You are viewing the site in preview mode

Skip to main content
Download PDF

Integrating HIV advanced disease management into a routine program setting: cohort from Mumbai, India

BMC Health Services Research volume 25, Article number: 595 (2025) Cite this article

Abstract

Background

The advanced disease management (ADM) package, which aims to reduce morbidity and mortality in people with Advanced HIV disease (AHD, WHO stage III/IV and/or CD4 count < 200 cells/mm3 or age < 5 years), is not fully implemented in India. We assessed the feasibility of implementing the full WHO ADM package as part of routine HIV care under the programmatic setting in antiretroviral therapy centers of Mumbai.

Methods

We implemented the ADM package (screening, treatment, and prophylaxis for major opportunistic infections, rapid ART initiation, and ART adherence support) in 17 ART centers from October 2020 to December 2021. Treatment naïve and experienced persons with AHD, including children, were enrolled. We assessed the feasibility through coverage of ADM package components and reported the proportion of rapid ART initiation (≤ 7 days), cotrimoxazole prophylaxis, TB preventive treatment (TPT) for those eligible [(excluded active TB disease (n = 280) and those completed TPT prior to enrolment (n = 1,186)], TB-LAM screening (excluded current TB disease), and cryptococcal antigen (CrAg) assay (excluded children < 10 years of age). We used a point of care test for TB (LAM) and cryptococcus (CrAg) screening. We followed the prospective cohort for one year (through 31 July 2022) to document outcomes for survival and lost to follow- up (LTFU).

Results

We identified 4,334 PLHIV with AHD and provided the full ADM package to 64% (2,779/4,334); 297 did not receive ADM (146 died, 151 LTFU), and 1,258 received routine standard of care (587 had TB, 366 were at decentralized sites, and 305 LAM/CrAg kits were not available) with existing ART center staff. Nearly 78% (385/494) of treatment naïve were rapidly initiated on ART. Nearly 82% (1,129/1,383) and 99% (2,751/2,779) received TPT and cotrimoxazole prophylaxis, respectively. Of the eligible, 99% (2,508/2,524) and 98% (2,715/2,758) were screened for TB and cryptococcal infection, respectively. At the end of 12 months, 88% (2,458/2,779) were alive, 8% (210/2,779) died, and 4% (111/2,779) were LTFU. Mean survival time was significantly (p < 0.001) higher among treatment experienced people; 11.6 months (95% CI: 11.5,11.7) compared to treatment naïve people 10.8 months (95% CI: 10.5,11.0).

Conclusion

With careful anticipatory planning, stakeholder engagement, and training, implementing the full ADM package is feasible in a routine program setting with existing human resources. Additional intensive case management may be necessary for the reduction of mortality among treatment naïve PLHIV.

Peer Review reports

Contributions to the literature

  • Our findings suggest that, with careful planning and involving stakeholders from health providers and communities, it is feasible to implement continuity-of-care innovations such as the HIV ADM package at all levels of health facilities to improve the survival and outcomes of PLHIV.

  • Efficient and person-centric referral mechanisms and additional intensive care are required for antiretroviral treatment naïve clients with AHD.

  • Training, mentoring, and monitoring of health care staff with the development of person-centric advanced HIV disease patient flow systems are crucial for ADM implementation.

Background

Expanded HIV testing and rapid access to antiretroviral therapy (ART) is a key pillar to reach the 2030 HIV elimination goals. Of the 39 million people living with HIV (PLHIV), an estimated 29.8 million are on life saving ART (2022), leading to a significant impact on reduction in mortality globally [1]. Despite ongoing improvements in ART access, advanced HIV disease (WHO stage III or IV and /or CD4 count < 200 cells/mm3 or age < 5 years) remains a significant cause of death among PLHIV [2, 3], in low- and middle-income countries. To decrease morbidity and mortality and expand evidence-based practice, WHO recommends an Advanced Disease Management (ADM) package for children [4] and adults [5]. The WHO ADM package components include screening and diagnosis of opportunistic infections (for active TB with Nucleic Acid Amplification Test and the lateral flow urine lipoarabinomannan (LAM) assay, systematic screening for serum or plasma cryptococcal antigen (CrAg) assay), cotrimoxazole prophylaxis, TB preventive treatment fluconazole primary prophylaxis, rapid ART initiation and intensive antiretroviral treatment adherence support.

India’s National AIDS Control Program has seen a decline in annual new HIV infections and AIDS related deaths by 86% and 78% (2021), with nearly 1.6 million PLHIV on ART [6] through expanded person-centric service delivery strategies, which have improved access and closed gaps in treatment continuity. Despite these advances, 30% of PLHIV newly presenting to care for enrollment in ART centers have advanced HIV disease [7] with CD4 counts < 200 cells/mm3. This necessitates a public health approach for managing people who present late with AHD [8, 9].

In 2020, with the recommendation of the National Technical Resource Group, we assessed the feasibility of implementing the full ADM package in the 17 government ART centers in the routine program setting in Mumbai. In 2021, India’s National AIDS Control Program reviewed the WHO guidance and drafted guidelines on Advanced Disease Management [10] for implementation at ART centers. Despite the broader adoption of the WHO guidance, there are barriers to implementation. Currently, the National AIDS Control Program implements a partial ADM package [4] that includes, symptom screening for TB followed by TPT for those negative screen, Nucleic Acid Amplification Test for TB diagnosis, cotrimoxazole prophylaxis] across government ART centers due to limited availability of TB-LAM and CrAg screening tests and fluconazole prophylaxis. Through an implementation science approach, we describe the ADM adoption and report barriers, moderators, and outcomes. The full results of TB LAM (included PLHIV > 18 years of age) and CrAg implementation referred to in this paper are reported elsewhere [11, 12].

Methods

From October 2020–December 2021, we implemented the WHO recommended full ADM package into routine HIV services in 17 public antiretroviral therapy centers in Mumbai. Six centers were in tertiary, eight in secondary, and three in primary health care facilities. Care provided at these ART centers is free of charge to the PLHIV. As described in our prior study, “ART centers consist of a team of different cadres of health care providers including a trained physician, nurse, pharmacist, counsellor, data manager, lab technician, and a community representative. In the programmatic setting, CD4 count is enumerated for all PLHIV at baseline and every six months while on ART, and viral load is done annually. ART centres refer PLHIV to higher health facilities for diagnostic or clinical management, if required” [11, 12].

To describe the process of translating the ADM package into routine service delivery at ART centers, we adopted Per Nilsen’s [13] implementation science theoretical approach that stratifies different theories based on the setting, process, and outcomes. We used the Ottawa Model of Research [14] approach to describe the process of integration of the ADM package into routine care at ART centers in Mumbai and have described the implementation through the six-step approach of the Ottawa Model. This approach is most suitable for implementing continuity-of-care innovations that involve multiple sectors, settings, agencies, and provider groups [15] that impact the adoption of changes at the organizational and systems level [16].

Application of the six-step approach of the Ottawa model for implementation of the ADM package

Step 1. Stakeholder engagement

Mumbai is one of India’s three mega Metropolitan cities, with a well-organized separate administrative body (the Mumbai Corporation). Apart from the routine budgetary allocation from the National AIDS Control Organization, the Mumbai Corporation was a critical stakeholder in resource mobilization and facilitation of policy. We included clinicians, microbiologists, program managers, community members, clinicians, administrators of hospitals and ART center staff as key stakeholders. We organized a series of consultative meetings with stakeholders to seek inputs on operational aspects, standard operating procedures (SOP) on care and treatment, patient flow, referral mechanisms, reporting, and monitoring tools.

Step 2. Components of ADM package of services

We developed SOPs and trained ART center staff on the ADM package as per the SOPs. The WHO ADM package [17] includes (1) rapid ART initiation (within 7 days), (2) prophylaxis and pre-emptive treatment including cotrimoxazole prophylaxis, TPT, provided TB disease is excluded by initial four symptom screening (4 S negative) and among 4 S positive TB was ruled out by nucleic acid amplification test and or TB-LAM and or chest radiography, and fluconazole pre-emptive therapy of 800 mg/day for 2 weeks, then 400 mg/day for 8 weeks and continued maintenance with fluconazole 200 mg/day for serum CrAg antigen using in vitro CrAg Lateral Flow Assay (Immy, Norman, OK, USA) positive people without meningitis, (3) expanded diagnostic options with TB-LAM assay using the in vitro Alere1 Determine TB LAM Antigen lateral flow assay (Abbott Laboratories, Lake Bluff, USA) to add to TB disease screening with Nucleic Acid Amplification Test and prompt initiation of anti-TB treatment and the systematic screening with serum cryptococcal antigen assay (excluded children < 10 years) and (4) intensive treatment adherence support during routine pill-pick-up visits by the counsellor to achieve 95% adherence and telephonic reminders for pill-pickup.

PLHIV who were not provided with an ADM package were provided with a routine standard of care that included other components of ADM such as screening and diagnosis of active TB with Nucleic Acid Amplification Test, cotrimoxazole prophylaxis, TB Preventive therapy, rapid ART initiation and intensive treatment adherence support along with CD4 and viral load monitoring which are a part of the routine program.

Step 3. Potential barriers and facilitators for implementing the ADM package

Although there were ADM guidelines at the national level, we did not have SOPs at the site level. Other site level barriers included the lack of guidance on rapid ART initiation, limited availability of drugs required for preventive therapy [cotrimoxazole, fluconazole, and isoniazid], and absence of urine LAM and serum CrAg assays in India’s National AIDS Control program. Additionally, and mirroring the impact of COVID-19 globally, during April–July 2021 there was a surge in the number of persons with COVID-19 across India; Mumbai was disproportionately hit with disruption in transportation services and other critical services including health. We received approval to procure a limited number of TB-LAM kits for use under research purpose as urine TB-LAM is not approved for clinical use in India. Despite these challenges, we identified several facilitators. Through strong political will and support from the Mumbai Districts AIDS Control Society (MDACS), the Society committed to the availability and forecasting of ADM package including drugs, consumables, and laboratory kits, along with the staff time at the ART centers. Additionally, we relied on an existing strong network of interdepartmental referrals and a robust lab-clinic interface with the ART center, in addition to existing monitoring, site mentoring and review mechanisms as facilitators for uptake of ADM implementation in Mumbai.

Step 4. Intervention

We enrolled all adolescents and adults who had current CD4 counts < 200 cells/mm3 or WHO clinical stage III / IV events, regardless of whether they were ART-naive or ART-experienced. We also enrolled all children < 5 years of age not established on ART and enrolled children who have been receiving ART for > 1 year and were clinically unstable. We trained the ART center staff to ensure uniform implementation and monitoring of PLHIV in the ADM package of services. We developed job aids and standard operating procedures (Fig. 1) for use in the ART center upon identification of a person with AHD and ensured ART and laboratory staff adhere to operational and technical aspects of ADM management. We provided hands-on training on the laboratory workflow, emphasizing the pre-analytical procedures for performing LAM and CrAg testing to the nurse and lab technician of ART centers. ART center staff assessed all PLHIV during their routine ART center visit for eligibility and ensured the provision of the ADM package and recorded details in the ADM register.

Fig. 1
figure 1

Operational flow of advanced disease management services at ART centers, Mumbai

Full size image

Step 5. Assess the adoption of the ADM package

Mumbai District AIDS Control Society provided on-site supportive supervision, clinical mentoring, and monitoring support to the ART center staff.

The ART facilities were assessed monthly for the availability of drugs, kits, and other consumables. During the monthly mentoring and monitoring on-site visits to the ART centers, the staff observed the process of enrollment of eligible PLHIV into the ADM package, reviewed registers for accuracy, and provided specific recommendations and course corrections on referral and management of PLHIV. Mumbai Districts AIDS Control Society routinely reviewed ART center performance every quarter based on key implementation measures e.g., number of PLHIV presenting to ART center with AHD, number of newly initiated PLHIV presenting with AHD, the number enrolled into ADM package, the number offered with specific components.

Step 6. Outcomes

We reported feasibility, program, and client outcomes.

Feasibility outcomes

Coverage of each component of the ADM package was assessed to determine the feasibility of implementing the ADM package. We calculated the proportion of PLHIV provided with ADM package of care among those presenting with AHD, the proportion of treatment naïve PLHIV rapidly initiated on ART, the proportion of eligible PLHIV initiated on TPT of those screened negative for TB [excluded persons with current TB disease and those having completed TPT prior to ADM enrolment], the proportion of eligible PLHIV initiated on cotrimoxazole prophylaxis, the proportion of PLHIV offered urine TB-LAM (excluded current TB disease), the proportion of PLHIV offered serum cryptococcal antigen (CrAg) assay (excluded children of < 10 years of age) and proportion offered ART adherence counselling. We reported the methods and results of the operational feasibility of implementing TB-LAM and CrAg assay elsewhere [11, 12].

Program outcomes

We defined a turnaround time of two hours for receipt of urine TB-LAM and serum CrAg results. We calculated the median turnaround time for both urine TB-LAM and serum CrAg. Clients who received the ADM package were followed for one year (through 31 July 2022) to document outcomes (alive on ART, died, lost to follow-up). We calculated the mortality rate using the number of deaths as the numerator and the duration of treatment (in person-years) as the denominator (including those LTFU and died). Data was censored on 31 July 2022. We used the Kaplan-Meier product limit estimation method to assess the cumulative probability of survival. The log-rank test was used to examine the statistical difference in survival by type of PLHIV (treatment experienced and treatment naïve).

Client outcomes

We calculated the proportion of PLHIV screened positive for urine TB-LAM and serum CrAg. The Cox proportional hazard regression model was used to calculate the hazard ratios for death as a primary outcome at any time during the follow-up period to determine predictors of mortality. Variables with p value of 0.2 or below and having biological relevance to the outcome were included in the final model.

Operational definitions

We defined ‘alive on ART’ as PLHIV receiving ADM package of services, picked up ART within 28 days of pill-pick date, and alive on care as of 31 July 2022; ‘died’ as PLHIV on ART who received ADM package but died due to any cause at the end of one-year follow-up and lost to follow-up (LTFU) as PLHIV who missed pill pick up for > 28 days at the end of one year of follow-up.

Data collection, data management, and analysis

Routine program data was collected from the patient records (treatment card, TB register, and ART register) maintained at the ART center. Variables such as age, sex, ART status (treatment experienced and ART naïve), duration of ART, CD4 count, serum and cerebrospinal fluid CrAg results, urine LAM results, follow-up outcomes (alive on ART, died, lost to follow-up), TPT initiation status, anti-TB treatment initiation status, cotrimoxazole prophylaxis were collated. All data were entered in Microsoft Excel (Version MSO (16.0.10383.20027). We calculated the mean, standard deviation, median, and interquartile range (IQR) for continuous variables, and proportions for categorical variables. We analyzed data using IBM SPSS Statistics for Windows (Version 23.0).

Results

We categorized the results based on the Ottawa model into assess, monitor, and evaluate (Fig. 2).

Fig. 2
figure 2

Ottawa model for implementation of advanced disease management package of services, Mumbai

Full size image

Assess

All the cadre of staff from 17 ART centers were trained on the ADM package of services. We provided 2,779 AHD persons with ADM package with existing staff at the ART center. Of those who received the ADM package, 68.1% (1,892) were males, the median age was 43 years [IQR: 35,50], and the majority (35.8%) were between 40 and 49 years of age. The median CD4 count was 137 cells/mm3 [IQR: 80, 218], and 34.5% (959) presented with CD4 count ≤ 100 cells/mm3. The majority, 79.2% (2,212/2,779), were treatment experienced, and 82.8% (2,302/2,779) did not have symptoms of TB on four symptom screening (Table 1).

Table 1 Demographic, immunological, and clinical characteristics of AHD clients provided with advanced disease management package of services, Mumbai (N = 2,779)
Full size table

Monitor

We forecasted the supply of drugs such as cotrimoxazole, fluconazole, and isoniazid to avoid stockouts during the implementation and follow-up period. The Mumbai District’s AIDS Control Society team conducted a monthly review with the ART center staff to review processes, including the lab clinical interface to ensure linkage and referral services for case management. The monthly review provided a real time opportunity to review progress while providing solutions for challenges with refresher training and through on-site mentoring to fast-track ADM implementation. During the initial quarter of implementation, there were challenges, such as identifying the PLHIV with AHD during the visit to ARTC and timely providing the ADM package by the ART center staff.

Evaluate

Feasibility outcomes

We identified 4,334 PLHIV who qualified for ADM services. During October 2020 to December 2021, we were able to provide the full package of ADM services to the majority who qualified (64%; 2,779/4,334) using existing staff. Of the 1,555 PLHIV who could not be provided with the full ADM package, 297 did not receive the ADM package (146 died, 151 LTFU) and 1,258 received routine standard of care (587 had TB, 366 were at decentralized sites, and 305 LAM/ CrAg kits were not available) with existing staff at ART centers (Fig. 3).

Fig. 3
figure 3

PLHIV provided with ADM package and routine care, Mumbai

Full size image

Of the treatment naïve PLHIV, 77.9% (385/494) were rapidly initiated (< 7 days) on ART. After excluding persons with TB disease (n = 280) and those having completed TPT prior to ADM enrolment (n = 1,186), 81.6% (1,129/1,383) received TPT and 99.0% (2,751/2,779) received cotrimoxazole prophylaxis. Of the eligible, 99.4% (2,508/2,524) and 98.4% (2,715/2,758) were screened for TB and cryptococcal infection by TB-LAM and CrAg Point of care test, respectively (Table 2).

Table 2 Feasibility of implementing components of advanced disease management package of services
Full size table

Program outcomes

All PLHIV screened for TB and or cryptococcal infection by urine TB-LAM and serum CrAg received test results within a turnaround time of 2 h. At the end of 12 months, among those provided with the ADM package, 88.4% (2,458/2,779) were alive, 7.6% (210/2,779) died, and 4.0% (111/2,779) were LTFU (Table 3). Of the 1,555 who could not be provided with the full ADM package, 297 did not receive an ADM package nor routine standard of care (146 died, 151 LTFU) and 1,258 received routine standard of care. Of the 1,258 who received routine standard of care, 80% (1001/1,258) were alive, 14% (178/1,258) died, and 6% (79/1,258) were LFTU.

Table 3 Twelve-month outcomes of clients with advanced HIV disease provided with ADM package of services, Mumbai (N = 2,779)
Full size table

The overall mean survival of the cohort was 11.4 months (95% CI: 11.30,11.47) at 12 months of follow-up. Mean survival time was significantly (p < 0.001) higher among treatment experienced 11.6 months (95% CI: 11.53,11.69) compared to treatment naïve 10.8 (95% CI: 10.51,11.03) at 12 months (Fig. 4).

The overall mortality rate of the cohort was 8.1 per 100-person years (210/2,596). The mortality rate at 90 and 180 days after treatment initiation was 3 per 100-person years and 7 per 100-person years, respectively. Of the 210 total deaths in the ADM group, 161 (76.6%) had occurred during the first 6 months after the ADM package was started. Of the 161 PLHIV who died within six months on ADM package of care, about 60% were between 40 and 59 years of age, the majority were female (66%), 51% presented with a CD4 count less than 100 cells/mm3, 26% had TB, and 45% were treatment naïve.

Fig. 4
figure 4

Cumulative survival probability of PLHIV with Advanced HIV Disease by type of PLHIV, Mumbai

Kaplan-Meier curves displaying the estimated survival probability for 2 different groups of patients (ART-Experience & ART-Naïve). Each vertical step in the curve indicates one or more events (i.e., deaths), and right censored patients are indicated by a vertical mark in the curve at the censoring time. A visual inspection suggests that survival seems to be more favorable for ART-Experienced patients than ART-Naïve patients. The log-rank test indicates a significant difference between the survival curves

Full size image

Client outcomes

Predictors of mortality

PLHIV aged 40–59 years (95%CI: 1.21, 13.97; p < 0.02) and ≥ 60 years (95%CI: 2.02, 24.88; p < 0.002), not initiated on TPT (95%CI: 1.53, 2.97; p < 0.001), serum CrAg positive (95%CI: 1.16, 7.0; p < 0.022), viral load ≥ 1000 (95%CI: 32.91,243.76; p < 0.001), without viral load after ADM enrolment (95%CI: 34.90, 261.98; p < 0.001), and treatment naïve (95%CI:1.08,2.05; p < 0.014) had higher risk of death compared to those with age < 20 years, initiated on TPT, serum CrAg negative, viral load < 1000 copies/ ml, and treatment experienced respectively (Table 4).

Table 4 Predictors of mortality among clients with advanced HIV disease provided with advanced disease management package of care, Mumbai (N = 2,779)
Full size table

TB-LAM and CrAg positivity

As reported previously [11, 12], a total of 2,508 PLHIV were offered urine TB-LAM. The overall proportion of PLHIV with urine TB-LAM positive result regardless of TB symptoms was 6.8% (171/2,508), and 91.8% (157/171) were initiated on anti TB treatment (Table 2). Among PLHIV with CD4 ≤ 100 cells/mm3, the positivity was 43.0% and 7.7% in symptomatic and asymptomatic patients, respectively. Among PLHIV with a CD4 > 100 cells/ mm3, the positivity was 26.7% and 2.7% in symptomatic and asymptomatic patients respectively. Of the eligible 2,758, 98.4% (2,715) were tested for serum CrAg. Of these, 25 (0.9%) had a CrAg positive result. Among CrAg positive patients, only one had symptoms (Table 2). Lumbar puncture was obtained in 20/25 patients within 4 days (range: 1–4 days) of positive serum CrAg result, and one person was confirmed to have meningitis. All serum CrAg-positive patients who had a negative cerebrospinal fluid CrAg were offered fluconazole pre-emptive therapy of 800 mg/day for 2 weeks, then 400 mg/day for 8 weeks, and continued maintenance with fluconazole 200 mg/day.

Discussion

We report on a large prospective cohort from India receiving the full WHO recommended ADM package of care and prospectively followed for twelve months to assess the feasibility and intervention outcomes in the government program setting. Implementing the ADM package in Mumbai entailed engaging several stakeholders, community members, healthcare providers, and patients in a real-world setting [16]. Most of the cohort provided with the ADM package of services in this analysis were treatment experienced, and about 60% were aged between 40 and 59 years. The increased representation of PLHIV in this age band is also observed at the national level. Per the national HIV estimates for 2022, about 36% of the total PLHIV were estimated to be in the age group of 50 years or older, which is significantly different from 2000 where only around 17% of the total PLHIV were aged 50 years or older [6].

During the planning stage, and because country specific guidance for ADM implementation was not available, we developed job aids, regular on-site clinical mentoring, hands-on laboratory training, and monitoring to inform the implementation process for the ADM package by the clinical and laboratory staff. During the initial quarter of implementation, there were challenges, such as the identification of PLHIV with AHD during the visit to the ART center and the timely providing the ADM package. Regular review, monitoring, and mentoring support during the initial implementation was vital to ensure a uniform ADM package of services. As described in prior studies, task sharing, training, and mentorship improved the uptake of laboratory and clinical ADM services among nurses and counsellors [17, 18]. We observed that the coverage of all ADM components did not depend on the patient volume (high or low) of PLHIV or the location (tertiary or secondary) of the ART centers. In fact, with anticipatory planning, implementation was possible without additional human resources.

Since ART centers are a part of the secondary or tertiary institutions, establishing linkage and referral systems for investigations, higher level clinical management, and strengthening lab-clinic interface are essential prerequisites for successful ADM implementation in a routine program setting. We established strong referral pathways that enabled serum CrAg positive PLHIV to access lumbar puncture services at a higher center in an inpatient setting. We trained and mentored staff on a job aid and algorithm to ensure appropriate investigation and higher-level clinical management when indicated in other studies [19]. In our intervention, the government stakeholders undertook anticipatory forecasting of drugs and lab commodities, human resource management, and capacity building in the planning stage leading to the high screening coverage of point of care test (TB-LAM (99%) and CrAg (96%). Similar to the experience from South Africa, in our study, the point of care test minimized the testing burden on central laboratories and provided results within a turnaround time of 2 h [20].

WHO recommends urine TB-LAM [21] among AHD patients for early TB diagnosis and prevention of mortality. Our study found an additional yield when TB-LAM was coupled with the standard program recommended diagnostics and documented the utility and feasibility in the program setting. However, clinical use is limited in India and other high HIV-TB burden countries [22, 23]. CrAg lateral flow assay is approved for patient management in India, but the National AIDS Control program may consider access at all ART centers for reflexive screening of all PLHIV with CD4 count < 100 cells / mm3 [24]. The ART center staff in Mumbai adapted to routinely screen PLHIV for AHD and continue providing the requisite ADM service package. Implementation of evidence-based practices from prior studies has indicated that adaptations are often made by systems, organizations, and/or service providers in the implementation process [25].

Rapid ART initiation is a critical component of ADM: however, in our study, we could achieve 78% coverage (84 had TB, 8 had serum positive CrAg and 17 died even before the clinical assessment for ART initiation). Similar barriers to rapid ART initiation are described in prior studies [26]. Similarly, TPT coverage was 83% and this lower rate could be attributed to the national program recommendation of delayed TPT initiation after three months of ART [27].

The 12-month mortality among PLHIV on ADM package was 8.1 per 100 person years; the majority (72%, 161/224) occurred within 6 months of ART initiation, and the mean survival was higher among the treatment experienced group compared to the treatment naive. Similar to our findings, a review of the meta-analysis and cohort studies from middle- and high-income countries in 2021, indicated a higher risk of mortality during the first six months [28]. Even after initiating ART, people with advanced immunosuppression have a 50% higher rate of mortality as compared to people with a CD4 count > 200 cells/ mm3 at the time of ART initiation [29]. WHO recommends additional close monitoring or intensive case management procedures such as. screening and diagnostic testing for major opportunistic infections and, where possible, access to radiology and laboratory services to be provided to assist with diagnosis and monitoring of PLHIV with severe AHD for a reduction in mortality [30].

Similar findings were observed in studies done in Ethiopia and Uganda wherein the higher odds of mortality rate were higher among PLHIV with CD4 < 200 mm3, viral load ≥ 1000 copies/ml, and advanced disease patients (stage III and IV), not initiated or not eligible for TPT [31, 32]. In the program setting, we describe a reduction in mortality with the ADM package as similar to that of the REMSTART [33] and Reality trial [34]. We also note that the National AIDS Control Program NACP introduced dolutegravir based regimens as the preferred ARV, which could have additionally contributed to the reduction in mortality.

Limitation

Our prospective cohort study followed people during the COVID-19 pandemic and LTFU and mortality could have been additionally impacted. Within the program setting, we may not have measured all opportunistic infections among patients presenting with AHD.

Conclusion

With careful anticipatory planning, stakeholder engagement, and training, implementing the full ADM package is feasible in a routine program setting with existing human resources. Availability of point of care tests allowed for additional diagnostic and clinical management options for patients with AHD. Efficient up-referral, including the development of person-centric advanced HIV disease patient flow systems, training and mentoring of health care staff, and monitoring are also crucial for ADM implementation. Additional intensive case management may be necessary for the reduction of mortality among treatment naïve PLHIV with AHD.

Data availability

There are ethical and legal restrictions on sharing the de-identified data set. As these data are related to PLHIV containing sensitive information, there are restrictions as per the National law (HIV prevention and control act, 2017). The ethics committee secretary Dr. Shivkar can be reached by email: mdacsec@gmail.com for data request.

Abbreviations

ADM:

Advanced Disease Management

AHD:

Advanced HIV Disease

ART:

Antiretroviral Therapy

CrAg:

Cryptococcal Antigen

Lf-LAM:

Lateral flow lipoarabinomannan

LTFU:

Lost to follow-up

PLHIV:

People Living with HIV

SOP:

standard operating procedures

TPT:

TB Preventive Therapy

References

  1. 2023 UNAIDS Fact sheet. https://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf

  2. Carmona S, Bor J, Nattey C, Maughan-Brown B, Maskew M, Fox MP, Glencross DK, Ford N, MacLeod WB. Persistent high burden of advanced HIV disease among patients seeking care in South Africa’s National HIV program: data from a nationwide laboratory cohort. Clin Infect Dis. 2018;66(suppl2):S111–7.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Osler M, Hilderbrand K, Goemaere E, Ford N, Smith M, Meintjes G, Kruger J, Govender NP, Boulle A. The continuing burden of advanced HIV disease over 10 years of increasing antiretroviral therapy coverage in South Africa. Clin Infect Dis. 2018;66(suppl2):S118–25.

    Article  PubMed  PubMed Central  Google Scholar 

  4. World Health Organization. Package of care for children and adolescents with advanced HIV disease: stop AIDS. Technical brief. Geneva: World Health Organization. 2020. Licence: CC BY-NC-SA 3.0 IGO. Accessed Jul 2023 https://www.who.int/publications/i/item/9789240008045

  5. World Health Organization. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: World Health Organization. 2021. License: CC BY-NC-SA 3.0 IGO. Accessed Jun 2023 https://www.who.int/publications/i/item/9789240031593

  6. National AIDS, Control Organization. Fifth edition,. Sankalak: Status of National AIDS Response (2023). New Delhi: NACO, Ministry of Health and Family Welfare, Government of India. 2023. Accessed Jan 2024 https://naco.gov.in/sites/default/files/Sankalak%20Booklet.pdf

  7. National AIDS Control Organization. National Guidelines for HIV Care and Treatment. New Delhi: NACO, Ministry of Health and Family Welfare, Government of India. 2021. Accessed Feb 2022 https://naco.gov.in/sites/default/files/National_Guidelines_for_HIV_Care_and_Treatment_2021.pdf

  8. Ford N, Meintjes G, Calmy A, Bygrave H, Migone C, Vitoria M, Penazzato M, Vojnov L, Doherty M. Guideline development group for managing advanced HIV disease and rapid initiation of antiretroviral therapy. managing advanced HIV disease in a public health approach. Clin Infect Dis. 2018;66(suppl2):S106–SS110.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Calmy A, Ford N, Meintjes G. The persistent challenge of advanced HIV disease and AIDS in the era of antiretroviral therapy. Clin Infect Dis. 2018;66(suppl2):S103–SS105.

    Article  PubMed  PubMed Central  Google Scholar 

  10. National AIDS Control Organization. Operational guidelines for HIV care and treatment. Ministry of Health and Family Welfare, Government of India; 2021.

    Google Scholar 

  11. Acharya S, Deshpande P, Asirvatham ES, Palkar A, Sarman CJ, Laxmeshwar C, Setia MS, Rathod D, Koli S, Dale J, Yeldandi V, Allam R, Agarwal R, Verma S, Upadhyaya S, Nyendak M. Utility of the lateral flow urine Lipoarabinomannan tuberculosis assay in patients with advanced HIV disease at antiretroviral therapy centres in Mumbai, India. PLoS ONE. 2022;17(9):e0273970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Acharya S, Allam RR, Karanjkar VK, Rathod D, Mahajan R, Deshpande P, Palkar A, Todmal S, Koli S, Dhande S, Dale J, Yeldandi VV, Harshana A, Agarwal R, Upadhyaya S, Nyendak M. Implementation of point-of-care testing and prevalence of Cryptococcal antigenaemia among patients with advanced HIV disease in Mumbai, India. BMJ Open. 2023;13(6):e070500.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nilsen P. Making sense of implementation theories, models, and frameworks. Implement Sci. 2015;10:53.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Graham ID, Logan J. Innovations in knowledge transfer and continuity of care. Can J Nurs Res. 2004;36(2):89–103.

    PubMed  Google Scholar 

  15. Logan J, Graham ID. Toward a comprehensive interdisciplinary model of health care research use. Sci Communication. 1998;20(2):227–46.

    Article  Google Scholar 

  16. Greenhalgh T, Robert G, Macfarlane F, Bate P, Kyriakidou O. Diffusion of innovations in service organizations: systematic review and recommendations. Milbank Q. 2004;82(4):581–629.

    Article  PubMed  PubMed Central  Google Scholar 

  17. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2nd ed. Geneva: WHO; 2016. ISBN 9789241549684. Accessed Jun 2022 https://www.who.int/publications/i/item/9789241549684.

  18. Rick F, Niyibizi AA, Shroufi A, et al. Cryptococcal antigen screening by Lay cadres using a rapid test at the point of care: a feasibility study in rural Lesotho. PLoS ONE. 2017;12:e0183656.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Walker AS, Prendergast AJ, Mugyenyi P, Munderi P, Hakim J, Kekitiinwa A, Katabira E, Gilks CF, Kityo C, Nahirya-Ntege P, Nathoo K, Gibb DM. DART and ARROW trial teams. Mortality in the year following antiretroviral therapy initiation in HIV-infected adults and children in Uganda and Zimbabwe. Clin Infect Dis. 2012;55(12):1707–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cassim N, Schnippel K, Coetzee LM, Glencross DK. Establishing a cost-per-result of laboratory-based, reflex Cryptococcal antigenaemia screening (CrAg) in HIV + patients with CD4 counts less than 100 cells/µl using a lateral flow assay (LFA) at a typical busy CD4 laboratory in South Africa. PLoS ONE. 2017;12(2):e0171675.

    Article  PubMed  PubMed Central  Google Scholar 

  21. WHO. Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV—Policy update. (2019). Geneva: World Health Organization; Licence: CC BY-NC-SA 3.0 IGO. 2019. Accessed Jun 2021 https://www.who.int/publications/i/item/9789241550604

  22. Singhroy DN, MacLean E, Kohli M, Lessem E, Branigan D, England K, Suleiman K, Drain PK, Ruhwald M, Schumacher S, Denkinger CM, Waning B, Van Gemert W, Pai M. Adoption and uptake of the lateral flow urine LAM test in countries with high tuberculosis and HIV/AIDS burden: current landscape and barriers. Gates Open Res. 2020;4:24.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ndlovu Z, Burton R, Stewart R, Bygrave H, Roberts T, Fajardo E, Mataka A, Szumilin E, Kerschberger B, Van Cutsem G, Ellman T. Framework for the implementation of advanced HIV disease diagnostics in sub-Saharan Africa: programmatic perspectives. Lancet HIV. 2020;7(7):e514–20.

    Article  PubMed  Google Scholar 

  24. Larson BA, Rockers PC, Bonawitz R, Sriruttan C, Glencross DK, Cassim N, Coetzee LM, Greene GS, Chiller TM, Vallabhaneni S, Long L, van Rensburg C, Govender NP. Screening HIV-Infected patients with low CD4 counts for Cryptococcal antigenemia prior to initiation of antiretroviral therapy: cost effectiveness of alternative screening strategies in South Africa. PLoS ONE. 2016;11(7):e0158986.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Aarons GA, Green AE, Palinkas LA, Self-Brown S, Whitaker DJ, Lutzker JR, Silovsky JF, Hecht DB, Chaffin MJ. Dynamic adaptation process to implement an evidence-based child maltreatment intervention. Implement Sci. 2012;7:32.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ford N, Migone C, Calmy A, Kerschberger B, Kanters S, Nsanzimana S, Mills EJ, Meintjes G, Vitoria M, Doherty M, Shubber Z. Benefits and risks of rapid initiation of antiretroviral therapy. AIDS. 2018;32(1):17–23.

    Article  PubMed  Google Scholar 

  27. National AIDS, Control Organization. Guidelines on Prevention and Management of TB in PLHIV at ART Centers. New Delhi: NACO, Ministry of Health and Family Welfare, Government of India. 2016. Accessed Jun 2022 https://tbcindia.gov.in/WriteReadData/l892s/8466816483Guidelines%20on%20Prevention%20and%20Management08Dec16_1.pdf

  28. Portilla-Tamarit J, Reus S, Portilla I, Fuster Ruiz-de-Apodaca MJ, Portilla J. Impact of advanced HIV disease on quality of life and mortality in the era of combined antiretroviral treatment. J Clin Med. 2021;10(4):716.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Brennan AT, Long L, Useem J, Garrison L, Fox MP. Mortality in the first 3 months on antiretroviral therapy among HIV-Positive adults in Low- and Middle-income countries: A Meta-analysis. J Acquir Immune Defic Syndr. 2016;73(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  30. WHO. Providing care to people with advanced HIV disease who are seriously ill: policy brief. Geneva: World Health Organization. 2023. Licence: CC BY-NC-SA 3.0 IGO. Accessed Sep 2023 https://www.who.int/publications/i/item/9789240068650

  31. Workie KL, Birhan TY, Angaw DA. Predictors of mortality rate among adult HIV-positive patients on antiretroviral therapy in Metema hospital, Northwest Ethiopia: a retrospective follow-up study. AIDS Res Ther. 2021;18(1):27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Byamukama A, Golding PM. Predictors of mortality among people living with HIV in the test and treat era within rural Uganda: a retrospective cohort study. Afr J AIDS Res. 2022;21(3):231–8.

    Article  PubMed  Google Scholar 

  33. Hakim J, Musiime V, Szubert AJ, et al. Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa. N Engl J Med. 2017;377:233–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, Chijoka C, Masasi A, Kimaro G, Ngowi B, Kahwa A, Mwaba P, Harrison TS, Egwaga S, Jaffar S. REMSTART trial team. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015;385(9983):2173–82.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank and acknowledge the invaluable contributions of the ART center staff and the participation of the patients and the PLHIV community without whom this activity would not have been possible. We also thank and acknowledge the support and guidance from Care, Support & Treatment Division, National AIDS Control Organization (NACO), Government of Inda.

CDC disclaimer

The findings and conclusions in this publication are those of the authors and do not necessarily represent the official position of the funding agencies.

Funding

The National AIDS Control Program’s existing staff and infrastructure were utilized. Additionally, this project has been partially supported by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of CoAG # GH002271.

Author information

Authors and Affiliations

  1. Mumbai Districts AIDS Control Society, Acworth Complex, R.A. Kidwai Marg, Wadala West, Mumbai, Maharashtra, India

    Shrikala Acharya, Vijay Kumar Karanjkar & Dhirubhai Rathod

  2. U.S. Centers for Disease Control and Prevention, Division of Global HIV and Tuberculosis (DGHT), Panchsheel Marg, Shantipath, Chanakyapuri, New Delhi, Delhi, 110021, India

    Ramesh Reddy Allam, Reshu Agarwal, Sunita Upadhyaya & Melissa Nyendak

  3. International Training and Education HIV (I-TECH), 808, 8th Floor, Ansal Bhawan, 16, Kasturba Gandhi Marg, Connaught Place, New Delhi, India

    Prashant Deshpande, Amol Palkar, Shashikant Todmal, Sagar Koli, Sachin Dhande & Amit Harshana

  4. Society for Health Allied Research and Education (SHARE INDIA), Ghanpur Village, Medchal Malkajgiri District, Hyderabad, Telangana State, India

    Nalini Chava & Vijay V Yeldandi

Authors
  1. Shrikala Acharya
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Ramesh Reddy Allam
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Vijay Kumar Karanjkar
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Dhirubhai Rathod
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Prashant Deshpande
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Amol Palkar
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Shashikant Todmal
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Sagar Koli
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Sachin Dhande
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Nalini Chava
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Vijay V Yeldandi
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Amit Harshana
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Reshu Agarwal
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Sunita Upadhyaya
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Melissa Nyendak
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

SA and RRA conceived the study; RRA, SA, VKK, AH, PD, MN, DR and VVY designed the project protocol; RRA, PD, RA, AH, JD, AP, and SA developed data collection tools. SA, RM, SK, RRA, ST, NC, SU, VKK, SD, RA, AP, MN, VVY analysed and interpreted the data; SA, RRA, MN and drafted the manuscript; All authors critically reviewed the manuscript for important intellectual content. All authors read and approved the final manuscript. SA is the guarantor of the paper.

Corresponding author

Correspondence to Ramesh Reddy Allam.

Ethics declarations

Ethics approval and consent to participate

Ethics approval was received for secondary data analysis from the ethics committee of Mumbai Districts AIDS Control Society (MDACS) (Ref: MDACS/140/STI Dated 27/10/2021). The CDC reviewed this activity, deemed research not involving human subjects, and was conducted consistent with applicable federal law and CDC policy.

There was a waiver of consent by the ethics committee of Mumbai Districts AIDS Control Society (MDACS)(Ref: MDACS/140/STI Dated 27/10/2021) as this is a routine program intervention.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Acharya, S., Allam, R.R., Karanjkar, V.K. et al. Integrating HIV advanced disease management into a routine program setting: cohort from Mumbai, India. BMC Health Serv Res 25, 595 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12913-025-12572-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12913-025-12572-5

Keywords

BMC Health Services Research

ISSN: 1472-6963

Contact us