
 tuberculosis is a major public health problem worldwide . although tuberculosis is a treatable disease ,
there were 8.8 million cases of tuberculosis and 1.45 million deaths from tuberculosis in 2010 . with an incidence of 2.3 million cases ,
india has the highest burden of tuberculosis in the world , and one out of every four cases of tuberculosis worldwide occurred in india in 2010 .
india is also the third country in the world in terms of number of people infected by hiv , and 9% of patients with tuberculosis who are tested of hiv are hiv - infected [ 1 , 2 ] .   hiv and tuberculosis form a deadly synergy .
latent tuberculosis is common in developing countries , and the immunodeficiency produced by hiv increases the risk of developing active tuberculosis infection .
patients with hiv infection have higher risk of extrapulmonary tuberculosis , tuberculosis relapse , and death than non - hiv - infected patients .
treatment of tuberculosis in india has been implemented under the revised national control tuberculosis programme ( rntcp ) .
rntcp follows the standard direct observed treatment short - course ( dots ) strategy recommended by the world health organization ( who ) in 2003 .
although the dots strategy has achieved impressive results in india , dots was endorsed by who based on observational studies performed in non - hiv - infected patients . despite the high burden of hiv - related tuberculosis and the high mortality of tuberculosis in hivinfected patients , data about the effectiveness of dots programmes in hiv - infected people
the aim of this study was to evaluate the natural history of hiv - infected patients who were treated of tuberculosis under dots in a large hiv cohort from india .
rural development trust ( rdt ) is a nongovernmental organization that has three hospitals in anantapur . in these hospitals ,
medical care of hiv - infected people is provided free of cost , including medicines and consultation or admission charges . the vicente ferrer hiv cohort study ( vfhcs )
is an open cohort study of all hiv - infected patients visited in rdt hospitals . since september 2009
all antituberculosis treatment ( att ) episodes of patients from the vfhcs database from september 1st 2009 , to september 1st 2011 , were included in the analysis .
all hiv - infected patients with suspicion of tuberculosis infection were admitted to the hospital for performing acid fast bacilli ( afb ) staining of sputum , chest radiograph , and , if clinically relevant , analysis of cerebrospinal fluid , pleural fluid , or ascitic fluid .
cryptococcus antigen was performed in all cerebrospinal fluid specimens to rule out cryptococcal meningitis . in smear - negative patients referring important weight loss but no other clinical sign of tuberculosis infection , an abdominal ultrasound
was performed for investigating signs of abdominal tuberculosis [ 12 , 13 ] . following who recommendations for the definition of tuberculosis case , diagnosis of tuberculosis
was based on the clinical judgment of the treating physician or a combination of the clinical judgment plus the presence of acid fast bacilli ( afb ) and/or caseating or necrotizing granuloma in clinical specimens , in addition to a clinical response to att .
disseminated tuberculosis was defined when there were signs of tuberculosis infection in two different sites .
initially , patients were initiated on att in the hospital , and , once they were stabilized , patients were referred to take att under rntcp , which provides antituberculosis drugs free of cost through a decentralized network of primary healthcare facilities .
the rntcp follows the standard who dots strategy , which provides antituberculosis drugs three times a week during six months ( category i ) for patients who initiate att for the first time and during 8 months ( category ii ) for patients who had previous att for at least one month or patients who experienced category i failures .
drugs were not given in fixed drug combinations as each drug was provided in a single formulation . for category i
treatment , rifampicin , isoniazid , pyrazinamide , and ethambutol were given for two months , followed by rifampicin and isoniazid for four months .
for category ii treatment , patients received streptomycin , rifampicin , isoniazid , pyrazinamide , and ethambutol for two months , rifampicin , isoniazid , pyrazinamide , and ethambutol for one month , and , finally , rifampicin , isoniazid and ethambutol for five months .  
scheduled caste community is the lowest caste in the traditional hindu caste hierarchy and , therefore , suffers social and economic exclusion and disadvantage .
scheduled tribe community is generally geographically isolated with limited economic and social contact with the rest of the population .
scheduled castes and scheduled tribes are considered a socially disadvantaged communities and are supported by positive discrimination schemes operated by the government of india .
backward castes form a collection of  intermediate  castes that were considered low in the traditional caste hierarchy , but above scheduled castes .
we used kaplan - meier survival curves and the log - rank test for comparing factors associated with mortality .
time was measured from the date of the att initiation to death or the last visit date .
multivariable analysis was performed with cox regression proportional hazard models . because cd4 + lymphocyte count was not available for 32 cases , missing values were imputed using the stratified hot deck imputation implemented for stata by martin schonlau ( hotdeckvar command ) .
the proportional hazard assumption was assessed performing log - log survival curves and statistical tests based on schoenfeld residuals .
the goodness of fit of the models was assessed using the harrell 's c concordance statistic .
because the proportional hazard assumption was violated with the initial global model , which included survival estimates from the initiation of att to the death or last visit date , we decided to build two different cox regression models , one for studying factors associated with death during the first three months after initiating att ( early mortality ) and another one for studying factors associated with death after completing three months of att ( delayed mortality ) .
two - way interactions for both early and delayed mortality models were checked . in both models , we found that gender had interactions with other variables , so finally we performed global and stratified by gender models of early and delayed mortality .
during the study period , we identified 1000  att episodes . characteristics and median cd4 + lymphocyte count of patients at the moment of initiating att are presented in table 1 .
the median age was 35 years ( interquartile range ( iqr ) , 3041 ) , and the median cd4 + lymphocyte count was 116 cells / mm ( iqr , 61190 ) .
almost two thirds of the patients were male , more than a half were illiterate , 4.6% were homeless , and 31.2% belonged to a socially disadvantaged communities .
one fourth of patients were smear positive , one fifth received category ii att , and 38% had started art before the initiation of att . of 590 patients who were alive after six months of att , 91 ( 15.4% ) had not initiated art .
the most common form of tuberculosis infection was pulmonary tuberculosis followed by meningitis , pleuritis , abdominal tuberculosis , lymphadenitis , and disseminated tuberculosis .  
the study involved 840 person - years with a mean followup of 10.1 months and 388 deaths .
the cumulative incidence of mortality was 15.7% ( 95% confidence interval ( ci ) , 13.518.1 ) at 1 month , 25.6% ( 95% ci , 22.928.5 ) at 3 months , 31.2% ( 95% ci , 28.334.3 ) at 6 months , 39.4% ( 95% ci , 36.242.7 ) at 12 months , and 46.3% ( 95% ci , 42.550.1 ) at 24 months .
the kaplan - meier survival curve with number at risk is presented in figure 1 . also in figure 1
patients with meningitis and disseminated tuberculosis had higher incidence of mortality during the first three months of att . the incidence of mortality was reduced after three months of att except in patients with smear - positive pulmonary tuberculosis , where the cumulative incidence of mortality remained more or less constant until approximately 14 months after the initiation of att .
kaplan - meier survival curves with log - rank test for other covariates are presented in figure 2 .
intuitively , differences among the covariates age , being homeless , and cd4 + lymphocyte count were visible since the initiation of att , whereas differences among the covariates gender , literacy , community , and having afb positive sputum were more visible after three months of att .
although there was not an important difference in the final survival , patients who were on art at the moment of initiating att had slightly higher mortality during the first three months of att and slightly lower mortality thereafter .
multivariable analysis of factors associated with death during the first three months of att is presented in table 2 . in descending order by hazard ratio , factors associated with increased risk of early mortality were being homeless , having low cd4 + lymphocyte count , having tuberculous meningitis , belonging to a socially disadvantaged caste , having more than 35 years , and being on art at the moment of initiating att .
the main difference between men and women was that , in women , belonging to a disadvantaged caste was not a so strong factor for early mortality as in men .
multivariable analysis of factors associated with death after three months of att is presented in table 3 . in descending order by hazard ratio , factors associated with increased risk of delayed mortality were having low cd4 + lymphocyte count , belonging to a socially disadvantaged caste , receiving category ii att because of a previous episode of att , and having afb positive sputum .
the main difference between men and women was that , in women , belonging to a disadvantaged caste was a less important factor for delayed mortality than being illiterate . although not statistically significant , being on art at the initiation of att was a protective factor for delayed mortality .
this study describes the high mortality of hiv - infected patients who received att under dots strategy in this district of india . in pune , india ,
a 51% mortality after 30 months of followup in 121  hiv - infected patients who received att under rntcp was observed .
these mortality rates are higher than the ones described in the observational studies from sub - saharan africa and other developing countries [ 2225 ] indicating that there is an urgent need to improve the treatment of tuberculosis for hiv - infected patients in india .
although we did not collect information about adherence to att , previous studies in india have shown that a high number of patients under  directly observed  rntcp regimens are poor or nonadherent to treatment [ 26 , 27 ] .
besides interventions to support the completion and the adherence of att , there is a need to improve current guidelines for treating tuberculosis in hiv - infected patients according to recent evidence .
current who guidelines strongly recommend daily att regimen for hiv - infected patients , especially during the intensive phase , because daily att regimens have higher cure rates and lower risk of relapse and treatment failure compared to intermittent att regimens . in a randomized trial performed with hiv - infected patients from india with a followup duration of 36 months , patients treated with intermittent category i treatment had 36% mortality , 15% bacteriological recurrence , and
all patients who experienced treatment failure developed acquired rifampicin resistance . this mortality is lower than the mortality found in our study , but moribund patients were excluded from the study , whereas we included all patients admitted to the hospital . in this randomized trial , extending intermittent treatment for three extra months did not improve mortality nor acquired rifampicin resistance but reduced by half the number of bacteriological recurrences . also recommended by who , the use of fixed dose combinations could improve the adherence to att .
new interventions for achieving early diagnosis of tuberculosis and hiv can have a dramatic impact in reducing the mortality of hiv - related tuberculosis . in india , still 4050% of hiv - infected patients are diagnosed of hiv when their cd4 + lymphocyte count is below 200 cells / mm , and , in many cases , tuberculosis is the first manifestation of hiv infection [ 30 , 31 ] . in our study ,
the cd4 + lymphocyte count was less than 200 cells / mm in 77% of the cases .
if patients could be diagnosed of hiv with higher cd4 + lymphocyte count , art could be started before the appearance of tuberculosis , averting the transmission of tuberculosis to others as well . in accordance with previous studies ,
the socioeconomic characteristics of the patients were important factors related to early and delayed mortality . in our study , homeless patients and people from disadvantaged communities had higher risk of death , especially men .
as seen before in india , receiving category ii att because of previous treatment of tuberculosis was associated with delayed mortality .
interestingly , the type of tuberculosis infection was an important factor for early mortality but not for delayed mortality , whereas having afb positive sputum was an important factor for delayed mortality but not for early mortality . among all types of tuberculosis , tuberculous meningitis had the highest incidence of death during the first three months of att and was an independent factor related to early mortality after adjusting by other variables .
being on art at the moment of initiating att was associated with increased early mortality .
it is probable that the immunity recovery after the initiation of art provokes an increased inflammatory response against the high mycobacterial organism load present in hiv - infected patients , unmasking the tuberculosis infection and increasing the risk of death due to the strong inflammatory reaction . in haiti , patients diagnosed of tuberculosis during the first three months of art were 3.25 times more likely to die than other hiv - infected patients with tuberculosis .
according to these findings , patients who are going to initiate art should undergo a complete evaluation to rule out tuberculosis before the initiation of art .
diagnosis of tuberculosis was performed according to the definition of tuberculosis case suggested by who , but it was not confirmed by culture of mycobacteria .
however , in most resource - limited settings , mycobacterial culture is not available , so including only those patients with a positive culture for mycobacterium tuberculosis would not reflect the common clinical practice in the management of tuberculosis in developing countries .
we did not perform drug sensitivity testing so it is possible that the presence of resistant tuberculosis could explain some of the deaths observed in the study . however , the proportion of patients having rifampicin resistance is only 2.2% in our area , so the possibility of a bias because of high prevalence of multidrug - resistant tuberculosis in unlikely .
in addition , we did not have information about the adherence of patients to att or the proportion of patients who defaulted from treatment or were lost to followup , which are very important factors for the success of dots .
the results of this study show the high mortality of hiv - infected patients treated of tuberculosis under dots in this area of india , confirming what was observed in previous studies from other parts of india .
these patients are diagnosed of tuberculosis with low a cd4 + lymphocyte count and a high proportion of them present with extrapulmonary tuberculosis . when investigating factors associated with mortality , it is useful to differentiate between factors associated with early mortality and factors associated with delayed mortality .
we found that tuberculous meningitis and being on art when initiating att are associated with early mortality .
factors related to poor socioeconomical status such as being homeless or belonging to a disadvantaged community are also associated with an increased risk of death .
patients who received att previously and patients having afb positive sputum have higher risk of delayed mortality .
these findings indicate that there is an urgent need to improve the treatment of tuberculosis in hiv - infected patients in india .
 despite the impressive global results of dots in india , the effectiveness of dots for the treatment of tuberculosis in hiv - infected patients is not well known . 
 this is an observational prospective cohort study performed in anantapur district , andhra pradesh , india . 
 the study included 1000  dots antituberculosis treatment ( att ) episodes and 840 person - years . 
 cd4 
 lymphocyte count was below 200  cells / mm3 in 77% of the cases , and 21% were retreatments . 
 two thirds were presented with extrapulmonary tuberculosis , and the most common form of extrapulmonary tuberculosis was tuberculous meningitis followed by pleuritis , abdominal tuberculosis , and lymphadenitis . 
 cumulative incidence of mortality was 16% , 26% , 39% , and 46% at 1 , 3 , 12 , and 24 months , respectively . 
 factors associated with three - month ( early ) mortality were being homeless , having low cd4 + lymphocyte count , having tuberculous meningitis , belonging to a socially disadvantaged community , having more than 35 years , and being on an antiretroviral therapy at the moment of initiating the att . 
 factors associated with delayed mortality were having low cd4 + lymphocyte count , belonging to a socially disadvantaged community , receiving a category ii att because of a previous episode of att and having acid fast bacilli in sputum before the att initiation . 
 these findings indicate that there is an urgent need to improve the treatment of tuberculosis in hiv - infected patients in india . 
1. Introduction
2. Methods
3. Results
4. Discussion 
5. Conclusions 