Effect of HIV infection on TB treatment outcomes and time to mortality in two urban hospitals in Ghana-a retrospective cohort study

Introduction Tuberculosis (TB) is currently causing more deaths than Human Immunodeficiency Virus (HIV) globally. Ghana as one of the 30 high burden TB/HIV countries has a high annual TB case-fatality rate of 10%. The study sought to assess the effect of HIV infection on TB treatment outcomes and assess the time to mortality after treatment onset. Methods We conducted a review of treatment files of TB patients who were treated from January 2013 to December 2015 in two urban hospitals in the Accra Metropolis. Modified Poisson regression analysis was used to measure the association between HIV infection and TB treatment outcomes. Kaplan-Meier survival estimates were used to plot survival curves. Results Seventy-seven percent (83/107) of HIV infected individuals had successful treatment, compared to 91.2% (382/419) treatment success among HIV non-infected individuals. The proportion of HIV-positive individuals who died was 21.5% (23/107) whilst that of HIV-negative individuals was 5.5% (23/419). Being HIV-positive increased the risk of adverse outcome relative to successful outcome by a factor of 2.89(95% CI 1.76-4.74). The total number of deaths recorded within the treatment period was 46; of which 29(63%) occurred within the first two months of TB treatment. The highest mortality rate observed was among HIV infected persons (38.6/1000 person months). Of the 107 TB/HIV co-infected patients, 4(3.7%) initiated ART during TB treatment. Conclusion The uptake of ART in co-infected individuals in this study was very low. Measures should be put in place to improve ART coverage among persons with TB/HIV co-infection to help reduce mortality.


Introduction
Antiretroviral therapy (ART) use in areas endemic with tuberculosis (TB) is highly beneficial but HIV treatment coverage remains suboptimal. Early initiation of ART improves survival of people living with human immunodeficiency virus (HIV), reduces the incidence of TB and delays the progression of HIV [1,2]. In patients with TB/HIV coinfection, concurrent ART during TB treatment is also associated with improved survival among patients [3,4]. ART suppresses viral replication; transforming HIV infection from a highly fatal to a chronic disease that can be managed with a favorable prognosis [5]. There has been more than a two-fold increase in the number of people receiving ART since 2010 in the world's most affected regions -Eastern and Southern Africa. This has made a huge contribution to the reduction in acquired immune deficiency syndrome (AIDS)-related deaths worldwide -from 1.4 million in 2010 to 940,000 in 2017 [6]. It is estimated that about 54 million deaths worldwide have been prevented by TB diagnosis and treatment between the year 2000 and 2017 [7]. Yet the TB/HIV syndemic continues to claim millions of lives each year [8].
Tuberculosis accelerates the progression of HIV infection to AIDS if left untreated [9]. Deaths from TB have fallen by 42% from the year 2000 to 2017, however, TB is still one of the leading causes of mortality in the world; now causing more deaths than HIV [7]. In 2015, about 75% of TB/HIV deaths worldwide occurred in Sub Saharan Africa, with case fatality rates varying from under 5% to over 20% among countries in the region [8]. Tuberculosis mortality rate in 2015 was 47% lower than in 1990 globally. The target was to reduce the mortality rate by 50% by the year 2015, which was achieved by the WHO Region of the Americas, South-East Asia Region, Western Pacific, Eastern Mediterranean and 11 of the high TB burden countries [10]. Latest reports suggest that the WHO African Region now has one of the fastest rates of reductions in mortality (4% per year, since 2013 to 2015); second to the WHO European Region with 5% per year in the same five years [7].
The post 2015 agenda of the WHO is to end TB by the year 2035.
One of the End TB Strategy targets is to eventually decrease the have been consistently about 10% over the past few years whilst annual rates of lost-to-follow up (LTFU) and treatment failure have remained at about 3% and 2% respectively [11]. Interventions are necessary to reduce deaths during TB treatment in order for the country to achieve the targets set in the End TB Strategy by 2035. A study among 1797 patients found no significant difference between the outcomes of treatment between HIV infected and non-infected patients whilst cure rates in TB/HIV co-infected patients were found to be significantly reduced in one retrospective cohort analysis [12,13]. Again, the odds of death was seven times higher among HIV-infected TB patients in an Ethiopian study [14]. A Nigerian study among 1424 TB patients reported a proportionate mortality of 50.6% and a mortality rate of 37.6 per 100 person months all in the first week of TB treatment onset [15]. In another study majority of the deaths occurred in the intensive phase however, the risk of death was significantly increased among persons who were TB/HIV co-infected in the continuation phase of TB treatment [16]. Even though studies have reported that HIV infection increases the risk of adverse outcome, there are some knowledge gaps with respect to death among co-infected patients in Ghana. Questions on the timing of death and the influential factors still need to be answered as this may be important for designing strategies to reduce mortality rated in TB/HIV co-infected patients. The objectives of the study were to assess the effect of HIV infection on TB treatment outcomes and the time to mortality after the onset of TB treatment.

Study design:
We conducted a review of treatment files and registers of TB patients who were treated from 1 st January 2013 to 31 st December 2015. A data extraction form was used to collect relevant information from TB treatment cards and registers. Study participants joined the cohort on the day TB treatment was initiated until the day any of the treatment outcomes was achieved.

Data measurement
Definition of terms: The following are standard World Health Organisation (WHO) definitions for the various TB treatment outcomes [19]. Treatment failure: a TB patient whose sputum smear or culture is positive at month 5 or later during treatment.
Death: All-cause mortality during anti-TB treatment.
Lost-to-follow up: A TB patient for whom treatment was interrupted for two consecutive months or more. It was previously  Table 1 Table 4. In Table 5, the highest mortality rates

Discussion
The probability of survival at the end of the analysis time among the total sample of patients in this study was 89.4%. Plotting the curves separately according to HIV status showed that those with HIV infection had a lower survival, confirming documented evidence that being HIV infection increases one's risk of mortality during TB treatment. Our finding of higher mortality in TB/HIV co-infected patients compared to those with TB only is similar to that reported among patients attending a chest clinic in a teaching hospital in Ghana, but in contrast, we did not find a difference in default rates between the two groups [20]. Again, in Sudan, a significantly higher case-fatality rate among persons with TB/HIV co-infection (12%) compared to those with TB infection only (1.8%) was found. HIV tests were conducted among patients in the study however, results were anonymised and not linked [13]. The proportion of LTFU and treatment failure which is less than 3% of the entire cohort corroborates with previous reports about TB treatment outcomes in other countries and in Ghana [11,13] were documented to have been given concurrent treatment and hence could not be included in the analyses. It is quite surprising to see that such a low proportion of HIV infected individuals in this study were given concurrent ART. In a study in Nigeria, 16% out of 568 TB/HIV co-infected patients received concurrent treatment.
Survival was lowest among those who were not on ART and their risk of mortality was aHR 1.39 (95 %CI 1.04 to 1.86) compared to those who were on ART [15]. The low uptake of ART in our study may have contributed to the high mortality among the HIV coinfected patients since several studies show that integrated therapy has significant survival benefit [21][22][23]. One retrospective study on the predictors of mortality among TB/HIV co-infected patients reported a significant increase in the risk of mortality (aHR = 3.15 95%CI 1.95 to 5.11) among patients who were not given cotrimoxazole preventive therapy during treatment. They also found that patients on antiretroviral therapy (ART) had a hazard ratio of 0.35 (95%CI 0.19 to 0.64) [24]. Agreeably, HIV patients in this study who were not started on cotrimoxazole preventive therapy during treatment had a hazard ratio of 4.18 (95%CI 1.71 to 10.21).
This report is also consistent with that of a study conducted in Cameroun [25].
Additionally, according to two other studies, patients who do not take cotrimoxazole preventive therapy have an increased risk of death or adverse outcome [26,27]. It is estimated that about 25% of TB/HIV co-infected people in Ghana receive concurrent treatment despite recommendations in the WHO guidelines for TB/HIV coinfection. ART should be initiated for all patients with TB/HIV coinfection regardless of their CD4 cell count. TB treatment should be started first, followed by ART as soon as possible and within the first eight weeks of starting TB treatment [19]. There is a need for qualitative studies to bring out the challenges or barriers to the implementation of the guidelines especially in the Ghanaian setting.
Possible solutions to this problem may include training health professionals in concurrent management of TB and HIV or to develop optimal models to facilitate integration of TB and HIV services in health facilities. The difference in the mortality rates between the two hospitals in this study may have been due to institutional factors, patient-factors or both. The rate of death among the HIV-positive persons in this study was almost twice (38.6 per 1000 person months) that found in an Ethiopian study where among TB/HIV co-infected patients, a rate of 20.6 per 1000 person months was recorded. However, the mortality rates among HIV non-infected persons were similar in both studies; 10.8 per 1000 person months in the Ethiopian study and 9.1 per 1000 person months in our study [16]. Most studies report that majority of these deaths occur in the first few weeks of treatment [15,28]. In our study, the proportionate mortality at the end of the first two weeks was 23.9% and 63.0% at the end of the first two months. A possible explanation to this observation is that those who die in the first few weeks of treatment report to the hospitals late. The causes of delay may be due to fear of drug toxicities, stigmatisation, selfmedication, delay in diagnosis of TB and/or HIV infection and counselling among other others [8,29].

Limitations of the study:
Missing data on variables such as weight and height made it impossible to test their associations with the outcomes. Also, information on CD4 cell counts, drug adherence, co-morbidities and other socio demographic variables that could have predicted outcomes could not be analysed because they were not available. What this study adds  The co-administration of ART and anti-TB therapy is suboptimal in some hospitals in the Accra metropolis;

Conclusion
 Health system factors in some hospitals in the Accra metropolis may influence mortality among TB patients. Tables   Table 1: Distribution of demographic and clinical characteristics among HIV infected and HIV non-infected TB patients in two urban hospitals in the Accra metropolis