HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017.

INTRODUCTION: The World Health Organization's framework for TB/HIV collaborative activities recommends provider-initiated HIV testing and counselling (PITC) of patients with presumptive TB. In Myanmar, PITC among presumptive TB patients was started at the TB outpatient department (TB OPD) in Mandalay in 2014. In this study, we assessed the uptake of PITC among presumptive TB patients and the number needed to screen to find one additional HIV positive case, stratified by demographic and clinical characteristics.
METHOD: This was a cross-sectional study using routinely collected data of presumptive TB patients who registered for PITC services at the TB OPD between August 2014 and December 2017 in Mandalay. RESULT: Among 21,989 presumptive TB patients registered, 9,796 (44.5%) had known HIV status at registration and 2,763 (28.2%) were people already living with HIV (PLHIV). Of the remainder, 85.3% (10,401/12,193) were newly tested for HIV. Patients <55 years old, those registered in 2014, 2015 and 2017, those employed and those having a history of TB contact had higher uptakes of HIV testing. Among 10,401 patients tested for HIV, 213 (2.1%) patients were newly diagnosed with HIV and this included 147 (69.0%) who were not diagnosed as having TB. The overall prevalence of HIV (previously known and newly diagnosed) among presumptive TB patients was 14.8% (2,976/20,119). The number needed to screen to find one additional HIV case was 48: this number was lower (i.e., a higher yield) among patients aged 35-44 years and among those who were divorced or separated.
CONCLUSION: Uptake of HIV testing among eligible presumptive TB patients was high with four out of five presumptive TB patients being tested for HIV. This strategy detected many additional HIV-positive persons, and this included those who were not diagnosed with TB. We strongly recommend that this strategy be implemented nationwide in Myanmar.

Introduction

Many developing countries are still faced with a dual public health burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. Globally, in 2018, 37.9 million people were living with HIV and 10 million people developed TB disease [1,2]. About 251,000 people died of HIV-associated TB [2]. Those with co-infection have high overall morbidity and mortality. The major challenge in dealing with co-infection is that nearly half of those living with HIV and associated TB are unaware of their status and remained untreated [1]. In 2017, only 3.8 out of 6.4 million notified TB cases had a documented HIV test [3]. To reduce this dual burden, the World Health Organization (WHO) in its 2012 policy on TB/HIV collaborative activities recommended routine provider-initiated HIV testing and counselling (PITC) to both diagnosed TB patients and persons with presumptive TB in order to promote early identification and treatment of HIV to reduce the HIV burden in TB patients [4].

PITC is the practice where HIV testing is offered routinely by health care providers to all patients attending health care facilities as a standard component of medical care [5]. Compared to voluntary HIV counselling and testing, which is a patient-initiated process, PITC has been shown to increase the uptake of HIV testing [6,7] leading to early HIV diagnosis, treatment, care and support services. PITC among diagnosed TB patients has become a standard practice in most national TB control programs in the last decade. However, PITC in patients with presumptive TB is not widely implemented globally, especially in low HIV burden countries, due to resource implications [8]. In the high HIV-burden countries of sub-Saharan Africa, studies have found that HIV-prevalence rates in presumptive TB patients are as high as those in diagnosed TB patients, with most of the HIV-positive patients being eligible for antiretroviral therapy (ART) and cotrimoxazole preventive therapy [9-17]. In the countries with low HIV prevalence, studies have found similar results and benefits from HIV testing of patients with presumptive TB [18-21]. Despite this, the uptake of HIV testing has been reported to be low in patients with presumptive TB in India, with context specific reasons including non-availability of HIV test kits, limited human resources, the fact that sputum specimens were sometimes sent to microscopy centers for investigation instead of the patients themselves being referred, lack of health care provider awareness, recording gaps and high workload. [19,22]. However, opt-out HIV testing; in which HIV testing is done unless the patient refuses to do so, has been found to have a higher uptake of HIV testing among patients admitted to the emergency departments of hospitals.[23]

In Myanmar, the national tuberculosis programme (NTP) started TB/HIV collaborative activities in 2005 after the publication of the WHO’s interim policy on HIV/TB collaborative activities in 2004. In mid-2014, the Union supported the NTP to initiate PITC in presumptive TB patients at the TB outpatient department (TB OPD) in Mandalay according to 2012 WHO recommendations [4]. To date, there has been no formal assessment of this service. Therefore, in this study, we assessed 1) the uptake of HIV testing among persons with presumptive TB, 2) demographic and clinical factors associated with HIV testing and 3) numbers needed to test to find one additional HIV positive case stratified by demographic and clinical characteristics among presumptive TB patients.

Materials and methods

Study design

This was a cross-sectional study using data routinely collected from the PITC service.

Setting

General setting

Myanmar is a country in South-East Asia with an estimated population of 52 million and is one of the 30 high TB/HIV burden countries (having the highest estimated number of incident TB cases among people living with HIV) [24]. There are 15 regions and states in Myanmar. Mandalay is the third most populated region in Myanmar with 6.2 million people, of whom 35% live in the urban area. There are seven districts in Mandalay region. Mandalay District has 1.7 million population and is administratively divided into seven townships [25].

Project setting

The PITC service to presumptive TB patients was started at the TB OPD at the Mandalay General Hospital, a tertiary hospital in Mandalay, in collaboration with the NTP and The International Union Against Tuberculosis and Lung Disease (The Union) in August 2014. This service has been expanded to other health facilities where The Union has been implementing its programmes. This service was also offered to all those referred from other public and private hospitals, township health departments, community-based active case finding projects, HIV clinics and some charity-based clinics. All patients visiting TB OPD are registered in the TB OPD patient register, given a unique serial number and are seen by medical staff. According to the NTP guidelines, a person who has signs and symptoms of TB (cough, fever, weight loss, night sweat, hemoptysis, lymph node enlargement) is considered to have presumptive TB. Persons with presumptive TB undergo diagnostic investigations for TB disease such as sputum microscopy and/or Xpert MTB/RIF, chest radiography and other tests for extrapulmonary TB based on suspected extrapulmonary sites.

At the same time during the first visit, all presumptive TB patients are also referred to the PITC service desk where HIV counselling and testing services are offered. Presumptive TB patients may visit TB OPD multiple times before the TB diagnosis is made but they are referred to PITC only once on their first visit. The unique identifier (created from an OPD serial number and year of registration) is recorded in the PITC register. This service is provided by three nurse counsellors who are supervised by a field associate employed by The Union. According to project standard operational procedures, the presumptive TB patients are eligible to undergo HIV testing if the patient tested HIV negative more than two weeks ago, there was no prior HIV test or no evidence of an HIV-test result in hand. Both HIV testing and TB diagnosis investigations are carried out on the same day.

At the PITC desk, after pretest counselling and receiving individual consent, an HIV screening test using Alere Determine™ HIV-1/2 rapid test is performed by trained nurse counsellors. Before July 2016, if the patient tested HIV-positive, the result was confirmed by Clearview® HIV 1/2 STAT-PAK® rapid test. After July 2016, the confirmatory test was changed to a parallel testing approach (Uni-Gold™ Recombigen® HIV rapid test and STAT-PAK® rapid test simultaneously) according to national guidelines [26,27]. Test results are given to the patient on the same day after post-test counselling. Post-test counselling is carried out by counsellors if the patient is HIV-negative and by a TB focal person if the patient tests HIV-positive. Patients who test HIV-positive are referred to the Integrated HIV Care (IHC) clinic for further HIV treatment and care using TB/HIV cross referral forms.

When the TB diagnosis is confirmed before or after referral to the IHC clinic, all TB diagnosed patients are referred to their resident townships for the continuation of anti-TB treatment because TB OPD provides only 1–2 weeks of anti-TB treatment to diagnosed TB patients. The referred patients are given standard NTP referral forms and the staff from the TB OPD get in touch with the township to inform about the referral. Patients’ demographics, testing and referral information are recorded in the PITC service register. The data from the register is regularly entered into EpiData entry software and extracted to Excel.

Study population

All presumptive TB patients registered at the PITC service of TB OPD at Mandalay general hospital between August 2014 and December 2017 were included in the study.

Data variables and sources of data

Data on the following variables were extracted to answer the study objectives: unique identification, known HIV status at registration, registration date, age, sex, marital status, education, occupation, known (self-reported) diabetes mellitus status, presence of cough, presence of fever, presence of night sweats, presence of weight loss, presence of lymph node enlargement, Determine HIV-test result, STAT-PAK HIV-test result, Uni-Gold HIV-test result, TB diagnosis and type of TB. Data were extracted from Excel databases.

Analysis and statistics

The electronic databases for four years (2014–2017) were combined into one Excel database and imported into STATA (version 14.1) for analysis. Any duplicate entries of patients were identified by combining name, age and sex for those who visited TB OPD more than once as new presumptive TB patients (they would therefore have been given different unique serial numbers) and only the first entries were kept for this study. The final HIV-test result for patients newly tested for HIV was based on the results of Determine HIV-test, STAT-PAK and Uni-Gold according to the HIV testing algorithm applied in the different time periods [26,27]. If patients had negative Determine tests, they were classified as HIV negative. If the Determine test was positive but there was no result from the confirmatory tests, the patient was classified as HIV screening positive. For the presumptive TB patients registered between 2014 and 2016, if the Determine test and STAT-PAK were both positive, the patient was considered as confirmed HIV positive. For those who were registered in 2017, if all three tests were positive, the patient was considered as confirmed HIV-positive and if the Determine test was positive and only one of the confirmatory tests were positive, the result was considered as HIV-inconclusive.

The number needed to screen to find an additional person living with HIV was calculated by dividing the number tested by the number of confirmed HIV positive cases. [N/n where N is the number tested and ‘n’ is the number who were HIV positive out of those who were tested]. A multivariable binomial log regression model was used to determine the characteristics associated with the uptake of HIV testing among patients with unknown HIV status at registration. A Poisson regression model with robust standard error estimates was used if the binomial log model failed to achieve convergence [28]. The association was then presented as prevalence ratios (PR) and 95% confidence intervals (CI). A p-value < 0.05 was considered statistically significant for all analysis and this value was included in the final multivariable model. The multicollinearity was assessed by using a variance inflation factor (>10 was considered as a cutoff for assessing collinearity).

Ethics approval

We obtained permission to conduct the study from the National Tuberculosis and HIV/AIDS Programme, Department of Public Health, Ministry of Health and Sports, Myanmar. We received ethics approval from the Ethics Review Committee of the Department of Medical Research, Ministry of Health and Sports, Myanmar (ERC/DMR/2017/110) and from the Ethics Advisory Group of the International Union Against Tuberculosis and Lung Disease (The Union), Paris, France (EAG number 44/17). The data was anonymized before the analysis. As this study involved the review of routinely collected data, obtaining informed consent from patients was waived by both ethics committees.

Results

A total of 21,989 patients with presumptive TB were registered at the PITC service between August 2014 and December 2017. Among them, 12,002 (54.6%) were referred from Mandalay General Hospital, 3,733 (17.0%) from General Practitioners, 2,530 (11.5%) were self-referrals and the remainder 3,724 (16.9%) were referred from other health facilities such as HIV clinics, township health departments and other private and public hospitals. The presence of cough was the most common presentation (65.3%) followed by loss of weight (43.8%). The mean age (standard deviation-SD) was 43 (18) years. Of these patients, 9,796 (44.5%) had a known HIV status at registration with 2,763 (28.2%) being people living with HIV. The remaining 12,193 (55.4%) patients were eligible for HIV testing.

Among 12,193 patients, 10,401 (85.3%) were tested for HIV and 213 (2.1%) were newly diagnosed with HIV, as shown in Fig 1. If we include all persons with inconclusive or screened positive results as being HIV-positive, the proportion who were HIV-positive was 2.8% (95% Confidence interval (CI): 2.5–3.1). If we include all persons with inconclusive or screened positive results as being HIV-negative, the proportion who were HIV positive was 2.0% (95% CI:1.8–2.3). The overall prevalence of HIV (previously known and newly diagnosed) among presumptive TB cases who had an HIV result was 14.8% (2,976/20,119) (95% CI; 14.3%-15.3%).

Fig 1

HIV testing and positivity among presumptive TB patients registered at the PITC services in the TB OPD, Mandalay, August 2014-December 2017.

HIV = Human Immunodeficiency Virus, TB = Tuberculosis, OPD = Outpatient Department, PITC = provider-initiated testing and counseling.

Of the total presumptive TB patients, 6,413 (29.3%) were diagnosed with TB: this included 3,995 (18.2%) pulmonary TB cases, 2,415 (11.0%) extrapulmonary TB cases and 3 (0.01%) MDR-TB cases. Of HIV positive presumptive TB patients (n = 213), only 66 (31.0%) were diagnosed as TB and 147 (69.0%) were not diagnosed with TB.

Table 1 presents the socio-demographic characteristics of presumptive TB patients eligible for HIV testing and their association with the uptake of HIV testing. In adjusted analysis, uptake of HIV testing was significantly higher in patients aged less than 55 years when compared to those aged ≥65 years, those who registered in 2014, 2015 and 2017 when compared to those registered in 2016, those who were employed and those who had a history of TB contact when compared to their counterparts. The number needed to screen to find one additional HIV case was 48 (95% CI: 42–55): this was lower among patients aged 35–44 years and those who were divorced or separated with the numbers needed to test being 20–21 in these categories. The number needed to test was highest among patients aged ≥55 years and patients with known diabetes status as shown in Table 2.

Table 1

Uptake of HIV testing and associated characteristics among presumptive TB patients with unknown HIV status at registration at PITC services in TB OPD, Mandalay, August 2014-December 2017.

Characteristics	Total	(Col%)	HIV testing	(Row %)	PR	(95% CI)	aPR	(95% CI)
Total	12,193		10,401	(85.3)
Age Group (years)
< = 14	584	(4.8)	512	(87.7)	1.16	(1.11–1.20)*	1.08	(1.04–1.12)*
15–34	3,866	(31.7)	3,529	(91.3)	1.20	(1.17–1.23)*	1.15	(1.12–1.18)*
35–44	1,778	(14.6)	1,590	(89.4)	1.18	(1.15–1.21)*	1.12	(1.09–1.15)*
45–54	1,838	(15.1)	1,590	(86.5)	1.14	(1.11–1.17)*	1.10	(1.07–1.13)*
55–64	1,800	(14.8)	1,415	(78.6)	1.04	(1.00–1.07)*	1.02	(0.99–1.05)
> = 65	2,327	(19.1)	1,765	(75.8)	ref		ref
Sex
Female	5,228	(42.9)	4437	(84.9)	ref		ref
Male	6,955	(57.0)	5961	(85.7)	1.01	(0.99–1.03)	1	(0.99–1.02)
Not recorded	10	(0.1)	3	(30.0)
Marital status
Single	3,852	(31.6)	3,438	(89.3)	1.15	(1.11–1.19)*	1.02	(0.98–1.06)
Married	7,072	(58.0)	5,966	(84.4)	1.09	(1.05–1.13)*	1.01	(0.98–1.05)
divorced/separated	137	(1.1)	119	(86.9)	1.12	(1.04–1.21)*	1.01	(0.94–1.08)
Widow	1,087	(8.9)	842	(77.5)	ref		ref
Not recorded	45	(0.4)	36	(80.0)
Literacy
Literate	11,349	(93.1)	9,683	(85.3)	1.00	(0.97–1.03)
illiterate	736	(6.0)	627	(85.2)	ref
Not recorded	108	(0.9)	91	(84.3)
Employment status
unemployed	3,615	(29.6)	2,883	(79.8)	ref		ref
employed	8,555	(70.2)	7,496	(87.6)	1.10	(1.08–1.12)*	1.03	(1.01–1.05)*
unknown	23	(0.2)	22	(95.7)
TB contact
No	8,730	(71.6)	7,211	(82.6)	ref		ref
Yes	3,463	(28.4)	3,190	(92.1)	1.12	(1.10–1.13)*	1.07	(1.06–1.08)*
Known DM
No	11,577	(94.9)	9,890	(85.6)	1.03	(0.99–1.07)
Yes	616	(5.1)	511	(83.0)	ref
Year of registration
2014	1,850	(15.2)	1,719	(92.9)	1.33	(1.30–1.36)*	1.30	(1.27–1.34)*
2015	4,010	(32.9)	3,556	(88.7)	1.27	(1.24–1.30)*	1.26	(1.23–1.29)*
2016	3,941	(32.3)	2,756	(69.9)	ref		ref
2017	2,392	(19.6)	2,370	(99.1)	1.42	(1.39–1.45)*	1.38	(1.35–1.41)*
TB Status
Pulmonary TB	2,245	(18.4)	2,112	(94.1)	1.14	(1.12–1.15)*
Extra Pulmonary TB	876	(7.2)	793	(90.5)	1.10	(1.07–1.12)*
MDR-TB	2	(0.02)	2	(100.0)	1.21	(1.20–1.22)*
No TB	9,070	(74.4)	7,494	(82.6)	ref

HIV = Human Immunodeficiency Virus, TB = Tuberculosis, PITC = provider-initiated testing and counselling, PR = Prevalence ratio, aPR = adjusted prevalence ratio, OPD = Outpatient Department, CI = confidence interval, Col% = column percentage, Row% = Row percentage, ref = reference, DM = Diabetes Mellitus

* = statistically significant

The variables which were significant in the unadjusted analysis were included in the adjusted model except TB status because it was measured after the outcome (HIV testing).

Table 2

Characteristics and number needed to screen among presumptive TB patients with unknown HIV status registered at PITC services in TB OPD, Mandalay, August 2014-December 2017.

Characteristics	Newly tested for HIV¥	New HIV positive cases	Row %	(95% CI)	NNS	95% CI
Total	10,323	213	2.1	(1.8–2.4)	48	(42–55)
Age Group (year)
< = 14	511	6	1.2	(0.4–2.5)	85	(39–231)
15–34	3,502	80	2.3	(1.8–2.8)	44	(35–55)
35–44	1,568	75	4.8	(3.8–6.0)	21	(17–26)
45–54	1,574	42	2.7	(1.9–3.6)	37	(28–52)
55–64	1,407	9	0.6	(0.3–1.2)	156	(83–341)
> = 65	1,761	1	0.1	(0.0–0.3)	1761
Sex
Female	4,404	82	1.9	(1.5–2.3)	54	(43–67)
Male	5,916	131	2.2	(1.9–2.6)	45	(38–54)
Not recorded	3	0
Marital status
single	3,426	65	1.9	(1.5–2.4)	53	(41–68)
Married	5,914	124	2.1	(1.7–2.5)	48	(40–57)
divorced/separated	118	6	5.1	(1.9–10.7)	20	(9–53)
widow	830	18	2.2	(1.3–3.4)	46	(29–78)
unknown	35	0
Education status
illiterate	620	13	2.1	(1.1–3.6)	48	(28–89)
Primary	4,604	90	2.0	(1.6–2.4)	51	(42–64)
secondary	2,260	57	2.5	(1.9–3.3)	40	(31–52)
high school	1,293	32	2.5	(1.7–3.5)	40	(29–59)
university/graduated	1,456	18	1.2	(0.7–1.9)	81	(51–136)
unknown	90	3	3.3	(0.7–9.4)	30	(11–144)
Literacy
Literate	620	13	2.1	(1.1–3.6)	48	(28–89)
illiterate	9,613	197	2.0	(1.8–2.4)	49	(43–56)
Not recorded	90	3	3.3	(0.7–9.4)	30	(11–144)
Employment status
unemployed	2,865	39	1.4	(1.0–1.9)	73	(54–103)
employed	7,436	174	2.3	(2.0–2.7)	43	(37–50)
unknown	22	0
TB contact
No	7,147	142	2.0	(1.7–2.3)	50	(43–60)
Yes	3,176	71	2.2	(1.7–2.8)	45	(36–57)
Known DM
No	9,813	209	2.1	(1.9–2.4)	47	(41–54)
Yes	510	4	0.8	(0.2–2.0)	128	(50–467)
Year of registration
2014	1,694	47	2.8	(2.0–3.7)	36	(27–49)
2015	3,524	91	2.6	(2.1–3.2)	39	(32–48)
2016	2,740	40	1.5	(1.0–2.0)	69	(50–96)
2017	2,365	35	1.5	(1.0–2.1)	68	(49–97)
TB Status
Pulmonary TB	2,095	54	2.6	(1.9–3.3)	39	(30–51)
Extra Pulmonary TB	778	12	1.5	(0.8–2.7)	65	(37–125)
MDR-TB	2	-
No TB	7,448	147	2.0	(1.7–2.3)	51	(43–60)

HIV = Human Immunodeficiency Virus, TB = Tuberculosis, PITC = provider-initiated testing and counselling, NNS = number needed to screen, PR = Prevalence ratio, OPD = Outpatient department, DM = Diabetes Mellitus, Row% = Row percentage, CI = confidence interval, MDR = multidrug resistant

¥ = Those who had completed the HIV testing algorithm (both Determine STAT-PAK between 2014–2016 and Determine, STAT-PAK and Uni-gold tests in 2017)

Discussion

This is the first study in Myanmar to explore the uptake of HIV testing and numbers needed to test to find one additional person living with HIV among presumptive TB patients visiting PITC services at the TB OPD where the majority of presumptive TB patients in Mandalay attended for TB screening. There were five important findings.

First, almost half of the presumptive TB patients knew their HIV status at registration at the TB OPD and 28% of them were already HIV positive. This is because half of the presumptive TB patients were referred from tertiary hospitals where HIV testing was already offered to all admitted patients with common symptoms of HIV and TB before referral to the TB OPD. In addition, medical officers from hospitals and HIV clinics do routine TB screening to all PLHIV and those with symptoms of TB were referred to the TB OPD.

Second, nearly 85% of the patients eligible for HIV testing were tested for HIV. This high uptake was similar to other studies done in Uganda, South India, the Democratic Republic of the Congo and Ethiopia which had testing rates ranging from 85% to 98%, and higher than the studies done in Puducherry District, India (44.6%) and Malawi (56%) [10,18,20,22,29-32]. The possible reason for not being tested for HIV (~15%) in our study is that we offered HIV testing to presumptive TB patients only once during their first visit. Some qualitative studies [conducted among TB patients and contacts of multi-drug resistant TB patients] have reported lack of awareness, stigma, long distances travelled by patients, non-availability of test kits and additional visits to PITC as barriers for HIV testing [33-35].

Third, the patient’s age, employment status and history of TB contact were associated with uptake of HIV testing. Younger patients had higher HIV-testing uptake probably due to receiving closer attention from health care providers or self-awareness of HIV transmission compared with older patients. A study done in Africa reported that older people were tested for HIV only when they were symptomatic or if the spouse was HIV positive [36]. Having a job was one of the factors associated with getting tested for HIV. The reason might be because employed people have more interaction with work colleagues which in turn might increase the awareness of HIV and its consequences. In Mandalay, TB contacts are actively traced by community volunteers or Basic Health Staff and are provided with health education for TB screening and HIV testing and this might explain the higher uptake amongst those with TB contacts in our study.

Fourth, through the PITC service, a considerable number of HIV cases were identified among presumptive TB patients with unknown HIV status. This included many patients who were not diagnosed with TB. It is clear that these are additional people with HIV who are being identified early as a result of this strategy. Without this strategy, these people will not discover their HIV status unless they have obvious symptoms of HIV or other major opportunistic infections.

Fifth, the number needed to screen to find one additional HIV case was less than those reported by studies done in Puducherry District, India, and more than those reported from Vizianagaram District of India, and this is probably due to the low HIV prevalence among the general population in Myanmar [20,22,37]. In the subgroup analysis, the number needed to screen was lower in the middle age group and in those who were divorced. Emphasizing PITC among these two groups can lead to a higher yield and result in optimal use of resources. Moreover, presumptive TB patients aged over 55 years had a lower yield and they might not be offered provider-initiated HIV testing if there is a need for prioritizing resources.

Strengths and limitations

The major strength of the study was that we used routinely collected programme data which reflects the ground reality. There were some important limitations. First, there were missing data in some of the variables and we are not sure of the effect of this on our study results. Second, patient factors such as TB contact and DM status were self-reported and therefore there could be some misclassification if there were any deficiencies in recall. Third, we did not know how many patients dropped out between registration for TB diagnosis and the PITC service and the yield we found might have been overestimated. However, we think this gap was minimal because the intervention was implemented in a project setting with dedicated medical officers and other resources.

Recommendations

As a result of this study, we would like to make a number of recommendations. First, there was a high HIV testing uptake at the PITC service which identified many additional HIV positive cases. Hence, we strongly recommend that this service be expanded nationwide. To have better evidence to support this strategy we would also like to conduct a similar study in another setting. Second, there were 1,770 patients who were not tested for HIV and we recommended that another study is conducted to explore the reasons for this. Third, emphasizing PITC among those who had a higher yield of HIV-positive results (the middle age group) and the withdrawal of PITC among those who had a lower yield (age over 55 years old) should be considered if resources are limited. Fourth, the gaps between registration for TB diagnosis and HIV screening at the PITC service should be analyzed and the reasons for dropping out of the whole cascade, including not being tested for HIV, should be explored. Fifth, it is important to study linkages to HIV care, uptake of ART and CPT, and the outcomes of TB-HIV co-infected patients and non-TB-HIV patients who are diagnosed from the PITC service. Finally, we recommend future research to focus on understanding the implementation challenges using qualitative research methods.

Conclusion

This study found a high HIV testing uptake amongst persons presenting with presumptive TB, with nearly four out of five eligible patients undergoing HIV testing. Through this service, many additional people were diagnosed with HIV. Due to the significant benefit of this strategy, we strongly recommend that the strategy is expanded nationwide in Myanmar.

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22 Jan 2020

PONE-D-19-33429

HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Review statistical errors:

The authors should cross check the figures and summations for alignment; in the abstract, result section and the main text. For, example, total HIV positives from previous pool of presumptive TB cases with known HIV status is 2,763 + 215 = 2,978 (not 2,976). However, 2,976 is used in the main text. The error is likely from use of 213 in the result section against 215 in the abstract.

Grammatical errors are noticed on lines 59, 83, 264…

Areas needing contextual review check:

- WHO does not recognize lymph node enlargement as a clinically high index for presumptive TB (line 114)

- In HTS practices with PITC- counselling is done after the test result - but quick health information is provided to obtain consent (line 125)

- Revise line 134-135. Sentence may be confusing, as the opening paragraph says patients are referred to the PITC service delivery point. Is this in reference to diagnosed co-infected TB/HIV patients? Except if there is a note that both TB and PITC service stations offer TB and HIV services simultaneously - this is the ideal though.

- Line 209: Fig 1 is labelled but located elsewhere.

- The statistical instrument used in table 2 to explain number needed to test to get one positive needs to be better explained and simplified.

Technical content:

- Even though 85.5% of the 10,401 new registrations accepted to do HIV test (positivity: 2.05%), it is not technically sound to conclude on `willingness to test` and `case finding yield` from the whole presumptive TB population of 21,989, when 44.6% (9,818) came with a known HIV status, and as presented in the main text, Mandalay is a referral TB hospital with most of the patients being referred from diverse health facilities, already biased with an `intention-to-test.

- Moreover, being an aggregated data over a couple of years (4), without information on the average duration of the last test to time of registration, combining the newly diagnosed HIV positives and those who came to registration with a known status for impact decision making is technically flawed.

- The recommendation to scale up PITC among presumptive TB case nation-wide could be based on other benefits of TB/HIV collaboration, and not on the yield noticed in this study population, as the data and study setting does not support such conclusion.

Reviewer #2: Overview: “HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017” is a cross-sectional study evaluating the outcomes of an HIV provider-initiated testing and counseling service among individuals presenting to a TB outpatient department with presumptive tuberculosis. The authors report that 85.5% of individuals with unknown HIV status agreed to HIV testing with 215 (2%) new infections identified. The majority 69% did not have tuberculosis. They found that the number needed to test to identify one new HIV infection was 48. This study does provide interesting information about a high-risk population in an area with lower rates of HIV testing. Enthusiasm was decreased for this manuscript by multiple grammatical/syntax errors and unclear methodology making it difficult to follow.

Major Comments:

Introduction:

1. The authors discuss Provider-initiated testing and counseling (PITC) but do not mention “Opt-out testing” or opt-out PITC which have been widely adopted. The authors should discuss alternative and more inclusive testing strategies and barriers to their implementation locally.

2. Line 80 – 81, “uptake of HIV testing is low” this is a generalized and vague statement. This should be more specific. Where? Under what circumstances? There certainly areas of high HIV testing uptake and opt-out testing in many TB centers.

Methods:

3. Line 99. The authors state the Myanmar is a “high burden” HIV and TB country. The authors should be more specific and highlight the prevalence and incidence of these.

4. Lines 123 – 126 eligibility for PITC in unclear and should be re-written

5. The definition of “known HIV status” is unclear since this included individuals who were positive and negative. Does this mean previously tested for HIV? If so when?

6. For individuals who previously tested negative when were they offered PITC?

7. How were inconclusive/screened positive HIV tests handled? Is there access to RNA PCR? Were these included in the totals? The authors should consider adding in the screened positive individuals in a sensitivity analysis.

8. How was missing data handled? Were they imputed, deleted, ignored?

Results:

9. Line 196 – it is unclear what definition of “aware of HIV status” means. Why were those that previously tested negative not offered repeat testing?

10. Lines 221 – 222. The authors should state the number needed to treat patients 35-44, those who were divorced/separated, >55, and with DM separately.

Discussion:

11. The authors should discuss how their PITC compare to opt-out testing and opt-out PITC in other settings.

12. The authors should state that self-described HIV negative status is a limitation to this study.

Minor Comments:

1. I would recommend using person-first language throughout. People living with HIV instead of HIV positive.

2. The manuscript should be reviewed for grammatical/syntax errors and multiple run on sentences making it difficult to follow.

3. Line 196. Authors should state the interquartile range instead of the standard deviation.

4. PLHIV should be defined with first use.

Reviewer #3: Review Comments

Manuscript title: HIV testing uptake and HIV positivity among presumptive tuberculosis patients in

Mandalay, Myanmar, 2014-2017:

Overall;

The manuscript is well written and addresses an important subject.

Objectives are clearly stated, and the results are well aligned with the objectives.

The authors describe HTS uptake and HIV positive yield among 21,989 presumptive TB patients served in Mandalay district of Myanmar over a period of three years (2 August 2014 and December). They report 85.5% HIV testing rate among eligible presumptive TB patients and a HIV +ve yield of 2% with TB coinfection rate of 31.6% among newly diagnosed HIV patients. The results reveal 15% non-testing among eligible presumptive TB patients; missed opportunity for identifying 37 HIV +ve clients among the 1,770 eligible presumptive TB patients who were not tested. The significance of this is not adequately discussed yet it is important for improving program performance. Minor inconsistencies are noted between the results section of the abstract vs the manuscript body.

Specific comments:

Line 45: HIV rate reported to 2 decimal places and 1 decimal place (need to be consistent with decimal places) e.g. Line 45-46: Among 10,401 patients tested for HIV, 215 (2.05%) patients were newly

diagnosed with HIV and 147 (69.0%) were among those who were not diagnosed as TB.

Line 59: …the… appearing before 10 million seems to be misplaced

Figure 1: It appears that 22 individuals with unrecorded HIV status were classified as “Known HIV status”…review this

Results

Line 46-47: The overall prevalence of HIV (previously known and newly diagnosed) among presumptive TB

patients was 14.7% (2,976/20,192). Please review the numerator and denominator for this calculation based on the cascade presented in Figure 1. The denominator should only include presumptive TB patients with known HIV status at baseline (9,818) and after PITC (10,401) = 20,219; While the numerator should only include known positives at baseline (2,763) and newly tested positives (215 or 213) = 2,978; PITC clients missing HIV test should be excluded from the denominator.

Line 171-172: The number needed to test to find an additional person living with HIV was calculated by

dividing 100 by the proportion of confirmed HIV positive cases. Apply 215/10,401 to re-affirm the validity of this statement.

Line 197-198: …… and the HIV result not recorded for 22 (0.2%) patients. Consider deleting this statement if the clients with unrecorded HIV status were treated as unknown status. It may confuse readers.

Line 200-201

Among 12,171 patients, 10,401 (85.5%) were tested for HIV and 213 (2.0%) were newly diagnosed as HIV, as shown in Fig 1. The number tested positive is reported as 215 (2.05%) in the abstract (Line 45-46). Please resolve this inconsistency.

Figure 1 presents 22 clients with known but unrecorded HIV status; were these treated as +ve or -ve in the analysis. It may confuse readers. Please review to improve clarity.

Similarly, table 1 Presents 73 patients with unconfirmed HIV +ve positives results and 5 with inconclusive results. It would be helpful to explain how these were ultimately classified for purposes of HIV treatment.

Line 203: Refer to Fig. 1 and re-affirm how its contents contributed to the denominator for estimating the overall prevalence of HIV among presumptive TB patients.

Line 240: Spell out NNS in full under the key for table 2.

Discussion

Line 264-265: ……remaining ~15% patients were not tested 265 for HIV in the study. A possible explanation for this is an important gap stated in line 118-120: The presumptive TB patients may visit TB OPD multiple times before the diagnosis is made but they are referred to PITC only on their first visit. Multiple referrals to PITC in the course of their diagnostic work up for TB may improve HIV testing uptake. This may is a possible programmatic recommendation to address missed opportunities for identification of 37 HIV +ve clients among the 1770 presumptive TB patients who did not undergo PITC.

Line 282-283:

..It is clear that those are additional HIV cases which could be identified early due to implementation of this strategy. The study did not include viral loads or any other measures of time since HIV infection. Therefore, early identification is possible but not clear. Consider editing the sentence to tone this assertion.

Reviewer #4: Review comments

Reviewer: Joseph Mugisha Okello

Title for manuscript: HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

General comment

1. This important manuscript covers an important subject on HIV testing uptake and HIV positivity among presumptive tuberculosis patients. As the authors rightly, say, HIV testing uptake is still low in patients with presumptive TB. Therefore this manuscript generates more literature on this important topic

2. The manuscript is well written, and coherent which makes it easy to read. My only concern is why the authors never followed up the 1770 patients that never tested for HIV. In the discussion, the authors talk about the reasons (from qualitative studies) why patients with TB do not test for HIV. However, since the study setting looks to be organised, it would have been better to follow up the 1770 patients (15%) that never tested for HIV to study the reasons why.

Specific comments

1. Data for this study was obtained from a TB program. Although the authors got ethical clearance from the National TB and HIV/AIDS programme and the ethics review committee, there is no mention in the manuscript on whether the authors received informed consent from the study participants/patients.

2. It is important that the authors give some details on how patients co-infected with TB and HIV are managed or how and where they are referred.

3. In addition, the authors should give details on how the program follows TB patients referred to the resident townships for continuation of anti-TB treatment.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Dr Joseph Mugisha Okello (PhD), MRC/UVRI and LSHTM Uganda Research Unit

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Submitted filename: Plos one manuscript Review comments.docx

Click here for additional data file.

12 May 2020

Dear Editor,

We thank you for the comments of the reviewers. We have been carefully through the review and have revised our paper accordingly in track change mode. We have attempted to address all the comments of the reviewers and give a point-by-point response. We submit a tracked-changes and a clean version of the paper. The line number stated in response are from tracked changes version. We hope this revised paper may now be acceptable for publication in Plos One.

On behalf of all authors,

Khine Wut Yee Kyaw

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

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Author’s response: Thank you. We have checked the revised manuscript.

2. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

Author’s response: Thank you. We have carefully checked and we have revised in the manuscript. [line number 197]

3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Author’s Response: Thank you. We have included the information on Data availability in the cover letter.

4. Thank you for stating the following in the Acknowledgments Section of your manuscript: "We thank the Department for International Development (DFD), UK for funding the Global Operational Research Fellowship Programme at the International Union Against Tuberculosis and Lung Disease (The Union), Paris, France in which the first author works as an operational research fellow. The funder had no role in study design, analysis and interpretation."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"The author(s) received no specific funding for this work."

Author’s Response: Thank you. We have revised in the manuscript. [line number 340-349]

5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Author’s Response: Thank you. We have included captions for supporting information file at the end of the manuscript. [line number 369]

Reviewer #1: Review statistical errors:

1. Reviewer comment: The authors should cross check the figures and summations for alignment; in the abstract, result section and the main text. For, example, total HIV positives from previous pool of presumptive TB cases with known HIV status is 2,763 + 215 = 2,978 (not 2,976). However, 2,976 is used in the main text. The error is likely from use of 213 in the result section against 215 in the abstract.

Author’s response: Thank you for this comment. We have revised in the manuscript. [line number 45]

2. Reviewer comment: Grammatical errors are noticed on lines 59, 83, 264…

Author’s response: Thank you. The grammatical errors have been corrected. [line number 59, 81-86, 278-281]

Areas needing contextual review check:

3. Reviewer comment: WHO does not recognize lymph node enlargement as a clinically high index for presumptive TB (line 114)

Author’s response: Thank you for this comment. This was accordingly to the criteria set by National TB Program but it is not available in published guidelines. Therefore, we have removed the reference and revised the sentence. [line number 120]

4. Reviewer comment: In HTS practices with PITC- counselling is done after the test result - but quick health information is provided to obtain consent (line 125)

Author’s response: Thank you. We have included about pre-test counselling in line number 135.

5. Reviewer comment: Revise line 134-135. Sentence may be confusing, as the opening paragraph says patients are referred to the PITC service delivery point. Is this in reference to diagnosed co-infected TB/HIV patients? Except if there is a note that both TB and PITC service stations offer TB and HIV services simultaneously - this is the ideal though.

Author’s response: Thank you. The PICT service counter is in TB OPD and patients are not referred to other service delivery point. We have changed the word “counter” to “desk” to give clear information. [line number 125, 135]

6. Reviewer comment: Line 209: Fig 1 is labelled but located elsewhere.

Author’s response: The figure was submitted as a separate TIFF file according to the journal guideline and it is available in submission system.

7. Reviewer comment: The statistical instrument used in table 2 to explain number needed to test to get one positive needs to be better explained and simplified.

Author’s response: Thank you. We have revised it as followed. “The number needed to screen to find an additional person living with HIV was calculated by dividing the number tested by the number of confirmed HIV positive cases [N/n where N is the number tested and ‘n’ is the number who were HIV positive of those who were tested]” [line number 180-182]

Technical content:

8. Reviewer comment: Even though 85.5% of the 10,401 new registrations accepted to do HIV test (positivity: 2.05%), it is not technically sound to conclude on `willingness to test` and `case finding yield` from the whole presumptive TB population of 21,989, when 44.6% (9,818) came with a known HIV status, and as presented in the main text, Mandalay is a referral TB hospital with most of the patients being referred from diverse health facilities, already biased with an `intention-to-test.

Author’s response: Thank you. We agree on this point. We have now clarified in the manuscript that the results on ‘uptake’ and ‘positivity’ are on those presumptive TB patients who were found eligible for HIV testing at the tertiary care hospital and but not among all the presumptive TB patients who were referred or who reached the TB OPD. The data contained in table 2 is only of those presumptive patients who did not know their HIV status at the time of registration at the tertiary care hospital. We agree that the uptake of HIV testing could be higher in presumptive TB patients attending tertiary care setting than when compared to presumptive TB patients found in the community. Therefore, we have included a sentence to reflect this aspect in the discussion section of the manuscript. [line number 324-326]

9. Reviewer comment: Moreover, being an aggregated data over a couple of years (4), without information on the average duration of the last test to time of registration, combining the newly diagnosed HIV positives and those who came to registration with a known status for impact decision making is technically flawed.

Author’s response: Thank you for this comment. We wish to clarify that though this study contains aggregate numbers, we have taken HIV positivity only among those who were found eligible for HIV testing. We have excluded persons whose HIV status was already known. We, therefore, feel that study is not technically flawed as commented by the reviewer.

10. The recommendation to scale up PITC among presumptive TB case nation-wide could be based on other benefits of TB/HIV collaboration, and not on the yield noticed in this study population, as the data and study setting does not support such conclusion.

Author’s response: Thank you. We agree that the country-wide scale-up of PITC should be based on several considerations and studies (such as ours) provides partial evidence in support of this policy. We have reflected this sentiment in the discussion/conclusion section of the manuscript. [line number 324-326]

Reviewer #2:

1. Reviewer comment: Overview: “HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017” is a cross-sectional study evaluating the outcomes of an HIV provider-initiated testing and counselling service among individuals presenting to a TB outpatient department with presumptive tuberculosis. The authors report that 85.5% of individuals with unknown HIV status agreed to HIV testing with 215 (2%) new infections identified. The majority 69% did not have tuberculosis. They found that the number needed to test to identify one new HIV infection was 48. This study does provide interesting information about a high-risk population in an area with lower rates of HIV testing. Enthusiasm was decreased for this manuscript by multiple grammatical/syntax errors and unclear methodology making it difficult to follow.

Author’s response: Thank you. We have carefully reviewed the whole manuscript and the grammatical/syntax errors were corrected accordingly.

Major Comments:

Introduction:

2. Reviewer comment: The authors discuss Provider-initiated testing and counselling (PITC) but do not mention “Opt-out testing” or opt-out PITC which have been widely adopted. The authors should discuss alternative and more inclusive testing strategies and barriers to their implementation locally.

Author’s response: Thank you for this comment. We have mentioned about “Opt-out testing” for HIV among patients admitted at emergency department in line number 84 and 85.

3. Reviewer comment: Line 80 – 81, “uptake of HIV testing is low” this is a generalized and vague statement. This should be more specific. Where? Under what circumstances? There certainly areas of high HIV testing uptake and opt-out testing in many TB centers.

Author’s response: Thank you for this comment. We have revised in the manuscript and have clarified about where and under what circumstances the HIV testing is low. [line number 80 to 85]

4. Reviewer comment: Methods: Line 99. The authors state the Myanmar is a “high burden” HIV and TB country. The authors should be more specific and highlight the prevalence and incidence of these.

Author’s response: Thank you for this comment. We wanted to say “highest TB/HIV burden countries” and this has been revised in the manuscript with the supporting information and the corresponding reference. [line number 103-104]

5. Reviewer comment: Lines 123 – 126 eligibility for PITC in unclear and should be re-written

Author’s response: Thank you. We have revised in the manuscript. [line number 131-133]

6. Reviewer comment: The definition of “known HIV status” is unclear since this included individual who were positive and negative. Does this mean previously tested for HIV? If so when?

Author’s response: Thank you. According to project SOP, the patients are categorized as “Known HIV status” when they had HIV positive result in hand or evidence of receiving HIV care at HIV care facilities or they had tested HIV negative within two weeks with the result in hand.

7. Reviewer comment: For individuals who previously tested negative when were they offered PITC?

Author’s response: Thank you for this comment. They were not offered HIV testing if they were previously tested HIV negative within 2 weeks. Those who were previously tested negative more than two weeks ago were offered PITC and they were categorized as “Unknown HIV status”.

8. Reviewer comment: How were inconclusive/screened positive HIV tests handled? Is there access to RNA PCR? Were these included in the totals? The authors should consider adding in the screened positive individuals in a sensitivity analysis.

Author’s response: The patients who had inconclusive or screening positive result should be re-tested after 14 days according to National guideline but unfortunately it was not captured in our data. HIV RNA PCR was not used for diagnosis confirmation in our setting. In this analysis, those who did not complete HIV testing algorithm were excluded in NNS calculation (table 2). We have done the sensitivity analysis and presented in the revised manuscript. If we assume all persons with inconclusive or screened positive results as positive, then the proportion positive is 2.8% (95% CI: 2.5-3.1) and if all persons with inconclusive or screened positive missing results were negative then the proportion HIV positive is 2.0% (95% CI:1.8-2.3). [line number 211-214]

9. How was missing data handled? Were they imputed, deleted, ignored?

Author’s response: In our study the number of persons with missing data (either age, sex, education, occupation, marital status, diabetes status and TB contact) were 381/21,989 (1.7%). As the amount of missing data for each variable was less than 2%, they were excluded in the regression analysis (Table 1). As you can see in the table 2, the presumptive TB patients who had missing data were shown and the NNS was calculated for them. Only those who had invalid HIV results (such as HIV screening test positive but no confirmatory test and those who had inconclusive HIV result) were excluded in NNS calculation.

10. Reviewer comment: Results: Line 196 – it is unclear what definition of “aware of HIV status” means. Why were those that previously tested negative not offered repeat testing?

Author’s response: Thank you for this comment. We have changed the word to “known HIV status” from the “aware of HIV status” to be consistent and clear. This includes people who had HIV positive result in hand or evidence of receiving HIV care at HIV care facility or those who had HIV negative result which was tested within 2 weeks. Those who have HIV negative result which was tested.

11. Reviewer comment: Lines 221 – 222. The authors should state the number needed to treat patients 35-44, those who were divorced/separated, >55, and with DM separately.

Author’s response: Thank you. We did say separately for those who had low NNS (35-44 years old and those who were divorced and separated) and those who had high NNS (people aged more than 55 years and those who know DM status).

12. Discussion: Reviewer comment: The authors should discuss how their PITC compare to opt-out testing and opt-out PITC in other settings.

Author’s response: Thank you. We have compared our findings on HIV testing uptake with other studies conducted in Uganda, Democratic Republic of the Congo, Ethiopia, India and Malawi. [line number 276-279].

13. Reviewer comment: The authors should state that self-described HIV negative status is a limitation to this study.

Author’s response: Thank you. We did not include known HIV negative status as a limitation of the study because the status was confirmed by verification with the HIV test result done within last 2 weeks rather than self-described.

14. Reviewer comment: Minor Comments: 1.I would recommend using person-first language throughout. People living with HIV instead of HIV positive.

Author’s response: Thank you. We have carefully checked and revised accordingly.

15. Reviewer comment: The manuscript should be reviewed for grammatical/syntax errors and multiple run on sentences making it difficult to follow.

Author’s response: We have carefully reviewed the grammatical/syntax errors and necessary changes have been made.

16. Reviewer comment: 3. Line 196. Authors should state the interquartile range instead of the standard deviation.

Author’s response: Thank you. As we used “mean” for measurement of central tendency, we want to keep standard deviation for dispersion.

17. Reviewer comment: 4. PLHIV should be defined with first use.

Author’s response: Thank you. We have revised in the manuscript. [line number 42]

Reviewer #3: Review Comments

1. Reviewer comment: Manuscript title: HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017: Overall;

The manuscript is well written and addresses an important subject.

Objectives are clearly stated, and the results are well aligned with the objectives.

The authors describe HTS uptake and HIV positive yield among 21,989 presumptive TB patients served in Mandalay district of Myanmar over a period of three years (2 August 2014 and December). They report 85.5% HIV testing rate among eligible presumptive TB patients and a HIV +ve yield of 2% with TB coinfection rate of 31.6% among newly diagnosed HIV patients. The results reveal 15% non-testing among eligible presumptive TB patients; missed opportunity for identifying 37 HIV +ve clients among the 1,770 eligible presumptive TB patients who were not tested. The significance of this is not adequately discussed yet it is important for improving program performance. Minor inconsistencies are noted between the results section of the abstract vs the manuscript body.

Authors’ response: We thank the reviewer for these encouraging comments. We have made several revisions in the discussion section of the manuscript. We hope that with these revisions your concern ‘The significance of this is not adequately discussed’ is addressed in the revised version of the manuscript. [line number 398-300]

Specific comments:

2. Reviewer comment: Line 45: HIV rate reported to 2 decimal places and 1 decimal place (need to be consistent with decimal places) e.g. Line 45-46: Among 10,401 patients tested for HIV, 215 (2.05%) patients were newly diagnosed with HIV and 147 (69.0%) were among those who were not diagnosed as TB.

Authors’ response: Thank you. We have carefully checked and revised in the manuscript. We kept one decimal place for proportion and two decimal places for prevalence ratio on purpose.

3. Reviewer comment: Line 59: …the… appearing before 10 million seems to be misplaced

Response: Thank you. We have revised in the manuscript. [line number 59]

4. Reviewer comment: Figure 1: It appears that 22 individuals with unrecorded HIV status were classified as “Known HIV status” review this.

Author’s response: Thank you for this comment. We agreed this point and the presumptive TB patients with unrecorded HIV status are now recategorized as “Unknown HIV status”. We have revised the figure 1 and result narrative accordingly. Due to implication of this changes, we have also revised the table 1.

5. Reviewer comment: Results Line 46-47: The overall prevalence of HIV (previously known and newly diagnosed) among presumptive TB patients was 14.7% (2,976/20,192). Please review the numerator and denominator for this calculation based on the cascade presented in Figure 1. The denominator should only include presumptive TB patients with known HIV status at baseline (9,818) and after PITC (10,401) = 20,219; While the numerator should only include known positives at baseline (2,763) and newly tested positives (215 or 213) = 2,978; PITC clients missing HIV test should be excluded from the denominator.

Author’s response: We have revised our calculation for overall prevalence of HIV. Now the denominator is (Known HIV status, 9796 + newly tested for HIV, 10,401) – (HIV result inconclusive, 5 + HIV screening positive only, 73) = 20,119. The numerator is 2,763 + 213 = 2,976.

6. Reviewer comment: Line 171-172: The number needed to test to find an additional person living with HIV was calculated by dividing 100 by the proportion of confirmed HIV positive cases. Apply 215/10,401 to re-affirm the validity of this statement.

Author’s response: Thank you for this comment. We wish to clarify that 78 persons (73 who were positive in screening test but no confirmatory test and 5 patients with inconclusive results) were excluded from the NNS calculations. As it can be seen in table 2, the denominator for calculating the proportion of new HIV positive was 10,323 because we took only those who completed HIV testing cascade according to different national guideline adopted in different time periods. (¥ = Those who had completed HIV testing algorithm (both Determine STAT-PAK between 2014-2016 and Determine, STAT-PAK and Uni-gold tests in 2017). Therefore, we got 2.1 by dividing 213 by 10,323. The number needed to test was calculated by dividing 100 by 2.1. We revised a sentence to better explain the NNS calculation as dividing the number tested by the number of confirmed HIV positive cases in the revised manuscript. [line number 180-182].

7. Reviewer comment: Line 197-198: …… and the HIV result not recorded for 22 (0.2%) patients. Consider deleting this statement if the clients with unrecorded HIV status were treated as unknown status. It may confuse readers.

Author’s response: Thank you. Patient with unrecorded HIV status were taken as “unknown status” and we have deleted this statement in the revised manuscript. [line number 208]

8. Reviewer comment: Line 200-201 Among 12,171 patients, 10,401 (85.5%) were tested for HIV and 213 (2.0%) were newly diagnosed as HIV, as shown in Fig 1. The number tested positive is reported as 215 (2.05%) in the abstract (Line 45-46). Please resolve this inconsistency.

Author’s response: Thank you. This is our mistake and we have corrected it in this revised manuscript. [line number 45]

9. Reviewer comment: Figure 1 presents 22 clients with known but unrecorded HIV status; were these treated as +ve or -ve in the analysis. It may confuse readers. Please review to improve clarity. Similarly, table 1 Presents 73 patients with unconfirmed HIV +ve positives results and 5 with inconclusive results. It would be helpful to explain how these were ultimately classified for purposes of HIV treatment.

Author’s response: Twenty-two patient with unrecorded HIV status are now categorized as “unknown HIV status” and they were not classified as HIV positive nor negative. The patients who had inconclusive or screening positive result should be re-tested after 14 days according to National guideline but unfortunately it was not captured in our data and those 78 patients were not included in our analysis.

10. Reviewer comment: Line 203: Refer to Fig. 1 and re-affirm how its contents contributed to the denominator for estimating the overall prevalence of HIV among presumptive TB patients.

Author’s response: denominator is (Known HIV status, 9796 + newly tested for HIV, 10,401) – (HIV result inconclusive, 5 + HIV screening positive only, 73) = 20,119. The numerator is 2,763 + 213 = 2,976.

11. Reviewer comment: Line 240: Spell out NNS in full under the key for table 2.

Author’s response: Thank you for this comment. We have revised in the manuscript. [line number 256]

12. Reviewer comment: Discussion Line 264-265: ……remaining ~15% patients were not tested for HIV in the study. A possible explanation for this is an important gap stated in line 118-120: The presumptive TB patients may visit TB OPD multiple times before the diagnosis is made but they are referred to PITC only on their first visit. Multiple referrals to PITC in the course of their diagnostic work up for TB may improve HIV testing uptake. This may is a possible programmatic recommendation to address missed opportunities for identification of 37 HIV +ve clients among the 1770 presumptive TB patients who did not undergo PITC.

Author’s response: Thank you for this insightful comment. We have added this in the discussion of the manuscript. [line number 275-278]

13. Reviewer comment: Line 282-283: It is clear that those are additional HIV cases which could be identified early due to implementation of this strategy. The study did not include viral loads or any other measures of time since HIV infection. Therefore, early identification is possible but not clear. Consider editing the sentence to tone this assertion.

Author’s response: Thank you. Although we did not viral load and CD4 data to determine the stage of HIV infection, we still believe that 147 presumptive TB patients without TB were diagnosed HIV early due to this strategy. Otherwise they will not know their HIV status unless they have obvious symptoms of HIV or other major opportunistic infections. We have explained this in the revised manuscript. [line number 297-299]

Reviewer #4: Review comments

Reviewer: Joseph Mugisha Okello

Title for manuscript: HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

General comment

1. Reviewer comment: This important manuscript covers an important subject on HIV testing uptake and HIV positivity among presumptive tuberculosis patients. As the authors rightly, say, HIV testing uptake is still low in patients with presumptive TB. Therefore this manuscript generates more literature on this important topic

Author’s response: Thank you for the encouraging comment.

2. Reviewer comment: The manuscript is well written, and coherent which makes it easy to read. My only concern is why the authors never followed up the 1770 patients that never tested for HIV. In the discussion, the authors talk about the reasons (from qualitative studies) why patients with TB do not test for HIV. However, since the study setting looks to be organised, it would have been better to follow up the 1770 patients (15%) that never tested for HIV to study the reasons why.

Author’s response: Thank you for very practical comments. As it is beyond our study objectives, we were not able to follow up these 1,770 patients. This is an area for future research.

Specific comments

3. Reviewer comment: Data for this study was obtained from a TB program. Although the authors got ethical clearance from the National TB and HIV/AIDS programme and the ethics review committee, there is no mention in the manuscript on whether the authors received informed consent from the study participants/patients.

Author’s response: Thank you. We have included a statement for this in the manuscript. [line number 196-198]

4. Reviewer comment: It is important that the authors give some details on how patients co-infected with TB and HIV are managed or how and where they are referred.

Author’s response: Thank you. The details on how patients are referred to their respective treatment centres are described in project setting. As we don’t have specific health facilities for receiving co-infected patients, we referred them to separate HIV and TB care facilities like we do for other patients with either of the two infections. [line number 141-149]

5. Reviewer comment: In addition, the authors should give details on how the program follows TB patients referred to the resident townships for continuation of anti-TB treatment.

Author’s response: Thank you. In the routine setting, the TB patients were referred to the resident townships by using NTP’s referral form. Since the facility where the study conducted was not actively checked for continuation of anti-TB treatment. Therefore, we did not include this in the manuscript.

Submitted filename: Response to Reviewers.docx

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19 May 2020

PONE-D-19-33429R1

HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

PLOS ONE

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24 May 2020

Review comments

Reviewer: Joseph Mugisha Okello

Title for manuscript: HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

General comment

1. This important manuscript covers an important subject on HIV testing uptake and HIV positivity among presumptive tuberculosis patients. As the authors rightly, say, HIV testing uptake is still low in patients with presumptive TB. Therefore this manuscript generates more literature on this important topic

Author’s response: Thank you for this encouraging comment.

2. The manuscript is well written, and coherent which makes it easy to read. My only concern is why the authors never followed up the 1770 patients that never tested for HIV. In the discussion, the authors talk about the reasons (from qualitative studies) why patients with TB do not test for HIV. However, since the study setting looks to be organised, it would have been better to follow up the 1770 patients (15%) that never tested for HIV to study the reasons why.

Author’s response: We agreed that those patients with presumptive TB should be followed up or HIV testing should be offered on their subsequent visits. . However, our current program practice does not require presumptive TB patients to come for follow-up unless they have other health issues or they develop TB symptoms later on. So we have added a recommendation to conduct a further study to explore the reasons for not having HIV testing among presumptive TB patients. We have included this in the manuscript. [line number 346-347]

Specific comments

1. Data for this study was obtained from a TB program. Although the authors got ethical clearance from the National TB and HIV/AIDS programme and the ethics review committee, there is no mention in the manuscript on whether the authors received informed consent from the study participants/patients.

Author’s response: Thank you for this comment. As the study involved routinely collected program data, informed patient consent was waived by both ethical committees. We have included this in the manuscript. [line number 209-211]

2. It is important that the authors give some details on how patients co-infected with TB and HIV are managed or how and where they are referred.

Author’s response: Thank you. We have provided this information in the manuscript. [line number 150-156]

3. In addition, the authors should give details on how the program follows TB patients referred to the resident townships for continuation of anti-TB treatment.

Author’s response: Thank you. We have revised this in the manuscript. [line number 154-156]

Submitted filename: Response to reviewers_Plos one.docx

Click here for additional data file.

27 May 2020

HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

PONE-D-19-33429R2

Dear Dr. Khine Wut Yee Kyaw

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Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

5 Jun 2020

PONE-D-19-33429R2

HIV testing uptake and HIV positivity among presumptive tuberculosis patients in Mandalay, Myanmar, 2014-2017

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