"I pity the TB patient": a mixed methods study assessing the impact of the COVID-19 pandemic on TB services in two major Indonesian cities and distilling lessons for the future.

INTRODUCTION: In Indonesia, a country with around 280 million people and the second-highest tuberculosis (TB) incidence rate in the world, the impact of the COVID-19 pandemic on TB care needs careful assessment so that future response strategies can be strengthened. We conducted a study comparing TB testing and treatment rates before and during the first 2 years of the COVID-19 pandemic in Indonesia, and the reasons for any disruptions to care. METHODS: We conducted retrospective secondary data analysis and qualitative interviews in Yogyakarta and Bandung, Indonesia. Routine data on TB testing and treatment were sourced from the national TB information system operated by the Indonesian Ministry of Health. TB testing and treatment outcomes were compared between two time periods: pre-COVID (2018-19); and during COVID-19 (2020-21). In-depth interviews were conducted with patients and health workers to explore their experiences in accessing and providing TB services during the pandemic. RESULTS: There was a 45% (21 937/39 962) reduction in the number of patients tested for TB during the pandemic compared with pre-COVID-19, while the proportion of TB tests returning a positive result increased from 12% (4733/39 962) to 50% (10 945/21 937). The proportion of TB patients completing treatment increased by 2.6% during the pandemic, yet the proportion cured and the number of patients successfully treated both decreased (by 7% and 4.4%, respectively). Our qualitative interviews highlighted several factors influencing TB service access and delivery, including fear of being diagnosed with COVID-19 during TB-related clinic visits, fear of COVID-19 exposure among patients and health workers, healthcare facilities prioritising COVID-19 over other services, and mandatory mobility restrictions affecting both patients and health workers. CONCLUSION: The COVID-19 pandemic impacted TB testing and treatment outcomes in Bandung and Yogyakarta. Policymakers should consider these findings in designing strategies to ensure TB services are maintained and supported during future health crises.

Anti-cytomegalovirus preemptive therapy to prevent cytomegalovirus disease in HIV-infected patients: a systematic review.

BACKGROUND: HIV patients are at higher risk of contracting and developing into an asymptomatic form of CMV infection. This review aimed to evaluate the efficacy and safety of preemptive therapy for preventing CMV disease in HIV patients. METHODS: The electronic search was conducted in MEDLINE/PubMed and CENTRAL from inception until 9 September 2022. Studies were included if they assessed the efficacy or safety of anti-CMV preemptive therapy compared to placebo or no therapy. Risk of bias were assessed using the Cochrane Risk of Bias tool for randomized trials version 2 or the Cochrane Collaboration Risk of Bias in Non-randomized Studies of Interventions. The random-effects model was used to calculate effect sizes. RESULTS: We identified six RCTs (2135 participants) and four observational studies (395 participants), with five RCTs were performed before highly active antiretroviral therapy (HAART) era. Preemptive therapy did not reduce the incidence of CMV disease (RR 0.84, 95% CI: 0.59-1.18), yet reduced the RR of all-cause mortality rate by 26% (RR 0.85, 95% CI: 0.74-0.97) with a low quality of evidence. The incidence of neutropenia as an adverse event increased significantly (RR 2.47, 95% CI: 1.12-5.45) with moderate quality of evidence. CONCLUSIONS: With the advent of HAART, a limited number of studies have been performed to explore anti-CMV preemptive therapy due to the improved outcomes of HIV patients with CMV viremia. Therefore, optimal HAART should take precedence over anti-CMV preemptive therapy. The protocol for this review was registered in the Prospective Register of Systematic Reviews (CRD42020145765).

Progressive Worsening of Neurological Manifestations in HIV-Associated Opportunistic Central Nervous System (CNS) Infection Patients After COVID-19 Vaccinations: A Possible Co-Incidence Causality.

BACKGROUND The iceberg phenomenon (in which the most of a problem is invisible) of people living with HIV/AIDS, particularly those with unknown HIV status, has been epidemiologically challenging. Central nervous system (CNS) opportunistic infections in patients with HIV/AIDS are one of the leading causes of morbidity and mortality in people living with HIV/AIDS. There are currently limited data on the immunogenicity, safety, and efficacy of COVID-19 vaccines in people living with HIV/AIDS with its associated opportunistic CNS infections as well as those without antiretroviral treatment. CASE REPORT Two young men with previously unknown HIV status and its related opportunistic infections received their first doses of COVID-19 vaccine (Vero Cell), inactivated. Both patients had the risk factor of having sex with men (men who have sex with men). Fever and first neurological symptoms occurred within the first few days after vaccination. Both patients were hospitalized and were tested positive for HIV for the first time. Both were further diagnosed from brain imaging as having CNS opportunistic infections. A presumptive diagnosis of cerebral toxoplasmosis was established as the working diagnosis according to the laboratory and epidemiological factors. Despite the treatment, neurological and clinical deficits worsened and eventually led to death in both patients. CONCLUSIONS The causality analyses showed that both adverse events had a possible inconsistent causal relationship to COVID-19 vaccination. Our cases may reflect the need for further studies on the safety of COVID-19 vaccines in people with HIV/AIDS-associated CNS opportunistic infection as well as people with HIV/AIDS who never receive antiretroviral treatment (ART).

HIV self-testing for men who have sex with men: an implementation trial in Indonesia.

We investigated oral fluid testing (OFT) among men who have sex with men (MSM) to increase HIV testing in Bali, Indonesia. We distributed OFT in January-December 2018 to 813 MSM in Bali. Supervised testing was offered first, and unsupervised was only offered to an individual who declined supervised testing. Included participants were MSM who did not have a HIV test result in the last 6 months and declined referral to facility-based testing. Of 813 participants, 93% (765/813) chose supervised testing and 7% (57/813) unsupervised. The OFT result was reactive for 83 (10%), of whom 52/83 (63%) underwent confirmatory testing with 47/52 (90%) found HIV positive. Among confirmed positives, 43/47 (92%) were enrolled in HATI study cohort, of whom 39 (91%) started treatment. At six months follow up, 25/39 (64%) of those initiating treatment were still receiving it, and all had a suppressed viral load. There was an increase in the mean number of MSM tested for HIV by HATI study Bali sites per month, from 100 (95%CI: 85-112) before the intervention to 152 (95% CI: 130-172) during the intervention. Our findings show the potential utility of offering HIV oral fluid self-test kits to scale-up HIV testing in MSM.Trial registration: ClinicalTrials.gov identifier: NCT03429842.

Two Cases of Hemophagocytic Lymphohistiocytosis Associated with Disseminated Histoplasmosis Presented with Transient Pancytopenia.

Transient pancytopenia due to reactive bone marrow suppression often occurs in hemophagocytic lymphohistiocytosis (HLH), a syndrome resulting from excessive immune activation following a severe infection. We reported two cases with pancytopenia and disseminated histoplasmosis accompanied by HLH, initially suspected to be blood malignancies. Our first case documented the relevance between the improvement of pancytopenia and the clearance of Histoplasma capsulatum in serial bone marrow aspirations. The second case showed immense Histoplasma engulfment by the macrophage in relation to a severe clinical condition, followed by improvement of clinical symptoms in accordance with the recovery of pancytopenia. These two cases highlighted the importance of comprehensive and critical analysis for cases with concurrent pancytopenia and severe infection, since it may be that the pancytopenia underlies the severe infection or vice versa.

Simplified clinical algorithm for immediate antiretroviral therapy initiation: The HATI [HIV awal (early) Test & Treat in Indonesia] implementation research in Indonesia.

Background & objectives: Although the World Health Organization recommends same day or rapid (< seven days) antiretroviral therapy (ART) initiation, delays in ART initiation remain common due to waiting for laboratory test results. This study employed a simplified clinical algorithm the HATI [HIV Awal (Early) Test & Treat Indonesia]-SAI (Simple ART Initiation) aimed to increase the proportion of ART uptake and decrease the time to ART initiation that can be used in various care settings. Methods: This study compared the percentage of ART uptake and retention, viral load (VL) suppression and time to ART initiation between the observation and intervention phases among newly diagnosed HIV patients from key populations. As part of the intervention, the newly diagnosed patients underwent screening using a simple form [consisting of data on age, height and weight (for body mass index calculation), questions on the presence of symptoms of HIV stages 1 and 2, tuberculosis, history of diabetes, hypertension and kidney disease], to determine eligibility for immediate ART initiation. Those who met the pre-defined criteria immediately received a combination of tenofovir lamivudine and efavirenz for two weeks. The baseline laboratory examination due to this was moved up to two weeks post ART. Factors significantly associated with ART uptake were also determined and their odds ratios were measured using logistic regression analysis. Results: A total of 2173 people newly diagnosed with HIV were recruited, with 1579 and 594 in the observation and intervention phases, respectively. In both phases, the majority were men who have sex with men, who were young (<30 yr old) and employed, with high levels of education. The intervention phase significantly increased the proportion of ART initiation [91%, 95% confidence interval (CI): 89-93% vs. 78%, 95% CI: 76-80%] but did not have any impact on the proportion of six months retention and VL suppression. The intervention also significantly decreased the time to ART initiation from median ± interquartile range: 9±20 days to 2±10 days. Interpretation & conclusions: The findings of this study suggest that the HATI-SAI intervention increased the uptake and decreased the time for immediate ART initiation. The HATI-SAI provides a simple and safe clinical approach that can readily be adopted in different settings without a costly investment in technology.

Nevirapine and tuberculosis predict first-line treatment failure in HIV patients in Indonesia: Case-control study.

INTRODUCTION: Indonesia antiretroviral therapy guideline suggests the use of Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-based regiments as first line of HIV treatment and Protease Inhibitor to replace NNRTI when treatment failure occurred. This case-control study was aimed to study factors predicting first-line ART treatment failure among HIV positive patients aged >15 years, non-pregnant, and registered in our institution, Indonesia. METHODS: Diagnosis of HIV treatment failure was made according to the standard WHO criteria. Demographic and outcome variables were recorded. The association between variables were analyzed by Chi-square test with odds ratios (OR) and 95% confidence intervals (95% CI), followed by multivariate analysis using logistic regression test. RESULTS: Twenty-six index cases and 26 age- and sex-matched control cases were included in the study with a mean age of 32.27 ± 8.7 years and 32.88 ± 8.15 years, respectively. Median time for switching to second-line (Lopinavir/ritonavir, LPV/r) was 46.32 ± 30.21 months. Patients presented with tuberculosis and treated by nevirapine as the first-line treatment were 26.6-folds (95% CI: 2.41-293.81, p = 0.007) and 6.7-folds (95% CI: 1.56-28.45, p = 0.011) higher risk for treatment failure, respectively. CONCLUSIONS: The presence of tuberculosis and the use of nevirapine in first-line treatment were strong predictors for first-line ARV treatment failure, suggesting for closer clinical monitoring for patients with those conditions. A further and larger prospective cohort study is needed to confirm the findings in this study.

Implementation fidelity of provider-initiated HIV testing and counseling of tuberculosis patients under the National Tuberculosis Control Program in Kathmandu District of Nepal: an implementation research.

BACKGROUND: There exists low uptake of Human Immunodeficiency Virus (HIV) testing among Tuberculosis (TB) patients through Provider-Initiated HIV Testing and Counseling (PITC) under the national TB control program in Nepal. The degree and quality of program delivery were explored through determining whether the PITC program is currently implemented as intended. This study aimed to assess three major components of the program's implementation fidelity: adherence to PITC service, exposure, and quality of program delivery in order to optimize and standardize PITC implementation by exploring its barriers and enablers. METHODS: This research used a sequential explanatory mixed method design. Retrospective cross-sectional study of TB patients enrolled in five TB treatment centers of the Kathmandu district from July 1, 2016, to June 30, 2017 was done to assess PITC adherence to Direct Observed Treatment-Short Course (DOTS) protocols. The centers' TB-DOTS readiness was assessed using the WHO Service Availability and Readiness Assessment checklist. A qualitative study was conducted to explore the barriers and enablers of PITC service implementation. RESULTS: From a total of 643 TB patients registered, 591 (92.1%) patients were offered HIV test counseling. Amongst those, 571 (96.6%) accepted and 523 (91.5%) were tested. Service providers' HIV knowledge was found to be good although only 2/5 (40%) had participated in PITC training. The key barriers experienced by service providers were: patients feeling offended, stigmatization and lack of human resources in DOTS centers. The main enablers for PITC were national TB program commitment, health workers' motivation, collaboration between stakeholders and external development partners' promotion of program implementation. CONCLUSION: In the selected study sites, PITC services are well integrated into the routine TB control program with a high uptake of HIV testing among registered TB patients. This achievement should be sustained by addressing the identified barriers mainly in the quality of the PITC program delivery.

The cascade of HIV care among key populations in Indonesia: a prospective cohort study.

BACKGROUND: Indonesia has had low uptake of HIV testing and treatment. We did a study to estimate the cascade of HIV care in key populations and identify predictors of outcomes at key cascade steps. METHODS: We used an observational cohort study design to recruit and follow up men who have sex with men (MSM), female sex workers, transgender women (known as waria in Indonesia), and people who inject drugs (PWID) diagnosed with HIV in four locations in Indonesia: Bali, Bandung, Jakarta, and Yogyakarta. Recruitment, baseline, and follow-up visits were done at collaborating clinical services, including both primary care sites and hospitals. Inclusion criteria for participants included identifying as a member of a key population, age 16 years or older, not previously tested positive for HIV, and HIV positivity at baseline. All participants were offered treatment as per national guidelines, with the addition of viral load testing and completion of study-specific forms. Estimates were calculated of proportions of participants linked to care, commencing treatment, adherent to treatment, and who achieved virological suppression. We used logistic regression to investigate characteristics associated with antiretroviral therapy (ART) initiation and viral suppression and Cox regression to identify factors associated with loss to follow-up. This study is registered with ClinicalTrials.gov, NCT03429842. FINDINGS: Between Sept 15, 2015, and Sept 30, 2016, 831 individuals were enrolled in the study, comprising 637 (77%) MSM, 116 (14%) female sex workers, 27 (3%) waria, and 51 (6%) PWID. Of those enrolled, 703 (84·6%, 95% CI 82·1-87·1) were linked to HIV care and 606 (86·2%, 83·7-88·8) who were linked with care started ART. Among participants who started treatment, 457 (75·4%, 71·8-78·9) were retained in care, of whom 325 (71·1%, 66·7-75·2) had a viral load test about 6 months after enrolment, with 294 (90·5%, 86·7-93·4) of those tested (294 [35%, 32·1-38·7] of the original cohort) virally suppressed. 146 (24%) of 606 who started treatment were lost to follow-up. People who enrolled at sites that offered both testing and treatment had a higher likelihood of treatment initiation than those who enrolled at sites offering testing only (p<0·0001 by multivariate analysis), and participants who had been linked to care and had a high school or university education were significantly more likely to achieve viral suppression than those with a primary school or lower level of education (p≤0·029 by mulivariate analysis). INTERPRETATION: HIV cascade data among key populations in Indonesia show very poor rates of retention in treatment and viral suppression. Site and individual characteristics associated with initiating and continuing treatment suggest an urgent need to develop and implement effective interventions to support patients in achieving viral suppression among all people with HIV. FUNDING: Australian Government Department of Foreign Affairs and Trade, WHO, and Indonesian Government.

Influence of Diabetes Mellitus on the Development of Multi Drug Resistant-Tuberculosis in Yogyakarta.

BACKGROUND: the correlation between diabetes mellitus (DM) and Multi-Drug-Resistant Tuberculosis (MDR-TB) has never been studied among patients with tuberculosis (TB) in Indonesia, while DM has been identified to alter immune response and pharmacokinetics of TB medications that may lead to a failure of TB treatment and develop MDR-TB. Our study aimed to analyze the influence of diabetes mellitus on the development of MDR-TB. METHODS: a retrospective cohort study was carried out on 356 TB patients at the Provincial Lung Clinics and Sardjito Hospital, Yogyakarta, Indonesia between 2010 and 2014. Diagnosis of MDR-TB was established based on GeneXpert or drug sensitivity testing, while DM was determined based on the criteria in the National Guidelines. Demographic, epidemiological and outcome variables were collected. Odds ratios and 95% confidence intervals (95% CI) were analyzed using simple logistic regression. RESULTS: among 356 TB patients, 23 patients were with binomial TB-DM, while 333 patients did not suffered from DM. Patients with TB-DM presented a 6.8-fold (95% CI:2.0-23.7, p=0.003) higher risk of developing MDR-TB. Individuals with TB-DM had a 4.4-fold (95% CI:1.5-12.9, p=0.008) greater chance to have positive sputum smear by the second month of treatment indicating a delay in the resolution of the tuberculosis infection. CONCLUSION: there was a significant correlation between diabetes mellitus and MDR-TB development. Therefore, it is suggested that clinicians at all levels of health care service should conduct any kind of screening test for MDR-TB in such group of patients. Further prospective cohort study is needed to confirm the findings of this preliminary study.

Impacts of stigma on HIV risk for women who inject drugs in Java: A qualitative study.

BACKGROUND: People who inject drugs have experienced stigma around the world. Stigma has been found to have negative consequences for individuals in relation to health-service use, psychological wellbeing and physical health; and for populations in terms of health inequalities. Indonesia has experienced a rapid growth in injecting drug use and HIV and little is known about drivers of HIV risk among Indonesian women who inject drugs. The purpose of this paper is to describe and consider the multiple impacts of stigmatization of injecting drug use on injecting behaviors among women who inject drugs in Java. METHODS: In-depth interviews were conducted with 19 women who inject drugs in Java. Mean age was 25 years, all but one was employed or at college. The interviewers were Indonesian women. RESULTS: Significant stigma around women's drug use was reported from multiple sources in Java including family, friends and health services, resulting in feelings of shame. To avoid this stigma, most of the study participants hid their drug use. They lived away from family and had few friends outside their drug-injecting circle, resulting in isolation from mainstream society and harm-reduction services. Sharing of injecting equipment was restricted to a small, closed circle of trusted friends, thus limiting possible HIV transmission to a small number of injectors. CONCLUSIONS: The stigmatization of drug use, particularly of drug use by women, in Indonesia appears to have contributed to significant shame, isolation from mainstream society and high rates of sharing injecting equipment with a small group of trusted friends (particularly the partner).

GB virus C infection in Indonesian HIV-positive patients.

GB virus C (GBV-C), a human virus of the Flaviviridae family that is structurally and epidemiologically closest to hepatitis C virus (HCV), has been reported to confer beneficial outcomes in HIV-positive patients. However, the prevalence of GBV-C in HIV-positive individuals in Indonesia is unknown. Since GBV-C is more prevalent in anti-HCV positive patients than in anti-HCV negative subjects, transmission of GBV-C and HCV could be by the same method. This study examined the prevalence and molecular characteristics of GBV-C infection in HIV patients in Yogyakarta, Indonesia. The prevalence of GBV-C among HIV patients (n = 125, median age 31 years) based on the 5'UTR region was 111/125 (88.8%), including 39/48 (81.3%) and 72/77 (93.5%) HIV-infected patients with and without HCV infection, respectively. GBV-C isolates were of genotype 2a, 3 and 6 in 58.3%, 12.6% and 28.4% of patients, respectively. Patients with genotype 3 were significantly younger than those with genotypes 2a or 6 (P = 0.001 and P = 0.012, respectively). Genotypes 3 and 6 were significantly associated with injection drug use (P = 0.004 and P = 0.002, respectively) and HCV co-infection (P < 0.001 for both genotypes), indicating a shared transmission route with HCV. In conclusion, the prevalence of GBV-C among HIV-positive patients in Indonesia is high, and three genotypes were detected, namely genotype 2a, 3 and 6.

Clinical and virological characteristics of hepatitis B or C virus co-infection with HIV in Indonesian patients.

Hepatitis virus-related liver disease increases substantially the mortality rate of patients with HIV on highly active antiretroviral therapy (HAART). Therefore, early diagnosis of hepatitis B virus (HBV) and hepatitis C virus (HCV) is important. However, the prevalence of HBV and HCV infection in Indonesian patients infected with HIV is unknown. Therefore, this study examined the molecular and clinical characteristics of HBV and HCV in 126 patients infected with HIV, mostly on HAART, at Dr. Sardjito Hospital, Yogyakarta, Indonesia. The rates of triple infection, HIV/HCV co-infection, HIV/HBV co-infection, and mono-infection were 4.8%, 34.1%, 3.2%, and 57.9%, respectively. Seven HCV genotypes were detected, with genotypes 1a, 1b, 1c, 3a, 3k, 4a, and 6n found in 23 (52%), 1 (2%), 4 (9%), 5 (11%), 7 (16%), 3 (6%), and 1 (2%) patients, respectively, indicating multiple modes of transmission. HBV-DNA was detected in 2/10 patients with hepatitis B surface antigen; both patients were HAART naive. Univariate analysis revealed that male sex, higher education level, injection drug use, sexual contact, alanine aminotransferase ≥40 IU/L, and aspartate aminotransferase-to-platelet ratio index > 0.5 were associated with HCV co-infection. In multivariate analysis, injection drug use (OR: 26.52; 95% CI: 3.52-199.54) and alanine aminotransferase ≥40 IU/L (OR: 6.36; 95% CI: 1.23-32.89) were independently associated with HCV co-infection. HCV co-infection was common among Indonesian patients infected with HIV, particularly among injecting drug users, and was a risk factor for disease progression of HIV.