EFFECT OF ANTIRETROVIRAL THERAPY ON SURVIVAL OF HIV / TB-INFECTED PATIENTS IN UKRAINE

Introduction: There is little information from Ukraine about the effect of highly active antiretroviral therapy (HAART) on survival of HIV/ TB-infected patients. We evaluated the survival and the effect of HAART on mortality on these patients. Methods: Prospective cohort study of HIV patients who developed TB from January 2005 to December 2006 in a Zaporizhzhya AIDS Center, and were tracked for 60 months after start HAART. Survival was determined by Kaplan-Meier method and effect of HAART on survival was evaluated using Cox proportional hazards models. Results: Eighty patients were studied (mean age 34 years, 50% male, median CD4 count 103 cell/μL). In 60 months of HAART 14 patients died. The probability of survival was 82%. In multivariate analysis, patients with a CD4 cell count <100 μL had a 5-fold higher risk of mortality (HR 5, 2; 95% CI 1.4-19, 4) and those with extra pulmonary tuberculosis a 2, 2-fold increased risk (HR 2, 2, 95% CI 1, 1-8, 3). Conclusions: HAART significantly increased probability of survival and reduced the risk of death for HIV/TB-infected patients in Ukraine.


Introduction
The global HIV pandemic has a dramatic impact on the epidemiology of tuberculosis (TB).It has been estimated that global prevalence of active TB was greater than one third of the estimated 36 million patients infected with HIV.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 [1][2][3].The HIV and TB epidemics overlap to a great degree in Eastern Europe countries, including Ukraine.In Ukraine tuberculosis is the most frequent major pportunistic infection (OI) and the leading cause of mortality among HIV-infected patients.In developed countries, prior to the introduction of highly active antiretroviral therapy (HAART), a wide range of survival times in people with TB-HIV was reported [4][5][6][7].Some of these reports showed associations between immunosuppression, history of AIDS and TB location with risk of death [5,6].In the HAART era morbidity and mortality of people living with HIV and AIDS has been reduced significantly, in both industrialized and less developed regions [8,9].Further, in settings of widespread use, HAART appears to have been responsible for a significant reduction in the incidence of TB, even in places with high prevalence of this disease [10,11].There is also increasing evidence about the efficacy or effectiveness of HAART when used together with anti-TB therapy [12].To date, there have been limited clinical data regarding survival rates among HIV/TB-infected patients and the impact of HAART on clinical outcomes in Ukraine.We therefore, conducted the present study to determine the survival rate among HIV/TB-infected patients who received HAART.This study also aimed to determine possible risk factors that related to death among these patients and the appropriate timing for initiating HAART after TB diagnosis.

Material and Methods
A prospective cohort study was conducted among HIV-infected patients who were diagnosed with active TB between January 2005 and December 2006.In study we included HIV-infected patients older than 18 years.TB diagnosis was confirmed by direct (positive Ziehl-Nielsen in sputum smear) or pathological (

Table I. Clinical characteristics of HIV/TB-patients
Extra-pulmonary TB was considered when there was clinical evidence and positive Ziehl-Nielsen in biopsy from at least one extra-pulmonary location, with or without pulmonary TB.
In general anti-TB therapy was standard according to the World Health Organization (WHO).All patients included in the study received antituberculosis medications as directly observed therapy and in accordance with standard Category 1 regimens.Prophylactic regimens against opportunistic infections were provided in accordance with national Ukrainian guidelines during all time of the study.
The HAART regimens consisted of three-drug therapy using combinations listed by the WHO as approved first-line regimens.

Statistical analysis
Median (interquartile range, IQR), and frequencies (%) were used to describe patients' characteristics in each group.The Kaplan-Meier test was used to estimate the probability of death and the median time to death.To compare survival by baseline immunological status, the Kaplan-Meier analysis was further stratified by baseline CD4 count (<100, 100-200, and >200 cells/μL).The hazard ratio (HR) and its 95% confidence interval (CI) derived from univariate and multivariate Cox proportional hazards models.All analyses were performed using STATISTICA 6.0 and SPSS 17.0.A P value less than 0.05 was considered statistically significant.

Discussions
To date, combined ART has been widely used for the treatment for HIV/TB-infected patients in the world.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 [13][14][15].However, the data regarding survival rates among HIV/TB-coinfected patients and the impact of HAART on clinical outcomes in Ukraine are still limited.For HIV/TB-infected patients who did not receive ART, approximately half of them died within 1 year after TB diagnosis.As known, the simultaneous use of HAART with anti-TB therapy in patients with TB-HIV significantly reduces the risk of death in the short and long term compared with the risk of death for those receiving only anti-TB therapy [16][17].The results from the present study point out that HAART is crucial to improve survival in HIV/TB-infected patients.We observed that degree of immunosuppression (CD4+ <100 cells/μL) were associated with increased risk of dying and exstapulmonary TB as a risk factor of death.Whalen et al. [8] have shown that survival time was shorter in HIVinfected 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.Most patients in the present study died of 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.Initiation of HAART and immunological restitution may "unmask» extrapulmonary sites of TB explains the high mortality in first 6 months of HAART.We observed 4 deaths that could be attributed to IRIS, of which 3 were attributable to central nervous system syndromes.The IRIS deaths primarily involved the central nervous system, suggesting that central nervous system manifestations may not be as well tolerated as manifestations in other body compartments and may require more-urgent attention.
In conclusion, HAART significantly reduced the risk of death for people with TB-HIV in Ukraine.These findings add further evidence to emphasize the importance of access to HAART, especially in regions where HIV infection and TB disease are highly prevalent.

Contributors
All authors contributed to conceptualization, design, data collection, and revision of the final draft of the study, which was written by M. Andreichyn and D. Zhyvytsia.

Figure 2 .
Figure 2. Survival time of HIV/TB-patients by CD4 T-lymphocyte count