been promising data supporting either early or deferred ART among these patients. For the patients with CD4 cell counts less than 100 cell/mm3, as most patients in the present study, there are no data to support either immediate or deferred ART. Thus, some physicians may be somewhat reluctant to initiate ART while the patients are receiving antituberculous drugs. Our results demonstrate that ART should be initiated within 6 months after TB diagnosis. In contrast, there was no difference of mortality between the patients who initiated ART before and after 2 or 4 months of TB diagnosis. Thus, improvement of survival rate would be achieved by early initiation of ART within the first 6 months of TB diagnosis.
There were limitations in the present study. First, it is the nature of retrospective study that patients' clinical condition may be underestimated and socioeconomic status was not routinely recorded. Some potential risk factors, such as patterns of chest radiographs and patterns of tuberculin skin test, were not included in the present study. Baseline socioeconomic status of patient was not included in the model of mortality analysis, although the cost of ART could be a reason that why some patients received ART and some did not. Second, CD4 cell count was not performed in more than half of the patients secondary to the limited resources. However, 197 patients (178 in ART+ group and 19 in ART− group) who had CD4 performed were included into another Cox proportional hazard model (data not shown) and did not show CD4 as a significant risk factor of death. This might be explained by the fact that most patients in the present study had homogenously low CD4 cell counts, and the proportion of patient who had baseline CD4 cell count is very low in ART− group. Third, the interpretation of the optimal timing to initiate ART is needed to confirm by future prospective study because there are a number of limitations such as current clinical status of each patient, decision of attending physician, and socioeconomic factor. Fourth, 80% of patients in ART+ group received daily 400 mg nevirapine-based ART. Herein, we did not analyze the safety and efficacy of this regimen in the patients who were receiving rifampicin. However, our recent well-designed comparative study demonstrated the favorable outcome and comparable incidences of adverse events of nevirapine 400 mg/d-based ART between HIV-infected patients who received and did not receive rifampicin.32 Lastly, a number of patients could not be identified the definite causes of death because they died outside the hospital. However, the results from the present study provide the clinical information of coadministration of ART and TB treatment for clinicians who care for patients with HIV and TB coinfection, particularly in the developing countries.
In conclusion, this study has demonstrated the substantial increase of survival in patients coinfected with HIV and TB who received ART. The patients who were diagnosed with MDR-TB or gastrointestinal TB increased the risk of death. Antiretroviral therapy should be initiated among advanced HIV-infected patients with TB within 6 months after TB diagnosis. The further collaboration between HIV and TB program will lead to either scale-up patients to access ART or effective treatment and control of TB among coinfected HIV and TB patients. Further prospective interventional studies regarding appropriate timing for initiating ART with an aim to minimize drug toxicity and decrease morbidity and mortality are needed in HIV and TB coinfected patients.
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Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
HIV; tuberculosis; antiretroviral therapy; survival rate; risk factors