Ongoing Studies – INA-RESPOND

InVITE Study

By: Cintya Naya Danastri, Ivana Yulian Hendarsin, Lois E. Bang, Eka Windari R., Nur Latifah Hanum, Restu Amalia Mukti

Figure 1. Tangerang Hospital

Preparation for the Site Closeout Visit (SCV) has been completed for all sites. The Site Regulatory Binder and Source Document Worksheet have been stored with the archiving vendor, Indo Arsip. Study documents, such as the final Authorized Signature and Delegation Log (ASDL) and Site Vis-it Log, will be archived after the SCV, which is expected to take place in February 2025. The next shipment will be conducted for the extracted RNA from the mid-turbinate swabs.

The remaining research assistants (RAs) for the InVITE study were from Site 01 (Tangerang Hospital, Tangerang, Banten): dr. Cintya Naya Danastri and dr. Ivana Yulian Hendarsin. Their dedication as INA-RESPOND-Warm Based RAs is evident through their contributions over nearly 3.5 years.

The Secretariat extends sincere gratitude to them for their spirit and enthusiasm, which were instrumental in the study’s success.

Tangerang Site stands out as the backbone of the study among other sites, recognized for its experienced team and supportive research environment. The site is integrated with the INA-RESPOND Reference Laboratory, led by dr. Dewi Lokida, Sp.PK(K), who contributed to the development of the InVITE Global protocol and diligently oversaw the study. As a respected clinical pathologist and re-searcher, she maintains strong relationships with all stakeholders involved in the study. Additionally, the ethical approval for the InVITE study was obtained from the Tangerang Hospital Ethical Com-mittee. In this edition, dr. Naya and dr. Ivana share their experiences as RAs at Site 01 over the past 3.5 years.

Figure 2. Site 01 study teams (left to right): Evi Herawati, S.ST (LT), dr. Cintya Naya Danastri (RA), Oriza Hamidiah Hariawati, Amd.Ak (LT), dr. Atindriya Tri Iswari (RA), Siti Nufus Eliyati, Amd.Ak (LT), Arif Muflikhun (RA), dr. Ivana Yulian Hendarsin (RA), dr. Amanda Samurti Pertiwi (RA), dr. Dewi Lokida, Sp.PK(K) (PI), dr. Hilwani (Co.PI)

As the first established site for the InVITE study, Site 01 (Tangerang Hospital) collaborated with two satellite sites—Kelapa Dua Puskesmas (Primary Health Care) and Bojong Nangka Puskesmas—to boost enrollment and diversify vaccine types and target populations, including people living with HIV (PLWH). dr. Dewi Lokida as the Principal Investigator (PI), with dr. Hilwani as the Co-PI, overseeing COVID-19 vaccination schedules at Tangerang Hospital. Laboratory Technicians (LTs) supporting the hospital site were Evi Herawati, Oriza Hamidiah Hariawati, and Siti Nufus Eliyati. The study teams at the satellite sites comprised Co-PIs who also served as Puskesmas heads (dr. Salmawati, MM, at Bojong Nangka and drg. Rr. Truly Kartikawatie at Kelapa Dua), LTs re-sponsible for sample collection (Rosidah at Bojong Nangka and Marini at Kelapa Dua), and Study Nurses who assisted with enrollment and follow-up (Endang Sri Rahayu at Bojong Nangka and En-dang Lina at Kelapa Dua).

Due to the high workload during the early period of the study, dr. Ivana and dr. Naya were support-ed by three additional RAs: dr. Amanda Samurti Pertiwi and dr. Atindriya Tri Iswari from the INA-PROACTIVE study, and Arief Muflikhun. Arief completed his role on September 1, 2022, followed by dr. Amanda on January 31, 2023, and dr. Atin on August 31, 2023.

Collaboration with satellite sites significantly in-creased the complexity of enrollment and follow-up processes compared to other studies in a single site. Fortunately, these challenges were successfully managed through effective coordination between the study teams at Tangerang Hospital and Puskesmas. This collaboration began during the study preparation phase, which involved stocking laboratory supplies, preparing enrollment locations, collecting samples, and ensuring proper sample storage and shipment from the satellite sites to Site 01.

Since the InVITE enrollment relied on individuals receiving COVID-19 vaccinations, there was an initial rush to ensure the team seized the opportunity provided by the National Program for Moderna booster vaccinations for health workers, which began on August 18, 2021. The team faced challenges, including the unavailability of some study supplies during the early enrolment period, which required them to be adaptable. The Site 01 study team divided tasks during enrollment to manage the tight preparation timeline. The first enrollment at Bojong Nangka Puskesmas was con-ducted by dr. Ivana and dr. Naya, with blood collection handled by the Puskesmas LTs. Meanwhile, dr. Amanda, dr. Atin, and Arief prepared the equipment and documentation for the next enrollment at the hospital, assisted by Mrs. Evi, the LT.

Figure 3. Subject enrollment and blood collection process in satellite sites

Figure 4. Study teams at Bojong Nangka Pusk-esmas, dr. Salmawati (Co-PI) (fourth from the left) Endang Sri Rahayu (SN) (sixth from the left)

Figure 5. Study teams at Kelapa Dua Puskesmas (left to right) Endang Lina (SN), drg. Truly Kartikawatie (Co-PI), Ma-rini (LT)

The screening and informed consent process was challenging due to the large number of people arriving for vaccination, but thankfully, most participants were cooperative. At one point, the study teams successfully enrolled 69 subjects in a single day. Recruitment at the satellite sites presented additional challenges. Some participants lived far from the sites, leading to missed follow-up visits. Some participants were reluctant to comply with study procedures due to fears about blood collection or concerns over the volume of blood being taken.

During the study, RAs conducted biweekly contact with participants to inquire about COVID-19 symptoms over the past 14 days, aiming to capture breakthrough infections. If symptoms were reported, participants were advised to attend an additional visit called the Symptomatic Visit for COVID-19 testing. These biweekly contacts and Symptomatic Visits were memorable for them due to the unique challenges of reaching participants. These challenges included participants sharing a single phone among family members, frequently changing phone numbers, or feeling annoyed by repeated calls despite being informed about the biweekly contact process during consent. Some participants refused to attend the Symptomatic Visit for various reasons, the most common being fear of testing positive for COVID-19 and facing quarantine, which could disrupt their work. Other reasons included relocating for work or personal matters, making attendance impossible. Despite these obstacles, the RAs did their best to maintain contact with participants through WhatsApp, SMS, or phone calls to monitor their health. While some participants declined the Symptomatic Visit, others were cooperative and eager to share updates about their condition. These individuals prioritized their health and appreciated the free COVID-19 testing, including nasal swabs and blood collection. They also valued receiving their COVID-19 antibody results, which reassured them about the positive impact of the vaccines on their immunity.

Figure 6. NIAID visit satellite site (Bojong Nangka Puskesmas

On December 5, 2022, Site 01 had the honor of hosting a visit from representatives of the US-NIAID (Renee Ridzon) and Leidos (Jackie Perodin), who were responsible for overseeing the InVITE study. During their visit, they toured Tangerang Hospital and Bojong Nangka Puskesmas. At Bo-jong Nangka Puskesmas, with the participant’s consent, they observed the follow-up process and held discussions with the Puskesmas team, including representatives from Kelapa Dua Puskesmas. They also observed the follow-up process at the hospital and reviewed source document worksheets and case report forms to identify and address any issues related to the study’s implementation.

Figure 7. Sample processing at Site 01

dr. Naya and dr. Ivana expressed their gratitude for the opportunity to participate in the InVITE study, which enabled them to broaden their knowledge of international studies, gain the latest insights on COVID-19, and collaborate with experienced researchers. Reflecting on their experiences, they hope that future studies will prioritize more thorough preparation in logistics, site readiness, and coordination to minimize challenges and improve anticipation of potential issues.

The InVITE study at Site 01 was a success, providing valuable insights to the INA-RESPOND Secretariat. Site 01 stands as clear evidence that long-term collaboration, a dedicated team, and a supportive environment led to smooth re-search operations. We greatly appreciate the Site 01 team’s outstanding efforts in achieving the highest participant enrollment numbers for the InVITE study in Indonesia. Despite the high workload and occasional misunderstandings, we are grateful for the team’s effective communication and resolution skills. We were particularly impressed by the RAs’ professionalism and comprehensive explanations during our visit with the US-NIAID team. We look forward to collaborating with Tangerang Hospital on future INA-RESPOND projects and wish the entire Site 01 team continued success.

PROACTIVE Study

By: Cintya Naya Danastri, Ivana Yulian Hendarsin, Lois E. Bang, Eka Windari R., Nur Latifah Hanum, Restu Amalia Mukti

The current phase of the INA-PROACTIVE (A Prospective Observational Cohort Study on HIV Infection and Risk-Related Coinfections/Comorbidities in Indonesia) study involves data analysis, discussions, and the implementation of manuscript writing based on the concept plans submitted by INA-PROACTIVE study teams. On December 13, 2024, the INA-PROACTIVE team received exciting news: the acceptance of their first manuscript in the BMC Infectious Diseases journal, titled “A Prospective Observational Cohort Study of HIV Infection in Indonesia: Base-line Characteristics and One-Year Mortality.” This manuscript provides a baseline description of the INA-PROACTIVE cohort, outlines the study methods, and identifies risk factors for one-year mortality. Subsequent manuscripts are expected to build upon this foundational work.

HIV/AIDS in Indonesia has seen significant progress since the first case was identified in 1987. National efforts have successfully reduced annual HIV incidence by 50%, from 21 per 100,000 in 2011 to 10 per 100,000 in 2021. However, the epidemic has still caused approximately 372,000 deaths and left an estimated 543,100 people living with HIV (PLWH). Achieving long-term favorable outcomes for PLWH in Indonesia remains a challenge. Despite free antiretroviral therapy (ART) and universal health coverage for CD4 testing, ART access and retention are uneven due to the country’s decentralized healthcare system. Viral load (VL) testing is also limited, with only 27% of PLWH on ART receiving VL testing as of January 2023, of whom 91% achieved viral suppression. Nevertheless, UNAIDS estimates overall viral sup-pression nationwide to be just 14%. The updated longitudinal data on PLWH in Indonesia will be vital in informing clinicians and health policymakers.

This first manuscript describes the INA-PROACTIVE study, a large HIV study conducted by INA-RESPOND from 2018 to 2020 at 19 hospitals across eight major islands in Indonesia. Eligible participants were adults (≥18 years) with HIV who adhered to study protocols; exclusions included plans to relocate or prior imprisonment. Participants completed baseline and six-monthly assessments over three years, including demographic data, medical history, and blood tests for CD4+, HIV VL, HBV, HCV, and syphilis. ART regimens followed national guidelines, with virological failure defined as VL >1,000 copies/mL and undetectable VL as ≤50 copies/mL. Opportunistic infections and comorbidities were managed locally, while deaths were recorded and reviewed for AIDS-related mortality.

Figure 1. Timeline of Manuscript Submission and Acceptance.

Figure 2. Map of INA-PROACTIVE study sites.

The analysis in the manuscript focused on one-year outcomes, including virological, immunological, and all-cause mortality. Risk factors for mortality were analyzed, encompassing demographics (e.g., age, gender, region), clinical characteristics (e.g., HIV transmission route, VL, CD4+, BMI, ART type/duration), and ART regimens categorized by treatment line. Survival analysis was conducted using Kaplan-Meier curves to compare survival across VL groups at enrollment. Univariable Cox regression was performed for each potential risk factor individually, followed by multivariable Cox regression to assess all potential mortality risk factors.

The study enrolled 4,336 HIV-infected outpatients. One participant withdrew, and six were excluded due to confirmed negative HIV status, resulting in 4,329 participants. Of these, 4,139 were adults, with 89 missing 6- and 12-month follow-ups, leaving 4,050 participants for the one-year survival analysis.

A total of 4,050 PLWH were included in the analysis, of whom 31.2% were women, with a median age of 35 years (Q1: 29, Q3: 41). Most infections were sexually acquired (53.5% heterosexual, 34.6% MSM). At diagnosis, nearly 56% of participants presented with advanced HIV (WHO stage III-IV), and while most had been on ART for over a year at enrollment, 47% still had CD4+ counts <350 cells/μμL. At enrollment, 92.1% were on ART (66.9% on efavirenz-based regimens), with 72.4% achieving undetectable VL. After one-year, viral suppression increased to 88.8% (3,282/3,694) and to 91.6% (2,328/2,542) among those on ART for more than 12 months. Survival by VL group at enrollment is illustrated in Figure 4, showing a Kaplan-Meier curve indicating decreasing survival with higher VL categories.

Figure 3. STROBE diagram of patient selection for analysis.

Figure 4 Kaplan-Meier plot comparing all-cause mortality over one year among study participants grouped by HIV viral load category.

Among the 115 deaths in the first year, 103 (89%) occurred in participants with detectable viremia at baseline, while 11 (1%) were in those with undetectable viremia. The median CD4+ counts at death were 38 cells/μμL for ART-naïve participants and 59 cells/μμL for ART-experienced participants. Of the 36 deaths among ART-naïve participants, 30 (83.3%) occurred within the first six months, despite 24 (80%) starting ART within one month and 27 (90%) within three months. Most deaths were AIDS-related: 33 (91.7%) among ART-naïve participants and 66 (83.5%) among ART-experienced participants. The leading comorbidities contributing to death included tuberculosis (34.3%), multiple infections (25.3%), pneumonia (16.2%), and toxoplasmosis (10.1%). Multivariable analysis identified significant mortality risk factors: being aged 40–49 years (adjusted hazard ratio [aHR] 2.19, 95% CI: 1.23–3.97, compared to age 18–29), being under-weight (aHR 1.84, 95% CI: 1.18–2.85), having a CD4+ count <200 cells/μμL at enrollment (aHR 8.02, 95% CI: 2.69–23.86), and having detectable VL at enrollment (with increasing aHR across higher VL categories compared to undetectable).

Suboptimal viral suppression rates, even after one year of observation, remained below the UNAIDS 95% target, underscoring the need for improved HIV testing, treatment, and monitoring. Barriers include limited VL testing and delayed ART initiation, particularly in resource-limited settings. The study’s observed one-year mortality rate (2.8%) was lower than the national estimate for 2022 (4.8%). This difference may be due to most study sites being referral hospitals with advanced care, a survival bias from 66.1% of participants being ART-experienced for over a year, and the provision of closer follow-up and VL testing during the study.

Key baseline risk factors for one-year mortality included detectable viremia, CD4+ counts <200 cells/μμL, and underweight BMI. High VL indicated active HIV replication, systemic inflammation, and accelerated progression to AIDS and death. In advanced HIV, incomplete CD4+ reconstitution in-creases vulnerability to opportunistic infections such as tuberculosis, pneumonia, and toxoplasmosis, which were leading causes of death in the cohort. Additionally, underweight BMI was independently linked to mortality, suggesting underlying physiological risks beyond its modest correlation with CD4+ count. Previous research has indicated that in PLWH initiating ART, lower baseline BMI is associated with poorer viral suppression during follow-up, while higher baseline BMI is linked to improved immune reconstitution.

The limitations of this study include the lack of assessment of other factors influencing mortality outcomes, such as socioeconomic status, mental health, social support, health literacy, and medication adherence. Additionally, the study population may not represent the general PLWH population in Indonesia, as it focused on large referral hospitals, which may attract participants with advanced disease but also provide better care. Furthermore, incarcerated individuals, an important PLWH population in Indonesia, were not included.

In conclusion, the INA-PROACTIVE study provides the largest nationwide observational data on PLWH in Indonesia to date. Findings from the first year of observation emphasize the critical im-portance of early diagnosis, early treatment, and routine monitoring of VL and CD4+ cell counts. Incorporating routine VL testing alongside CD4+ monitoring into the national treatment pro-gram should be considered, as it can improve decision-making, reduce mortality, and enhance treatment outcomes.

Hopefully, this first publication from INA-PROACTIVE will serve as a valuable reference for HIV management in Indonesia and globally. Additionally, it can act as a driving force for the further dissemination of INA-PROACTIVE data.