Introduction

Gates Open Res

Gates Open Research

2572-4754

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10.12688/gatesopenres.14424.1

Research Article

Articles

Uptake of same-day initiation of HIV treatment among adult men and women in Malawi, South Africa, and Zambia: the SPRINT retrospective cohort study

[version 1; peer review: 4 approved with reservations]

Huber

Amy

Conceptualization Data Curation Formal Analysis Methodology Supervision Writing – Original Draft Preparation Writing – Review & Editing 1 Hirasen

Kamban

Data Curation Formal Analysis Project Administration Writing – Review & Editing 1 Brennan

Alana T.

Formal Analysis Writing – Review & Editing 1 2 3 Phiri

Bevis

Data Curation Writing – Review & Editing 4 Tcherini

Timothy

Data Curation Writing – Review & Editing 5 Mulenga

Lloyd

Data Curation Writing – Review & Editing 6 Haimbe

Prudence

Data Curation Project Administration Writing – Review & Editing 4 Shakwelele

Hilda

Data Curation Project Administration Writing – Review & Editing 4 Nyirenda

Rose

Data Curation Writing – Review & Editing 7 Wilson Matola

Bilaal

Data Curation Writing – Review & Editing 7 Gunda

Andrews

Data Curation Project Administration Writing – Review & Editing 5 Rosen

Sydney

Conceptualization Formal Analysis Funding Acquisition Methodology Project Administration Supervision Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0002-6560-2964 a 1 2 1Health Economics and Epidemiology Research Office, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, 2193, South Africa 2Department of Global Health, Boston University School of Public Health, Boston, MA, 02118, USA 3Department Epidemiology, Boston University School of Public Health, Boston, MA, 02118, USA 4Clinton Health Access Institute-Zambia, Lusaka, Zambia 5Clinton Health Access Institute-Malawi, Lilongwe, Malawi 6Ministry of Health, Lusaka, Zambia 7Ministry of Health, Lilongwe, Malawi

a sbrosen@bu.edu

Competing interests: LM, RN, and BWM hold positions in government agencies that have supervisory authority over the healthcare facilities involved in this study. No other competing interests were declared.

14 2 2023

2023

7 2 2023

2023

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Since 2017 global guidelines have recommended “same-day initiation” (SDI) of antiretroviral treatment (ART) for patients considered ready for treatment on the day of HIV diagnosis. Many countries have incorporated a SDI option into national guidelines, but SDI uptake is not well documented. We estimated average time to ART initiation at 12 public healthcare facilities in Malawi, five in South Africa, and 12 in Zambia.

Methods: We sequentially enrolled patients eligible to start ART between January 2018 and June 2019 and reviewed their medical records from the point of HIV diagnosis or first HIV-related interaction with the clinic to the earlier date of treatment initiation or 6 months. We estimated the proportion of patients initiating ART on the same day or within 7, 14, 30, or 180 days of baseline.

Results: We enrolled 826 patients in Malawi, 534 in South Africa, and 1,984 in Zambia. Overall, 88% of patients in Malawi, 57% in South Africa, and 91% in Zambia were offered and accepted SDI. In Malawi, most who did not receive SDI had not initiated ART ≤6 months. In South Africa, an additional 13% initiated ≤1 week, but 21% had no record of initiation ≤6 months. Among those who did initiate within 6 months in Zambia, most started ≤1 week. There were no major differences by sex. WHO Stage III/IV and tuberculosis symptoms were associated with delays in ART initiation.

Conclusions: As of 2020, SDI of ART was widespread, if not nearly universal, in Malawi and Zambia but considerably less common in South Africa. Limitations of the study include pre-COVID-19 data that do not reflect pandemic adaptations and potentially missing data for Zambia. South Africa may be able to increase overall ART coverage by reducing numbers of patients who do not initiate ≤6 months.

Registration: Clinicaltrials.gov ( NCT04468399; NCT04170374; NCT04470011).

HIV antiretroviral therapy same-day initiation Malawi South Africa Zambia

Gates Foundation

OPP1136158

National Institutes of Health

1K01MH105320-01A1

This work was supported by the Gates Foundation [OPP1136158] to Boston University. ATB was supported by NIH grant 1K01MH105320-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Gates Foundation or the NIH.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction

In 2017, the World Health Organization (WHO) began recommending “same-day initiation” (SDI) of treatment for patients with HIV considered clinically and personally ready for antiretroviral therapy (ART) ¹. This recommendation was based on a series of randomized trials and observational studies that had demonstrated improved retention in care and viral suppression rates for patients offered SDI, compared to those offered what was then the standard of care, which typically required multiple clinic visits before a patient received an initial supply of antiretroviral medications (ARVs) ². In the clinical trials, most of the improvement arose from a reduction in loss to follow up between testing positive for HIV and initiating ART. Observational studies have reported that among patients actually starting ART on the same day under routine care, loss to follow up during the first year after initiation has tended to be higher than in the pre-same day initiation period ^{3,
4}, but these studies have generally compared outcomes among patients who started on the same day to outcomes among those known to have started within a specified number of days, ignoring patients who never started ART at all.

In response to the WHO recommendation, many countries adopted SDI into their national guidelines. Instructions to healthcare facilities as to exactly how to implement SDI and to which patients it should be offered, however, were not precise, allowing the interval between a patient’s first clinic visit and ART initiation to be determined by provider judgment and/or patient preference. Time intervals from a patient’s initial presentation (HIV diagnosis or first HIV-related healthcare interaction) to initiation of ART are not routinely reported in electronic medical record (EMR) systems, which typically only create a record for a patient starting at the time of ART initiation. Little evidence is available on the proportion of patients actually starting ART on the same day or the characteristics of those who do or do not, including age, sex, and other characteristics. Without this information, it is difficult to understand observed differences or identify opportunities for improving care.

This paper reports quantitative results of the SPRINT study (Survey of Procedures and Resources for Initiating Treatment of HIV in Africa). It documents uptake of SDI, time to ART initiation for those not accepting SDI, and predictors of SDI for adult men and women in three high HIV burden countries in sub-Saharan Africa.

Methods Ethics

Ethical clearance was provided by the Boston University Medical Campus Institutional Review Board (IRB) (Ref No. H-40354 (Malawi, May 21, 2020), H-39330 (South Africa, October 15, 2019) and H-40488 (Zambia, July 10, 2020)), the University of the Witwatersrand Human Ethics Research Committee in South Africa (Ref No. M200238 (Malawi, July 10, 2020), M190745 (South Africa, November 6, 2019) and M200599 (Zambia, July 10, 2020)), the National Health Sciences Research Committee in Malawi (Ref No. 20/04/2458, April 24, 2020) and the ERES Converge Institutional Review Board in Zambia (Ref No. 2020-Feb-009, February 27, 2020). The Ministry or Department of Health in all three countries and the National Health Research Authority in Zambia also approved the study.

As this was a retrospective review of medical records and no identifiers were collected, a waiver of informed consent was provided. Data transcription from patient records began on May 27, 2020 in Malawi, September 28, 2020 in Zambia, and November 12, 2020 in South Africa.

IRB approval from the University of the Witwatersrand was sought to allow individuals on the team who were based in South Africa to access Malawi data for analysis purposes. There was no need for University of the Witwatersrand approval in order to collect the data, as that was only under the purview of the IRBs of Boston University and the National Health Sciences Research Committee in Malawi, whose approval was secured prior to the start of data collection. All required approvals were in place before data collection began in all three countries. Team members at the University of the Witwatersrand did not access the data from Malawi prior to their own institutional IRB approval.

Study sites

SPRINT was a retrospective record review conducted in Malawi, South Africa, and Zambia. In each country, in collaboration with national health officials, we first purposively selected provinces and districts that provided diversity of setting (rural/urban) and of nongovernmental supporting partner organizations. We then identified a convenience sample of public sector primary healthcare clinics within these provinces or districts and conducted visits to these sites to assess facility-level and HIV testing and initiation-specific aggregate indicators. The final sites selected provided diversity in size and geographic setting, had relatively strong routine data collection, and were welcoming of the research team. Selected study sites are described in Table 1. The SPRINT studies are registered with Clinicaltrials.gov ( NCT04468399, July 13, 2020, Malawi; NCT04170374, Nov 20, 2019, South Africa; NCT04470011, July 14, 2020, Zambia).

Table 1. SPRINT study sites.

Characteristics	Malawi	South Africa	Zambia
Number of sites	12	5 *	12
Geographic locations	Lilongwe District (Central Region), Blantyre District (Southern Region), Chiradzulu District (Southern Region)	Ehlanzeni District (Mpumalanga Province), King Cetshwayo District (KwaZulu-Natal Province)	Central Province, Lusaka Province
Settings
Rural	7	3	4
Urban	5	2	8
ART patient volume
1,000-2,000	1	1	2
2,000-5,000	5	2	6
5,000+	6	2	4

*We originally collected enrollment data from eight sites in South Africa but were unable to access medical records from three of them, leaving a total of five study sites. SPRINT, Survey of Procedures and Resources for Initiating Treatment of HIV in Africa; ART, antiretroviral treatment.

At the time of study enrollment, guidelines for ART initiation in the three study countries encouraged but did not require that SDI be offered to patients whom providers determined to be eligible, without waiting for CD4 count results. Tuberculosis (TB) symptom screening was recommended in all three countries, with a TB test conducted for symptomatic patients prior to ART initiation. Guidelines did not specify how long to delay ART initiation among patients diagnosed with active TB but generally encouraged starting HIV treatment as soon as possible ^{5–
7}.

Enrollment and data collection

Patients were eligible for enrollment in the study if they were 1) non-pregnant adults (≥18 years old); 2) tested HIV-positive or provided documentation of HIV infection (prior positive test); and 3) were eligible to start or re-start ART at one of the study sites between 01 January to 31 December 2018 in South Africa or between 01 July 2018 and 30 June 2019 in Malawi and Zambia. We sequentially enrolled up to 200 patients per site, starting on the latest date in the enrollment period and working backward in time until the target sample size was reached. Study-eligible patients were selected from the register, database, or files kept by the site. Medical record data were downloaded from EMRs where available. If an enrolled patient was not found in the EMR or if an EMR entry was incomplete, we manually accessed individual clinic files and/or other clinic registers or databases. All data, including sex, were accepted as recorded by the healthcare facilities in patient records.

Records were reviewed from the point of HIV treatment eligibility (HIV diagnosis or first interaction with the clinic) to the point of treatment initiation or for a 6-month period, whichever was shorter. By starting with eligibility for treatment, rather than with treatment initiation, the study captured information about patients who failed to initiate treatment within 6 months (dropped out of care before being dispensed medications) and allowed us to observe services received and days elapsed before initiation.

Sample size, outcomes, and statistical analysis

Study enrollment numbers were determined by resource availability. Our maximum sample size was 200 patients per site, or up to a total of 2,400 patients each in Malawi and Zambia and 1,600 in South Africa. The primary outcome of interest for the study was SDI, defined as being dispensed an initial supply of ARV medications on the day of testing positive for HIV or the day of first HIV-related clinic interaction, if a positive test had been conducted previously at another location, without subsequent linkage to care.

Simple descriptive statistics were used to describe the study sample and time to SDI, by sex. Predictors of SDI were assessed using modified Poisson regression ⁸, clustered by study site to allow intragroup correlation in the standard errors. For our first model (Model 1) including data from all three countries, we controlled for biological sex, age (categorized as 18–29, 30–39, 40–49 and >50 years of age), WHO stage III/IV ( vs. I/II) and country, all assessed at ART initiation, as potential risk factors for SDI. Considering that there were no CD4 cell count or TB symptom data from Malawi, we then ran the same model (Model 2) restricted to Zambia and South Africa and included a variable indicating whether the patient received a CD4 count (yes/no) and the presence of TB symptoms (yes/no) at initiation.

Results

We enrolled a total 3,374 participants whose ART initiation dates were between 01 January to 31 December 2018 in South Africa or between 01 July 2018 and 30 June 2019 in Malawi and Zambia. After excluding 30 participants who were found to be ineligible (under 18 years old or initiated treatment outside the study period), the final analytic sample included 3,344 participants (826 patients in Malawi, 534 in South Africa, and 1,984 in Zambia). CD4 counts and TB status were not available for patients in Malawi. There were no important differences in patient characteristics among the three countries, as shown in Table 2.

Table 2. Characteristics of the analytic study sample (n=3,344).

Characteristics (n (%))	Malawi		South Africa		Zambia
Number enrolled	826	(100)	534	(100)	1,984	(100)
Age (years)
18–29	269	(32.6)	172	(32.2)	656	(33.1)
30–39	309	(37.4)	217	(40.6)	781	(39.4)
40–49	164	(19.9)	100	(18.7)	389	(19.6)
50+	84	(10.2)	45	(8.4)	158	(8.0)
Sex (female)	429	(51.9)	301	(56.4)	1,015	(51.2)
WHO stage III/IV at ART initiation ( vs. stage I/II)	207 (25.1)		185 (34.6)		401 (20.2)
CD4 count at ART initiation
Number with baseline CD4 counts recorded	0 (0.0)		281 (52.6)		470 (23.7)
Median (IQR) (cells/mm3)			299 (181-476)		378 (214-581)
TB symptoms reported enrollment	*		62 (11.6)		327 (16.5)

*The study was unable to collect data on reported TB symptoms in Malawi. WHO, World Health Organization; ART, antiretroviral treatment; TB, tuberculosis.

Time to ART initiation

Time to ART initiation is presented in Table 3. SDI was the norm in Malawi and Zambia, where a vast majority of patients did start ART on the day of diagnosis or first HIV-related clinic interaction. It was much less common in South Africa, where a third of patients had not initiated ART at all within the 6-month study observation period. Among patients who did not initiate on the same day, varying proportions proceeded to initiate within 1, 2, 4, and 24 weeks, as shown in Table 3.

Table 3. Time to ART initiation (n=3,344).

Time to ART initiation after HIV diagnosis or first HIV- related clinic visit (n (%))	Malawi			South Africa			Zambia
	Male (n=396)	Female (n=429)	Total (n=825)	Male (n=233)	Female (n=301)	Total (n=534)	Male (n=969)	Female (n=1,015)	Total * (n=1,984)
Same-day initiation (0 days)	356 (89.9)	370 (86.3)	726 (88.0)	132 (56.7)	172 (57.1)	304 (56.9)	883 (91.1)	930 (91.6)	1,813 (91.4)
Between 0 days and 6 months, of whom:	13 (3.3)	20 (4.7)	33 (4.0)	53 (22.7)	64 (21.3)	117 (21.9)	84 (8.7)	84 (8.3)	168 (8.5)
>0 to ≤7 days	7 (1.8)	11 (2.6)	18 (2.2)	33 (14.2)	37 (12.3)	70 (13.1)	56 (5.8)	39 (3.8)	95 (4.8)
>7 to ≤14 days	2 (0.5)	2 (0.5)	4 (0.5)	3 (1.3)	9 (3.0)	12 (2.3)	12 (1.2)	22 (2.2)	34 (1.7)
>14 to ≤30 days	2 (0.5)	3 (0.7)	5 (0.6)	11 (4.7)	6 (2.0)	17 (3.2)	8 (0.8)	6 (0.6)	14 (0.7)
>30 days to ≤6 months	2 (0.5)	4 (0.9)	6 (0.7)	6 (2.6)	12 (4.0)	18 (3.4)	8 (0.8)	17 (1.7)	25 (1.3)
No initiation within 6 months	27 (6.8)	39 (9.1)	66 (8.0)	48 (20.6)	65 (21.6)	113 (21.2)	2 (0.2)	1 (0.1)	3 (0.2)

*As explained in text, the very small number of patients reported as not having initiated ART in Zambia may reflect missing data. ART, antiretroviral treatment.

Across all three countries, as shown in Table 3 and Table 4, we identified a total of 182 participants who did not initiate treatment within 6 months of HIV diagnosis or their first recorded HIV-related clinic visit (non-initiators). These patients comprised 8% of the cohort in Malawi, 21% in South Africa, and just 0.2% in Zambia. We note that while these proportions are consistent with expectations in Malawi and South Africa, it is likely that non-initiators in Zambia who should have been included in our sample were not. Although we made multiple attempts to confirm the completeness of our cohort in Zambia, we believe it is likely that more than 0.2% of patients in Zambia who were eligible to initiate ART did not start within 6 months. Among those who did not initiate within 6 months, in Malawi most either died or remained alive and in care, but not on ART, while in South Africa most had died or were simply missing follow up records ( Table 4).

Table 4. Outcomes for those who did not initiate (n=182).

6-month outcome for those who did not initiate within 6 months (n (%))	Malawi n=66	South Africa n=113	Zambia n=3	Total n=182
Alive and in care	20 (30.3)	4 (3.5)	-	24 (13.2)
Lost to follow up	1 (1.5)	1 (0.9)	-	2 (1.1)
Died	38 (57.6)	44 (38.9)	-	82 (45.1)
Transferred out	4 (6.1)	15 (13.3)	-	19 (10.4)
Missing (no follow up record)	3 (4.6)	49 (43.4)	3 (100)	55 (30.2)

Predictors of same-day initiation

Table 5 presents the results of the modified Poisson regression. In Model 1, which included data from all three countries, we found that patients with a WHO stage III/IV ( vs. stage I/II) had a 34% decrease in the likelihood of SDI (adjusted risk ratio (aRR): 0.66; 95% confidence interval (CI): 0.54-0.81)). Patients in South Africa had a 28% decrease in the likelihood of SDI (aRR: 0.72; 95% CI: 0.63-0.82) compared to Zambia, while the uptake of SDI in Malawi was comparable to that of Zambia. We did not control for CD4 counts or TB symptoms in this model, as these were not available in Malawi.

Table 5. Crude and adjusted models clustered by study site for the outcome of SDI for the entire sample (Model 1) and for South Africa and Zambia where CD4 counts and TB data were collected (Model 2).

Characteristic	Measure	Model 1 SDI (n=3,344)		Model 2 SDI (n=2,518) *
		Crude RR (95% CI)	Adjusted RR (95% CI)	Crude RR (95% CI)	Adjusted RR (95% CI)
Sex	Female	ref.	ref.	ref.	ref.
	Male	1.02 (0.98-1.05)	1.01 (0.99-1.03)	1.01 (0.97-1.05)	1.00 (0.98-1.03)
Age (years)	18-29.9	ref.	ref.	ref.	ref.
	30-39.9	1.00 (0.95-1.05)	1.00 (0.96-1.03)	1.00 (0.94-1.06)	0.99 (0.95-1.04)
	40-49.9	1.01 (0.96-1.07)	0.99 (0.95-1.02)	1.01 (0.94-1.09)	0.99 (0.95-1.03)
	>50	1.00 (0.96-1.05)	0.99 (0.96-1.03)	1.02 (0.97-1.08)	1.01 (0.97-1.06)
WHO stage	I/II	ref.	ref.	ref.	ref.
	III/IV	0.64 (0.51-0.80)	0.66 (0.54-0.81)	0.62 (0.46-0.83)	0.66 (0.52-0.85)
Country	Zambia	ref.	ref.	ref.	ref.
	Malawi	0.96 (0.88-1.05)	0.98 (0.91-1.05)
	South Africa	0.62 (0.47-0.82)	0.72 (0.63-0.82)	0.62 (0.47-0.83)	0.69 (0.60-0.78)
TB symptoms	no			ref.	ref.
	yes			0.83 (0.70-0.98)	0.84 (0.73-0.96)
CD4 count done	no			ref.	ref.
	yes			1.07 (0.96-1.19)	1.09 (0.97-1.22)

*Restricted to South Africa and Zambia only. SDI, same-day initiation; TB, tuberculosis; WHO, World Health Organization.

In Model 2, restricted to South Africa and Zambia, we found similar results to Model 1. Patients with a WHO stage III/IV ( vs. stage I/II) had a 34% decrease in the likelihood of SDI (aRR 0.66; 95% CI: 0.52-0.85) and those in South Africa had a 31% decrease in the likelihood of SDI compared to Zambia (aRR: 0.69; 95% CI: 0.0.60-0.78). We also found that those with TB symptoms had a 16% decrease in the likelihood of SDI (aRR 0.84; 95% CI: 0.73-0.96). Our results also suggest that patients who did have a CD4 count done may have been slightly more likely to initiate on the same day (aRR: 1.09; 95% CI: 0.97-1.22). Sex and age were not predictors of SDI in either model.

Discussion

In this study, we found that by 2020, uptake of SDI was extensive in Zambia and Malawi, reaching 80–90% of patients initiating or re-initiating ART. It was much less common in South Africa, where just 57% of patients initiated on the same day. We did not find significant differences in time to initiation by sex; men were equally likely to start on the same day as women. Among patients who did not initiate same-day, roughly one third in Malawi, half in South Africa, and nearly all in Zambia went on to initiate within 6 months; the rest had no record of treatment initiation by the end of the 6-month follow-up period.

We found several other publications that reported the rate of SDI in various countries in sub-Saharan Africa, mostly at earlier time periods than our study, which was conducted between 2018 and 2020. A multi-country cohort study using data from The International epidemiology Databases to Evaluate AIDS (IeDEA) Network through 2018, including South Africa but not Malawi or Zambia, reported an overall rate of SDI of 64% ⁹. Three studies from South Africa were all completed roughly one year earlier than our study, in 2017-2018. The first, in Johannesburg, reported 20% uptake of SDI ³. The second, in Johannesburg and Limpopo Province, reported that 40% of patients received SDI, with an increase in uptake from 30.3% at the start of the study period to 54.2% at the end ⁶. The third, with data from four provinces, reported 54% SDI uptake in 2018, an increase from 18% in 2016 ¹⁰. The difference between these findings and our result of 57% SDI in South Africa in 2018-2020 likely reflects the impact of an additional year of facility experience in implementing the SDI guideline.

In Zambia, uptake of SDI increased from 42% to 75% of newly initiating patients between the beginning of 2016 and the beginning of 2018, a phenomenon attributed largely to the adoption of universal treatment eligibility in 2017 ¹¹. By the time our data were collected in 2018-2020, Zambia’s SDI rate had increased to more than 91% ( Table 3). We did not find any published data on SDI uptake in Malawi to compare to our estimate of 88%. Reports from neighboring countries showed SDI rates of 65% in Zimbabwe ⁷ and 52% in Mozambique in 2017 ¹²; in Botswana uptake increased from 28% to 59% between 2018 and 2019 ¹³. SPRINT adds both geographic breadth and, importantly, more recent experience to these prior publications.

Reasons for uptake of SDI or of having delays in ART initiation in our study are not clear. In our data from South Africa and Zambia, only the presence of TB symptoms or a WHO stage of III or IV predicted a delay in initiation. This result likely reflects concerns about starting ART while patients may be experiencing co-infections, such as TB or cryptococcal meningitis. Global guidelines continue to regard these conditions as justification for delaying ART initiation ¹⁴, but recent studies suggest that many patients with TB symptoms can and should start ART immediately, as the risk of becoming lost to follow up if ART initiation is delayed may exceed the very low risk of experiencing TB immune reconstitution inflammatory syndrome ¹⁵. Other reasons for delaying initiation may include clinicians’ individual views on SDI, patient preferences ( e.g., concerns about stigma, disclosure, or side effects; feeling healthy or not in need of treatment ¹⁶), and/or lack of resolve or resources to adopt new SDI procedures at some facilities.

At the same time, valuable as SDI may be as a strategy for minimizing loss to follow up before starting ART treatment, it is likely that some patients should indeed delay initiation, as they require more urgent medical care before starting ART or have personal concerns about or barriers to treatment that cannot be addressed in a single visit ^{17,
18}. The proportion of patients falling into this latter category is unclear, and it likely varies across different populations. Based on findings of the SLATE II trial in South Africa, a reasonable guess may be that 10–15% of patients are not good candidates for SDI ¹⁹. If this is correct, then both Zambia and Malawi have achieved near-universal uptake of SDI. South Africa still has some distance to go, however, before it has saturated demand for SDI.

The advent of COVID-19 as a major health risk in all three study countries as of the second quarter of 2020 is likely to have changed both patient and provider behavior with regard to ART initiation. On one hand, COVID-19 morbidity, fear of transmission, and societal restrictions kept many potential patients away from the clinic. In South Africa, for example HIV initiations are known to have fallen by 28% in the first year of the pandemic ¹⁹. Conversely, the desire to minimize personal interaction and clinic visits to avoid COVID-19 transmission could have favored SDI for patients who did make it to the clinic to start ART. It is also not clear whether provider and/or patient behavior will revert to earlier norms as pandemic restrictions wane or will sustain any changes that were made. A new round of data collection will be needed to answer those questions.

The SPRINT study had a number of limitations. Our final enrolled sample size was smaller than intended, due to resource limitations that shortened the data collection period. We relied entirely on routinely collected data, which resulted in many missing values for key variables. Despite every effort to enroll a representative sample of patients eligible for ART initiation, we are not confident that all patients who did not initiate ART during the study period were captured in Zambia, potentially leading to overestimates of total initiation in Zambia. Finally, we cannot discern from our data exactly why certain patients faced a delay in starting ART—whether it was a result of patient or provider preference, patient condition, social pressures, or some other barrier. To achieve the full potential of SDI in increasing treatment uptake for those who are eligible and willing—and not creating risks for or coercing those who are not—a better understanding of how decisions are made at healthcare facilities would be of value.

Data availability Underlying data

Data used in this study, which were abstracted from routinely collected medical records at public sector healthcare facilities, are owned by the Ministry of Health or Department of Health in each study country and cannot be shared by the authors. Requests for data access can be made to the national research authority of each study country. In Malawi, requests can be directed to the National Health Sciences Research Committee of the Ministry of Health and Population, P.O. Box 30377, Lilongwe 3, Malawi. In South Africa, requests can be directed to Mr. Xolile Ndzulu, National Health Information System ( ndzulx@health.gov.za, +27 12 395 8105). In Zambia, requests can be directed to the National Health Research Authority, P.O. Box 30075, Lusaka, Zambia. The authors may be able to advise on or offer updated data access information.

Acknowledgments

An earlier version of this article can be found on medRxiv (doi: https://doi.org/10.1101/2022.11.28.22282854). Data included in this article were previously presented at AIDS 2022, Montreal, July 29-August 2, 2022 ( https://programme.aids2022.org/Abstract/Abstract/?abstractid=11081).

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: Same-day antiretroviral therapy is associated with increased loss to follow-up in South African public health facilities: a prospective cohort study of patients diagnosed with HIV. J Int AIDS Soc. 2020;23(6):e25529. 32510186

10.1002/jia2.25529

7277782

Mody

Sikazwe

Namwase

: Effects of implementing universal and rapid HIV treatment on initiation of antiretroviral therapy and retention in care in Zambia: a natural experiment using regression discontinuity. Lancet HIV. 2021;8(12):e755–e765. 34656208

10.1016/S2352-3018(21)00186-7

8639712

Magro

Cerini

da Gloria

: The cascade of care of HIV after one year of follow-up in a cohort of HIV-positive adult patients in three health settings of Morrumbene in rural Mozambique. Trop Med Int Health. 2021;26(11):1503–1511. 34455661

10.1111/tmi.13671

9293170

Montebatsi

Lavoie

MCC

Blanco

: Improving same-day antiretroviral therapy in Botswana: effects of a multifaceted national intervention. AIDS. Publish Ah,2022;36(4):533–538. 34873088

10.1097/QAD.0000000000003139

World Health Organization: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach.Geneva;2021. 34370423

Maskew

Brennan

Fox

: A clinical algorithm for same-day HIV treatment initiation in settings with high TB symptom prevalence in South Africa: The SLATE II individually randomized clinical trial. PLoS Med. 2020;17(8):e1003226. 32853271

10.1371/journal.pmed.1003226

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Phiri

Mphande

: Optimizing Test and Treat in Malawi: health care worker perspectives on barriers and facilitators to ART initiation among HIV-infected clients who feel healthy. Glob Health Action. 2020;13(1):1728830. 32098595

10.1080/16549716.2020.1728830

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Chilyabanyama

Kalunkumya

: Immediate and Early Engagement of Same-Day Antiretroviral Therapy Initiation among newly diagnosed people living with HIV in Urban Zambia: A Retrospective Cohort Study. PAMJ - One Health. 2023;10:1. 10.11604/pamj-oh.2023.10.1.37012

Pry

Chipungu

Smith

: Patient-reported reasons for declining same-day antiretroviral therapy initiation in routine HIV care settings in Lusaka, Zambia: results from a mixed-effects regression analysis. J Int AIDS Soc. 2020;23(7):e25560. 32618137

10.1002/jia2.25560

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: Reduction in initiations of HIV treatment in South Africa during the COVID pandemic. BMC Health Serv Res. 2022;22(1):428. 35361209

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8970413

10.21956/gatesopenres.15737.r32935

Reviewer response for version 1

Koenig

Serena P.

1 Referee 1Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Competing interests: No competing interests were disclosed.

4 4 2023

2023

This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

recommendation

approve-with-reservations

Thank you for asking me to review this interesting and important paper, which presents routinely collected data on SDI in Malawi, South Africa, and Zambia. A total of 3344 records from 29 health facilities were recorded, which is lower than the target sample size of 6400 due to resource limitations. Overall, 91% of non-pregnant adults in Zambia, 88% in Malawi, and 57% in South Africa initiated SDI. Predictors of not initiating SDI were clinical Stage 3 or 4 disease, and TB symptoms.

I have read the paper, and also the comments from 3 other reviewers. I agree with all comments by the other reviewers. This manuscript is clear and well written, and is an important contribution to the evidence base around SDI initiation. However, it’s difficult to know if differences in how data are captured and recorded could be contributing to the country-level differences which were found.

I have included some additional details below, with the attempt at avoiding comments which have already been stated by the other reviewers:

Abstract:

Methods:

I suggest substituting another phrase for “sequentially enrolled patients eligible to start ART” because this is a retrospective record review.

Please state the eligibility criteria to start ART.

Results:

Please describe the different study periods from South Africa, Malawi and Zambia. As it is currently written, it appears that this is 18 months in each country, but in the Methods section it clarifies that this is 12 months in each country, with different start and stopping periods. If possible, it would also be helpful to include the actual dates of inclusion, since it appears that these periods were shorter than 12 months (i.e. started at the last date in the 12-month period, and sequentially moved backward by day.

Please add numbers as well as percentages for those who were offered and accepted SDI. Do you also have the number of patients who were offered SDI and didn’t accept it?

For clarity, please give the numbers of patients who had not started SDI, but started within 7, 14, 30, or 180 days by country.

Please add p-values and confidence intervals for the predictors of SDI.

Introduction: The last sentence states that this paper documents “update of SDI, time to ART initiation for those not accepting SDI, and predictors of SDI ….” However, it appears that it is not possible to distinguish those who were not offered SDI from those who did not accept SDI. Please clarify this distinction.

Methods: Enrollment and data collection.

I recommend changing the wording “patients were eligible for enrollment in the study if…” and “we sequentially enrolled up to 200 patients per site” as this is a retrospective chart review.

Results:

I suggest changing the wording “we enrolled a total of 3374 participants” as this was a retrospective chart review, with a waiver of informed consent.

Time to ART Initiation: The first paragraph states that a third of patients in South Africa had not initiated ART within 6 months, but according to Table 3, this is 21.2%. I would also suggest deleting this sentence, because in Table 4, it indicates that many of these non-initiators actually had missing follow-up data.

I agree with the review by Burke, in which she clearly the concerns about data quality, particularly for Zambia. I agree with comments and suggested approach in this regard. This is the most important critique of the paper.

Discussion: In Paragraph 4, I disagree with the statement “recent studies suggest that many patients with TB symptoms can and should start ART immediately, as the risk of becoming lost to follow up if ART initiation is delayed may exceed the very low risk of experiencing TB immune reconstitution inflammatory syndrome.” The authors should cite the systematic review by Burke et al. (2022 ¹), which found insufficient evidence to recommend this approach. There are additional concerns about starting ART in the presence of undiagnosed TB, including post-TB lung disease.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Partly

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

Infectious diseases, HIV, TB, clinical research

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

References 1

: Same-day antiretroviral therapy initiation for people living with HIV who have tuberculosis symptoms: a systematic review. HIV Med .2022;23(1) : 10.1111/hiv.13169 4-15

34528368

10.1111/hiv.13169

Rosen

Sydney

Competing interests: None

14 4 2023

Response: We thank the reviewer for these comments.

Response: We agree that it is hard to distinguish true differences from data discrepancies. Like virtually every other observational analysis of routine records in this region, our study almost certainly includes a mix of both. We believe, however, that it is still worth reporting the observed findings and discussing this problem in the manuscript. We have noted this in the limitations of the study.

I have included some additional details below, with the attempt at avoiding comments which have already been stated by the other reviewers:

Abstract:

Methods:

I suggest substituting another phrase for “sequentially enrolled patients eligible to start ART” because this is a retrospective record review.

Response: We have revised this phrase to “retrospectively identified.” This is the language suggested in https://journals.plos.org/plosmedicine/article/info:doi/10.1371/journal.pmed.0040297, the instructions for reporting cohort studies.

Please state the eligibility criteria to start ART.

Response: Thank you for this suggestion. There is a limit of 300 words for the abstract, and we cannot add this information without exceeding that limit or replacing something that may be more important. We have therefore not included the eligibility criteria to start ART in the abstract but have confirmed that this information is included in the manuscript text with the description of the study sites.

Results:

Response: We have added the actual dates of inclusion for each country. We assume that the reviewer refers to the period from January 2018 and June 2019 mentioned in the abstract as the 18 month study period. This is correct as the overall interval of ART initiation for participants in the study. The details for each country are provided in the text.

Please add numbers as well as percentages for those who were offered and accepted SDI. Do you also have the number of patients who were offered SDI and didn’t accept it?

Response: We have added numbers where there were previously only percentages. We have changed “offered and accepted” to “received,” as we do not know for certain that SDI was offered to those who did not start on the same day. It may have been offered but not accepted, or it may not have been offered.

For clarity, please give the numbers of patients who had not started SDI, but started within 7, 14, 30, or 180 days by country.

Response: This information is reported in Table 3. We have avoided repeating it in the text to keep manuscript length under control.

Please add p-values and confidence intervals for the predictors of SDI.

Response: Confidence intervals are reported in the text and in Table 5. P-values add no information for an observational study beyond that provided by confidence intervals and are widely misinterpreted. Based on American Statistical Association guidance ( https://amstat.tandfonline.com/doi/full/10.1080/00031305.2016.1154108#.Vt2XIOaE2MN%5D) we would therefore prefer not to report p-values for this work.

Response: Thank you for this comment. We agree, we cannot make this distinction. We have thus changed the sentence from “accepting” to “receiving” SDI.

Methods: Enrollment and data collection.

I recommend changing the wording “patients were eligible for enrollment in the study if…” and “we sequentially enrolled up to 200 patients per site” as this is a retrospective chart review.

Response: We have revised this sentence.

Results:

I suggest changing the wording “we enrolled a total of 3374 participants” as this was a retrospective chart review, with a waiver of informed consent.

Response: We have revised this sentence.

Response: Thank you for catching the error in the first paragraph—it should have read “a fifth,” not a third. We have adjusted the language in the sentence to note that the result is based on records found.

Response: We agree about the importance of this issue and have addressed Dr. Burke’s comments above.

Discussion: In Paragraph 4, I disagree with the statement “recent studies suggest that many patients with TB symptoms can and should start ART immediately, as the risk of becoming lost to follow up if ART initiation is delayed may exceed the very low risk of experiencing TB immune reconstitution inflammatory syndrome.” The authors should cite the systematic review by Burke et al. (20221), which found insufficient evidence to recommend this approach. There are additional concerns about starting ART in the presence of undiagnosed TB, including post-TB lung disease.

Response: We acknowledge that this is an ongoing debate in the literature and have added this point to the manuscript. Beyond that, we believe it is a judgment call, as some evidence supports and other evidence argues against this approach. Our statement “many patients can and should start ART immediately” appears to be correct for the setting in which our study took place, based on the reference cited. We did not say, and certainly do not believe, that all patients with TB symptoms should start ART immediately—only that many can and should, particularly in light of the high loss to follow up experienced between HIV testing and ART initiation at many of our sites. We would therefore like to keep this sentence in the manuscript. We have added the citation suggested, so that readers may pursue it if they wish.

10.21956/gatesopenres.15737.r32934

Reviewer response for version 1

Burke

Rachael M.

1 2 Referee https://orcid.org/0000-0002-2156-5030 1Malawi Liverpool Wellcome, Blantyre, Malawi 2London School of Hygiene & Tropical Medicine, London, UK

Competing interests: No competing interests were disclosed.

17 3 2023

2023

recommendation

approve-with-reservations

Many thanks for asking me to review. This paper presents information gathered from routine data sources on Same Day ART initiation in three Southern African countries. It is well reported and clear. These are important data for understanding programmatic ART implementation. I have read the paper and also the comments from the other two reviewers. I don't have much to add that the other reviewers haven't already mentioned.

To echo Dr Lessells, it would be helpful to know a bit more about why the sample size wasn’t reached in Malawi and Zambia? Did this introduce bias? Was this a smaller number of participants from all clinics? Or were some clinics under-represented? I see the discussion says results limitations, but it might be good if this were a little more detailed.

I agree with the other reviewers that it might be helpful to describe the data extraction process in a bit more detail by country and possibly by clinic. In what clinics were EMR data used vs. paper records? What happened if EMR data and paper data disagreed? (For example, same day ART recorded on one but not the other)?

What was the process of ascertaining HIV testing or first contact with systems? You say in the introduction often people are only entered into database at the point of starting ART (rather than point of first contact with system)? How were you able to get "one step" back from what is routinely reported?

There is presumably an issue with under-ascertaining people who tested positive but didn’t ever start ART was a problem in Zambia (as the authors have said they don’t think their estimate of % who started ART is accurate), describing the data sources might help with understanding this.

Was there a process of reconciling paper HIV testing registers with ART registers? How were similar-but-not-identical names or ages etc. dealt with? Do you think data collection processes at different clinics was similar?

This information might be useful, particularly for understanding the Zambia context and how data on people who had a positive HIV test but didn’t initate might be lost.

I do understand that this is all observational data from routine records, and some of these items might be very difficult to ascertain or not available at all. That is very understandable and doesn’t invalidate the research. Nonetheless, I think it would be good to describe a little further about the process of gathering/extracting data.

I agree with other reviewers that it might be helpful to see data broken down by clinic to see how much variation there is by clinic.

In table 5 from the model predicting SDI, is this comparing SDI vs. initiated ART (but not on the same day)? Or is it SDI vs. initiated not same day and not initiated at all? From the description of variables being collected at the point of ART initiation, it sounds like it is the former but it would be good to clarify.

In general, I agree with the comments from the other reviewers.

Minor comment

I am not familiar with Zambia and South Africa ART guidelines, but the authors are correct in saying that in Malawi 2022 guidelines the timing of ART in people with diagnosed TB (or TB symptoms but not diagnosed TB) is not specified in detail.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Partly

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

Infectious disease, epidemiology

Rosen

Sydney

Competing interests: None.

14 4 2023

Response: We thank the reviewer for these comments.

Response: We have added mention of this at the start of the results section. We do not believe that this limitation introduced bias, as it resulted simply from slower data collection than expected (due in part to COVID-19 restrictions), which reduced the time available for the overall study. We enrolled sequentially from registers, which should produce a representative sample, even if smaller than we originally desired. (Supplemental Table 1, which we added in response to reviewers’ comments, indicates enrollment numbers for each study site.)

Response: We have added further details about the data extraction process to the Methods section. We have clarified that we did not use both EMR and paper record data for any single patient, only one or the other. After reviewing the overall state of the EMR data for Malawi and Zambia, we decided to use manual data extraction from paper files only in these two countries. In South Africa, as explained above, we relied on EMR data only where paper files could not be found (lost or misfiled).

This information might be useful, particularly for understanding the Zambia context and how data on people who had a positive HIV test but didn’t imitate might be lost.

Response: We thank the reviewer for understanding the challenges in using routine records. These are all really good questions. We don’t think it’s really possible to get “one step back” from routinely reported data in a retrospective, observational study. That said, as explained above, by starting with HIV testing, we went farther back than do most other studies of ART uptake. We believe that the HIV testing registers are relatively accurate and complete, though probably not perfect. In the end we did not enroll anyone who did not have a positive HIV test recorded in the HIV testing registers, which meant that all participants were enrolled as of the date of their HIV test. (We note that this might not have been a participant’s first positive HIV test ever, but it was the first at the study facility during the study period.)

Matching HIV register patients to those in the ART registers was not a major concern, as the time period of interest for the ART registers was limited. Most patients initiated ART on the date of their HIV test, which allowed easy matching by date. For those who did not, we searched the ART registers and EMR records and matched by name and date of birth. We believe that for the sample enrolled this was likely an accurate reflection.

The study had an established protocol, SOPs, and data collection forms that were used by all three countries and at all study sites. Where we had concerns about inconsistency, data collectors re-visited sites and re-checked registers and data. We do not know what happened in Zambia, or even if our speculation that some of those who tested positive and should have been enrolled were not captured. We just think it likely in view of the very high proportion of same-day initiation observed.

In sum, we believe that the study has done everything possible to collect a complete data set for a representative sample of those eligible for same-day initiation. It is not perfect but we think it is better than has been done previously.

I agree with other reviewers that it might be helpful to see data broken down by clinic to see how much variation there is by clinic.

Response: We have now reported results by facility in Supplemental Table 1. We h have also mentioned site-level variations in the Results section.

Response: The model compares SDI vs initiated not same day and not initiated at all (the latter option above). We created outcome variables of SDI = 1, anything else =0. This makes sense to us since the purpose of our analysis is identifying predictors of same-day initiation specifically, and the outcomes of those who did not initiate at all in our data set are unknown. As mentioned in the manuscript (now), some may have initiated at another facility, within 6 months but not same-day from our study site’s perspective.

Minor comment

Response: Thank you, we also rechecked this in response to other reviewers’ questions.

10.21956/gatesopenres.15737.r32933

Reviewer response for version 1

Lessells

Richard

1 Referee https://orcid.org/0000-0003-0926-710X 1KwaZulu-Natal Research Innovation & Sequencing Platform, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa

Competing interests: No competing interests were disclosed.

7 3 2023

2023

recommendation

approve-with-reservations

This paper reports the main quantitative results from the SPRINT study, an observational study using routinely collected health data in Malawi, South Africa and Zambia. This study evaluated same-day antiretroviral therapy initiation for people with HIV in routine care settings. A total of 3344 records from 29 health facilities were analyzed (lower than target sample size of 6400 records due to resource limitations). Overall, the proportion of non-pregnant adults receiving same-day ART initiation was 91% in Zambia, 88% in Malawi and 57% in South Africa; and the proportion initiating ART within 6 months was 100% in Zambia, 92% in Malawi and 79% in South Africa. Individuals with clinical stage 3 or 4 disease and individuals with TB symptoms were less likely to receive same-day ART.

This is an important contribution to the evidence base around same-day ART initiation, and adds to our understanding of how this is being implemented in HIV programmes in Africa. Despite not meeting the target sample size, the study still provides useful information that will be of interest to policy makers, programme managers and health care workers involved in HIV care delivery. Important differences between the three countries were found, with far fewer people receiving same-day ART at the South African sites. However, it’s difficult to know the extent to which this reflects true differences in practice, or whether differences in how data are captured/recorded could also contribute to these findings.

The manuscript is clear, concise and well-written. I have a few comments that the authors might want to consider, mainly highlighting areas where I think additional information or clarity would be helpful for the reader.

Major comments:

As this is an observational study using routinely collected health data, I would recommend that reporting is in line with the RECORD statement and that the completed checklist is added as a supplementary file ( https://www.equator-network.org/reporting-guidelines/record/).

In the study registrations on clinicaltrials.gov, there are two primary outcome measures listed - Average number of visits required to start ART and Time to ART initiation. In this article, only Time to ART initiation has been reported. Please clarify if the protocol and primary outcomes were amended at some stage, or explain why the average number of visits required to start ART has not been reported.

For me, it’s critical to see more details of the data sources (e.g. electronic, register, files), and particularly what variables were used at each site/in each country to calculate the time to ART initiation. This seems key to understanding whether differences in data sources and data collection procedures might underlie any of the difference between sites/countries. Essentially it would be helpful to know how reliably the date of HIV testing or date of first engagement in care is captured, so that we know how confident we can be that if there is a true delay until ART initiation this will be reliably ascertained from the data source.

Minor comments:

Abstract, Methods: ‘We sequentially enrolled patients…’ sounds like this was a prospective cohort study where participants were enrolled. I would suggest rewording this to make clear that this was retrospective analysis of prospectively collected routine health data.

Abstract, Results: ‘…were offered and accepted SDI’ again is slightly misleading as it suggests you know more about who was offered SDI and who accepted this. Unless I’m mistaken, from the data available to you, you only know who received SDI.

Methods, Study sites: ‘Guidelines did not specify how long to delay ART initiation among patients diagnosed with active TB…’ This does not seem correct, as certainly SA guidelines stipulate when ART should be started for people being treated for active TB and I suspect this is also the case for guidelines in Zambia and Malawi.

Methods, Study sites: It would be helpful to know for the three countries, or for the specific study sites, who was involved with ART prescribing/initiation. Was ART initiated by nurses at all sites, or did any sites require a doctor to initiate at the time of the study? This would give important context, especially to understanding any reason for lower proportion receiving SDI in South Africa.

Results: It would be good to see a table with the proportion receiving SDI by individual site/clinic – so that we can see how much variability there was, and particularly see whether the lower proportion was consistent across the five SA sites.

Results, Table 2: Were there no missing data for WHO stage?

Results, Table 2: Were there no missing data for TB symptoms at enrollment? Or does this just capture any records where there was positive documentation of TB symptoms?

What was the reason that the actual CD4 count was not included in the model, and only whether or not the CD4 count was done/recorded?

As the study specifically selected a mix of urban and rural sites, and higher/lower volume sites, was there a reason these were not included in the model – this might have helped to understand whether site characteristics were associated with SDI?

Discussion: The explanation about not meeting target sample size is only presented late in the discussion section. I think it would be good practice for this to be reported in the results.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

Infectious diseases, HIV, clinical research

Rosen

Sydney

Competing interests: None.

14 4 2023

Response: We thank the reviewer for these comments.

Major comments:

Response: The RECORD checklist has been completed and will be posted to the Open BU repository ( www.open.bu.edu), as this journal does not accept supplementary files. (Editor: when the final page numbering is available, we will update the checklist and post it to the repository.)

Response: For this manuscript, we originally chose to report only one of the two primary outcomes in order to focus on the uptake of same-day initiation, with the intention to report visit numbers elsewhere. In response to the reviewer’s request, however, we now report visit numbers for those not initiating on the same day, as a final row in Table 3. The median for clients not initiating on the same day was two visits, including the visit at which ART was initiated.

Response: Dates of HIV testing were collected from clinic registers and records, as mentioned. We cannot say how reliable these data are, but in our experience, dates of discrete events like HIV tests are usually accurate. We did not mean to imply, however, that these dates necessarily reflect a participant’s first HIV test, or even first positive test, only the test associated with starting ART now. We have clarified this in the Methods section.

Minor comments:

Response: Thank you. We have reworded the abstract as suggested.

Response: We agree that more detail in this regard may be important to the reader and have added it to the manuscript in the Methods section. In our view, however, none of the guidelines is definitive; even South Africa’s call for clinician judgment. South Africa’s guidelines at the time of the study stated “Initiate ART after 2 weeks of TB treatment, when the client’s symptoms are improving, and TB treatment is tolerated.” Zambia’s guidelines simply indicate that ART should be deferred for patients with TB. Malawi’s guidelines for patients with active TB state “Start ART within 14 days of diagnosis. TBT + ART can be started on the same day if the patient is stable. Don’t delay TBT or ART.”

Please also see the response to Reviewer 1 with regard to delays due to TB.

Response: We have added this information to the Methods section. ART initiation, including prescribing, is conducted by clinical officers or trained ART nurses in Malawi and Zambia and by nurses in South Africa.

Response: We have added this information into Supplemental Table 1 and to the results section of the text.

Results, Table 2: Were there no missing data for WHO stage? Were there no missing data for TB symptoms at enrollment? Or does this just capture any records where there was positive documentation of TB symptoms?

Response: We have added the information on missingness for WHO stage and TB symptoms to Table 2.

What was the reason that the actual CD4 count was not included in the model, and only whether or not the CD4 count was done/recorded?

Response: Malawi did not routinely conduct CD4 count tests at initiation during the study period. In South Africa and Zambia (Model 2), data completeness for actual CD4 counts, rather than for whether a test was conducted or not, was poor. Actual CD4 count was recorded for only 751 of the 2,518 participants who had tests done. Rather than limiting Model 2 to only 751 subjects, we preferred to use the data for all 2,518. Additionally, when we controlled for CD4 count, we did not find it was a predictor of SDI. We have added a row to Table 2 to show the discrepancy between numbers of tests conducted and numbers of actual result values available.

Response: We have added setting (urban/peri-urban and rural) and total remaining on ART (TROA) categorized into 4 groups (500-2,000, 2,000-5,000, 5,000-10,000 and >10,000) to both models (Table 5) and to Table 1. Only 1 site was peri-urban in Zambia, so we grouped urban/peri-urban settings together. We have added the following text to the results section at the bottom of page 13 in reference to model 2 results, “…larger vs. smaller clinic size (5,000-10,000 vs. <2,000 patients – aRR 1.09; 95% CI: 1.01-1.18 and >10,000 vs. <2,000 patients – aRR 1.07; 85% CI: 0.99-1.15) were more likely to initiate ART on the same day. Sex, age and location (urban, peri-urban or rural) were not predictors of SDI in either model.”

Discussion: The explanation about not meeting target sample size is only presented late in the discussion section. I think it would be good practice for this to be reported in the results.

Response: We have now noted this in the first paragraph of the Results section.

10.21956/gatesopenres.15737.r32932

Reviewer response for version 1

MacPherson

Peter

1 Referee https://orcid.org/0000-0002-0329-9613 1University of Glasgow, Glasgow, UK

Competing interests: No competing interests were disclosed.

22 2 2023

2023

recommendation

approve-with-reservations

Many thanks for asking me to review this manuscript. Great to see these data, and very clearly reported. I have only a few comments that the authors should address.

In the introduction, it might be worth adding a sentence or two explaining some of the reasons why same day ART initiation may not always be possible or recommended.

Page 3, in the paragraph describing country guidelines for SDI. Did any country guidelines have recommendations for ART initiation in people with TB symptoms who were not able to produce sputum samples, or did not receive results? This is likely a common reason for ART initiation delay.

Methods: good to provide assurance that, in each of the study clinics, people were systematically recorded in registers/records at the point of eligibility assessment. i.e. is it possible that some people who attended the clinic, but felt to be not eligible for ART initiation by staff, did not have their attendance recorded? If this was a possibility, did practice vary by clinic/country, and what biasing effect may it have had on estimates of same-day initiation?

Similarly, in ascertaining outcomes (ART initiation as defined by dispensing of an initial supply of medication), did recording practices differ between sites/countries, and what methods were put in place to ensure ascertainment bias was minimised?

In Table 1, would it be possible to add a row to provide the number of clinics per country from which electronic data records were available for extraction?

Table 2: interesting to see that the prevalence of reported TB symptoms was lower in the South African clinics compared to the Zambian clinics. Were there any differences in definitions of “TB symptoms” or recording between countries?

Table 4 - do you have data on the timing of death?

Great to see that clinic-level random intercepts were included in the modified Poisson regression models, if I am understanding correctly. Are you able to quantify the variation in percentage achieving same-day initiation between clinics (e.g. standard deviation of the random intercepts), and any particular patterns that might help explain why clinics had higher or lower rates of same-day initiation (e.g. urban vs. rural clinics, size of clinic)? Investigating this may help untangle some of the potential reasons for delay rightly highlighted by the authors as a remaining knowledge gap in the Discussion.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Yes

Reviewer Expertise:

Public Health, HIV, Tuberculosis, Epidemiology, Global Health

Rosen

Sydney

Competing interests: None.

13 4 2023

Many thanks for asking me to review this manuscript. Great to see these data, and very clearly reported. I have only a few comments that the authors should address.

Response: We thank the reviewer for these comments.

In the introduction, it might be worth adding a sentence or two explaining some of the reasons why same day ART initiation may not always be possible or recommended.

Response: Thank you for this suggestion. We have added a sentence about this to the introduction.

Response: This is a good point. We agree that concerns about undiagnosed TB have been a major reason for delaying ART initiation. South Africa’s guidelines explicitly exclude patients with a positive TB symptom screen from the recommendation for same-day initiation. Malawi’s guidelines do require TB symptom screening but do not explicitly recommend delaying ART initiation on the basis for the screening results. Zambia’s guidelines recommend deferring initiation if there is suspicion of TB but do not specify what should be considered for “suspicion.” We have added this information to the Methods section where the guidelines are described.

Response: Another good point. It is true that recording of patients not eligible for ART initiation is poor in many clinics in the study countries. This is the reason for enrolling SPRINT participants at the point of testing positive for HIV, which is the very first step in the ART eligibility determination process. Even patients who arrive with documentation of a positive HIV test from somewhere else are re-tested so that the facility has confirmation of their status. SPRINT enrolled on the basis of HIV testing registers and then followed patients forward in time. We did not enroll anyone who was not tested at the study clinic, though there was no requirement that the test used for study enrollment was the individual’s first positive HIV test—a prior test at any time in the past was certainly possible. While we cannot be certain that every individual who tested positive was included in the registers, we believe that the study captured as many of them as is possible in a retrospective analysis. We have clarified the wording about this in the methods section and, since missing some positive testers is a possibility, we added a note about this to the study limitations section.

Response: Ascertainment bias is always a possibility when relying on routinely collected data, as the reviewer suggests. Prescribing medications is usually one of the best-recorded indicators in routinely kept medical records, however, so we are not too concerned about bias in this regard. A more serious concern arising from our reliance on routinely collected records within unlinked EMRs is that patients who appeared not to have initiated ART at all during the six-month follow up period (last row of Table 4) could actually have transferred informally (“silent transfers”) to other healthcare facilities. The number of such participants is very low in Zambia and Malawi but this may explain the larger number of missing outcomes in South Africa, where mobility is high. We have added this explanation to the results section and the limitations section in the discussion.

In Table 1, would it be possible to add a row to provide the number of clinics per country from which electronic data records were available for extraction?

Response: Since Table 1 describes the study sites, we assume that this question pertains to the study sites and not the study countries as a whole. All study sites had electronic data records available for extraction, but none of the study sites reliably entered into their EMRs patients who did not start ART. We therefore relied entirely on paper record data extraction in Zambia and Malawi, where the EMRs were of greater concern. In South Africa, we used EMR data to supplement paper records for all 5 clinics, as we were not able to find all paper files (EMR used for 92 of 534 participants, 17%). In these cases, the paper records were likely misfiled or misplaced after original EMR data entry by the clinic. We have added these details to the manuscript.

Response: We agree that this was a bit surprising, given what we think we know about the prevalence of TB in the two countries, but we have no way of answering the reviewer’s questions. Both countries use the standard WHO four-symptom screening tool. It is possible that Zambian clinic staff are more diligent about recording results, but we have no evidence of this. Since we don’t know, and cannot even really guess, we’d prefer not to speculate in the manuscript.

Table 4 - do you have data on the timing of death?

Response: Unfortunately, date of death is rarely recorded in routine ART clinic records, so we do not.

Response: We thank the reviewer for this suggestion. We only clustered by clinic, so we are unable to quantify the variation in percentage achieving SDI between clinics. We felt it would be informative to stratify uptake of SDI by country, site location (urban/peri-urban and rural) and tuberculosis symptoms present and to rank them by size of clinic based on the total volume of patients on ART at each site.

We have added Supplemental Table 1 below with the facility-level results for these variables to the manuscript. The following text into the results section in reference to any variation by site, “When we stratified results by country, clinic, and TB symptom status and ranked sites according to ART patient volume (Supplemental Table 1), our results suggested that patients presenting with TB symptoms in South Africa were less likely to initiate ART on the same day than were those with TB symptoms. In rural clinics in South Africa, the likelihood of SDI tended to decline as patient volume increased. We did not see these associations in Zambia or Malawi.”

(Please note that we cannot include tables in these responses. Supplemental Table 1 will be submitted to the journal with the revised manuscript.)

Additionally, we have added setting (urban/peri-urban and rural) and volume on ART, categorized into 4 groups (500-2,000, 2,000-5,000, 5,000-10,000 and >10,000), to both models (Table 5) and to Table 1. Only 1 site was peri-urban in Zambia, so we grouped urban/peri-urban settings together. We have added the following text to the results section at the bottom of page 13 in reference to model 2 results, “…larger vs. smaller clinic size (5,000-10,000 vs. <2,000 patients – aRR 1.09; 95% CI: 1.01-1.18 and >10,000 vs. <2,000 patients – aRR 1.07; 85% CI: 0.99-1.15) were more likely to initiate ART on the same day. Sex, age and location (urban, peri-urban or rural) were not predictors of SDI in either model.”