Effect of HIV status and antiretroviral treatment on treatment outcomes of tuberculosis patients in a rural primary healthcare clinic in South Africa

Background Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV) infected individuals in South Africa. Despite the implementation of HIV/TB integration services at primary healthcare facility level, the effect of HIV on TB treatment outcomes has not been well investigated. To provide evidence base for TB treatment outcome improvement to meet End TB Strategy goal, we assessed the effect of HIV status on treatment outcomes of TB patients at a rural clinic in the Ugu Health District, South Africa. Methods We reviewed medical records involving a cohort of 508 TB patients registered for treatment between 1 January 2013 and 31 December 2015 at rural public sector clinic in KwaZulu-Natal province, South Africa. Data were extracted from National TB Programme clinic cards and the TB case registers routinely maintained at study sites. The effect of HIV status on TB treatment outcomes was determined by using multinomial logistic regression. Estimates used were relative risk ratio (RRR) at 95% confidence intervals (95%CI). Results A total of 506 patients were included in the analysis. Majority of the patients (88%) were new TB cases, 70% had pulmonary TB and 59% were co-infected with HIV. Most of HIV positive patients were on antiretroviral therapy (ART) (90% (n = 268)). About 82% had successful treatment outcome (cured 39.1% (n = 198) and completed treatment (42.9% (n = 217)), 7% (n = 39) died 0.6% (n = 3) failed treatment, 3.9% (n = 20) defaulted treatment and the rest (6.6% (n = 33)) were transferred out of the facility. Furthermore, HIV positive patients had a higher mortality rate (9.67%) than HIV negative patients (2.91%)”. Using completed treatment as reference, HIV positive patients not on ART relative to negative patients were more likely to have unsuccessful outcomes [RRR, 5.41; 95%CI, 2.11–13.86]. Conclusions When compared between HIV status, HIV positive TB patients were more likely to have unsuccessful treatment outcome in rural primary care. Antiretroviral treatment seems to have had no effect on the likelihood of TB treatment success in rural primary care. The TB mortality rate in HIV positive patients, on the other hand, was higher than in HIV negative patients emphasizing the need for enhanced integrated management of HIV/TB in rural South Africa through active screening of TB among HIV positive individuals and early access to ART among HIV positive TB cases.

Background Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV) infected individuals in South Africa. Despite the implementation of HIV/TB integration services at primary healthcare facility level, the effect of HIV on TB treatment outcomes has not been well investigated. To provide evidence base for TB treatment outcome improvement to meet End TB Strategy goal, we assessed the effect of HIV status on treatment outcomes of TB patients at a rural clinic in the Ugu Health District, South Africa. Methods We reviewed medical records involving a cohort of 508 TB patients registered for treatment between 1 January 2013 and 31 December 2015 at rural public sector clinic in KwaZulu-Natal province, South Africa. Data were extracted from National TB Programme clinic cards and the TB case registers routinely maintained at study sites. The effect of HIV status on TB treatment outcomes was determined by using multinomial logistic regression. Estimates used were relative risk ratio (RRR) at 95% confidence intervals (95%CI). Results A total of 506 patients were included in the analysis. Majority of the patients (88%) were new TB cases, 70% had pulmonary TB and 59% were co-infected with HIV. Most of HIV positive patients were on antiretroviral therapy (ART) (90% (n=268)). About 82% had successful treatment outcome (cured 39.1% (n=198) and completed treatment (42.9% (n=217)), 7% (n=39) died 0.6% (n=3) failed treatment, 3.9% (n=20) defaulted treatment and the rest (6.6% (n=33)) were transferred out of the facility. Using completed treatment as reference, HIV positive patients not on ART relative to negative patients were more likely to have unsuccessful outcomes [RRR, 5.41; 95%CI, 2.11-13.86]. Conclusions When compared HIV positive and HIV negative status, antiretroviral treatment had no effect on the likelihood of TB cure in rural primary care. The TB mortality rate in HIV positive patients, on the other hand, was higher than in HIV negative patients. Various HIV/TB indicators should be reviewed, and gaps filled to achieve the "End TB strategy" in rural South Africa. the two concepts. It now reads: "The increase in incidence is also attributed to the development of multidrug resistant (MDR) and extremely drug resistant (XDR) strains of Mycobacterium tuberculosis [34]. Both MDR/XDR-TB are the causes of high TB mortality [4]".
Comment 7: This sentence appears out of sync as the previous discussion only relate to mortality and this sentence intends on providing reason for increased risk for TB. Response: The sentence has been deleted and removed.
Comment 8: Which countries as the authors quoting facility based postmortem findings. Response: In track change document on pages 4-5 and lines 75-77. Thanks, we have listed the countries reporting post-mortem TB rate. It now reads: "such as South Africa [9][10][11], Botswana [11,12], Zimbabwe [11,13,14], Mozambique [11,15], Uganda [11,16] and Kenya [11,17]". Comment 9: I am sure that the WHO global report on TB provides data in resource limited countries. Response: In track change document on page 5 and lines 77. Thanks, we have provided TB data in Africa. "In contrast, the WHO reported 16% of HIV/TB related death in Africa [1]". Comment 10: please update this data as later information is available. Response: In track change document on pages 5 and lines 80-81. Thanks, this data has been updated. "TB accounted for the third highest number of deaths in 2018 (6 %; n = 454 014)" Comment 11: specific data for Ugu district Response: In track change document on page 5 and lines 87-88. "Ugu district reported 60.5% of TB/HIV co-infection rate [25]". Comment 12: provide information on South Africa antiretroviral treatment programme in terms of number of patients on treatment and accessibility to treatment. Response: In track change document on pages 6 and lines 89-90. Thanks, we have reported this: "According to recent data, 90% of people are aware of their HIV status of these 68% are on antiretroviral therapy (ART) of which 87% are virally suppressed in SA [26]". Comment 13: this paragraph is out of sync in building the case. it may be more suited to a discussion Response: In track change document on pages 19-20, lines 360-367. Thanks, this paragraph has been moved to the discussion section.
Comment 14: with a view to? Response: In track change document on page 7 and lines 141. Thanks, we state as follows: "with a view to Ugu district".
Comment 15: the author needs to separate study design, population and study setting Response: In track change document on pages 8-9 and lines 122-142.Thanks, we have separated the study design, population and study setting. It is now reads: "Study design This retrospective cohort study of TB patients initiated on TB treatment was conducted from 1 January 2013 to 31 December 2015. Study population We included all patients diagnosed with TB irrespective of their age and HIV status in the study. Further, we registered patients that were in the TB register in 2012 and died in 2013. We also included as well as those that died or survived during the treatment period. Patients with unknown outcome were from the study or those with incomplete record were excluded. Basic demographic information including the age, gender, comorbidities, tobacco Use, alcohol Use, substance use and duration on treatment were collected. Study setting The Ugu district is located in the rural KwaZulu-Natal province ( Figure 1). Ugu district has a population of 733 228 people [37]. During the study period, Ugu district had the highest HIV prevalence and TB incidence of any district in KZN, 41.7% and 1096 per 100,000 people, respectively [37]. In terms of infectious TB (pulmonary smearpositive), Ugu ranks 12th, with 325 cases per 100,000 people, which is higher than the country's average of 208 cases per 100,000 people [37]. Elim clinic, a primary health care facility was selected based on convenience, the study goal and the availability of information on HIV and TB infections".
Comment 16: this is about uGu-what about the specific area of your study-what is catchment population, what is outpatient headcount? what proportion or incidence of TB per year over the study period? Response: In track change document on pages 7 and lines 136-142. Thanks, we have stated the following: "Ugu district has a population of 733 228 people [37]. During the study period, Ugu district had the highest HIV prevalence and TB incidence of any district in KZN, 41.7% and 1096 per 100,000 people, respectively [37]. In terms of infectious TB (pulmonary smear-positive), Ugu ranks 12th, with 325 cases per 100,000 people, which is higher than the country's average of 208 cases per 100,000 people [37]. Elim clinic, a primary health care facility was selected based on convenience, the study goal and the availability of information on HIV and TB infections".
Comment 17: was provincial authorization obtained? I am confused by the term Director of Health as no such position exists in the organogram. Response: Thanks for this comment. Authorisation to access clinic records was granted by the Ugu Health District Manager. Apologies for the incorrect use of word 'Director'.
Comment 18: it would be good to also provide the socio-demographic profile of patients first before the HIV status of patients. Response: In track change document on page 12and line 240. Thanks, before the HIV status table (Table 2), we have provided a socio-demographic Comment 21: to evaluate TB outcomes in HIV positive patients in rural primary healthcare in South Africa Response: In track change document on page 17, lines 300. Thanks, it now reads: "This study evaluated the effect of HIV status and antiretroviral treatment on the treatment outcome of TB patients in a primary healthcare facility in rural South Africa".
Comment 22: what about findings from your analytical study? Response: In track change document on page 17, lines 312-317. We have reported the findings from the analytical study as follows: "Longer treatment periods were associated with a lower risk of death in both the bivariate and covariate log-binomial regression models. Furthermore, in bivariate and covariate analysis, younger ages had a lower likelihood of being cured than older ages. However, HIV positive status of a TB patient had no effect on the likelihood of TB cure when compared to HIV negative status of a TB patient". Comment 23: please clarify this-is this initiation of treatment or treatment duration Response: In track change document on page 17, lines 315-317. It now reads "However, HIV positive status of a TB patient had no effect on the likelihood of TB cure when compared to HIV negative status of a TB patient".
Comment 24: how does this study relate to your findings. what is the plausible explanation for the similarities and differences? Response: In track change document on page 18, lines 329-340. Thanks, the plausible explanation for the similarities and differences is stated as follows: "The similarities and differences between studies could be explained by ART uptake percentage and TB diagnosis. Following a review of these studies, the findings of our study was consistent with the study conducted in Kenya, owing to the ongoing scale-up and uptake of ART programs in both South Africa and Kenya. Comment 27: please discuss the study limitations Response: In track change document on page 20, lines 381-388. We have included the study strengths and limitations. It now read: "The strength of our study is our sample size which was representative of the study population thereby minimizing selection bias. This is substantial to estimate HIV/TB outcomes in rural settings. Our study has several limitations that could lead to underestimation HIV/TB outcomes. Retrospective cohort design uses records that have already been collected and we did not obtain the information on treatment completed outcome, HIV viral load and CD4 cells. As the fact, we were unable to accurately link all our patients to the various outcomes. It is also possible that some of the patients included in our study misclassified in the current analysis". Comment 28: this is a repetition of results without adequate considering for the overall aim and why the study was done? Response: In track change document on page 21, lines 392-395, 400-404. Thanks, we have improved the conclusion as follows: "In conclusion, HIV positive status and antiretroviral treatment had no effect on the likelihood of TB cure in rural primary care when compared to HIV negative patients. However, the TB mortality rate in HIV positive patients was higher than in HIV negative patients". And further recommendation: "TB mortality in rural SA. Furthermore, the TB success rate in rural SA may be lower than the WHO target. This study could have a significant impact on the HIV/TB program in rural SA. To achieve the End TB strategy in rural SA, various HIV/TB indicators should be reviewed, and gaps filled".
Reviewer #2: Comment 1: The abstract is well written. It contains the main findings and the conclusion of the study. The background is comprehensive and well written. Although, it does not reflect on the decreasing TB cases that South Africa is experiencing. Response: In track change document on page 5-6, lines 103-108. Thanks, we have improved the background as follows:" TB incidence and mortality are declining in SA [7]. Data from a well-characterized rural SA population with high HIV prevalence and TB incidence demonstrated considerable spatial heterogeneity in people with recentlydiagnosed TB and has shown that every percentage increase in ART coverage was associated with a 2% decrease in the odds of recently-diagnosed TB [23]". Comment 2: The methodology is clear, well defined. The paper does not clearly define treatment cure, treatment completed.
Response: In track change document on pages 8, lines 160-167. We have referred to the WHO definitions. Cured: A pulmonary TB patient with bacteriologically confirmed TB at the beginning of treatment who was smear or culture negative in the last month of treatment and on at least one previous occasion. Treatment completed: A TB patient who completed treatment without evidence of failure but with no record to show that sputum smear or culture results in the last month of treatment and on at least one previous occasion were negative either because tests were not done or because results are unavailable [37]. Comment 3: The researcher used the outcome allocated by the facility. I am not sure whether these outcomes were checked. Sometimes patients who fulfil the cure criteria are captured as completed. It is also important to highlight that the outcomes are allocated mainly on the basis of negative TB smear microscopy. TB microscopy has a low sensitivity. TB culture is not done routinely in susceptible TB patients. Response: In track change document on page 20, lines 384-388. Thanks, we have addressed this issue in the study weaknesses. As a retrospective cohort study, we conducted the records review of the patients. As a matter of fact, we were unable to accurately link all of our patients to the various outcomes due to missing data. It is also possible that some of the patients included in our study might have been misclassified in the current analysis.
Comment 5: My other issue is the choice of comparing cure or death. TB programme targets are based on treatment success rate (Cure and Completion). I agree that it is better to have a higher cure rate although for several reasons I have noted over the years the final sputum is often not collected hence the outcome will be "treatment completed". Response: Thanks for the observation, as previously stated, retrospective cohort design used records that have already been collected and we did not obtain the information on treatment completed from the records. Comment 6: Also, Table 1 indicates that 30 % of the cohort had a negative smear microscopy. Such patients may not have a "cure" outcome. Favorable outcomes include cure and completion rate. I am not sure what is the motivation for having cure, death, and other outcomes. It would have been useful to briefly explain why are there more treatment completion than treatment cure in this facility. Response: In track change document on page 9, lines 160-163. Thanks, "cured" is defined as a pulmonary TB patient with bacteriologically confirmed TB at the beginning of treatment in an individual who was smear or culture negative in the last month of treatment and on at least one previous occasion. So, people may complete TB treatment without necessarily being cured. In this study we used these outcomes because they are key TB Program indicators as defined by the National TB Control Program. The focus of our study was to assess the effect of HIV status and antiretroviral treatment on TB treatment outcomes including cure. Our data has shown that HIV status and antiretroviral treatment did not have effect on TB cure but on TB mortality. We suggest that further studies are warranted to help explain low TB cure in this setting. Comment 7: Data analysis is very clear except the issue of separating cure and completion. On page 11 of the manuscript, the Authors stated that among tobacco users the cure rate was for TB was 60 % and it was only 37 % among the non-tobacco users. In the conclusion, it is stated that the use of tobacco appeared to decrease the TB cure. It is also said that the cure rate was below district and provincial targets.    About 82% had successful treatment outcome (cured 39.1% (n=198) and completed 39 treatment (42.9% (n=217)), 7% (n=39) died 0.6% (n=3) failed treatment, 3.9% (n=20) 40 defaulted treatment and the rest (6.6% (n=33)) were transferred out of the facility.

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Using completed treatment as reference, HIV positive patients not on ART relative to   The End TB Strategy aims to reduce TB deaths by 90% and TB incidence rates by   The first outcome of interest was "cured" defined as 1 if the patient was declared  used to test association between independent variables and TB outcomes (cured, 192 completed treatment, interrupted treatment, moved, transferred out, failed, and died).

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Given the fact that cured was a common outcome (39%), we fitted a log-binomial 194 regression model to estimate the relative risk of being declared cured versus not being 195 cured (Table 3). Finally, we fitted a multinomial logistic regression model predicting

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Overall, the study included 508 patients. Of this total, 2 patients were dropped from 212 further analysis because one was transferred to another facility the same day of 213 admission to the hospital and the other one was on prophylaxis TMP-SMX and was       records. As such, we were unable to accurately link all our patients' outcomes to these 382 specific exposures. It is also possible that some of the patients included in our study 383 were misclassified based on exposure or outcome status during analysis.           Tobacco, and tuberculosis: a qualitative systematic review and meta-analysis.       The End TB Strategy aims to reduce TB deaths by 90% and TB incidence rates by  to detect a significant difference in mortality between HIV positive and negative TB 145 patients on anti-tuberculosis treatment. We used a 95% precision of estimate with 146 power of 80% and estimated risk difference of 6% in outcome between exposed and 147 unexposed. The first outcome of interest was "cured" defined as 1 if the patient was declared used to test association between independent variables and TB outcomes (cured, 194 completed treatment, interrupted treatment, moved, transferred out, failed, and died).

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Given the fact that cured was a common outcome (39%), we fitted a log-binomial 196 regression model to estimate the relative risk of being declared cured versus not being 197 cured (Table 3). Finally, we fitted a multinomial logistic regression model predicting

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Overall, the study included 508 patients. Of this total, 2 patients were dropped from HIV negative. Hence, our final analytical sample included 506 patients for whom we 217 had valid data on the TB treatment outcomes.
218 Table 1 reported the demographic characteristics and TB outcomes. The findings 219 revealed that 39.13% (n=198) were reported as being cured at the end of treatment.

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The remaining 60.87% patients were classified as dead or alive, but not cured. Some         Comment 2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed; c) the date range (month and year) during which patients whose medical records were selected for this study sought treatment. If the ethics committee waived the need for informed consent, or patients provided informed written consent to have data from their medical records used in research, please include this information. Comment 3. Thank you for stating the following financial disclosure:

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Response:
In track change document on page 26, Line 492. Thanks, we state this: "Financial Disclosure: The author(s) received no specific funding for this work".
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