The importance of assessing out-of-pocket payments when the financing of antiretroviral therapy is transitioned to domestic funding: findings from Vietnam.

OBJECTIVE: To assess out-of-pocket payments and catastrophic health expenditures among antiretroviral therapy (ART) patients in Vietnam, and to model catastrophic payments under different copayment scenarios when the primary financing of ART changes to social health insurance. METHODS: Cross-sectional facility-based survey of 843 patients at 42 health facilities representative of 87% of ART patients in 2015. RESULTS: Because of donor and government funding, no payments were made for antiretroviral drugs. Other health expenditures were about $66 per person per year (95% CI: $30-$102), of which $15 ($7-$22) were directly for HIV-related health services, largely laboratory tests. These payments resulted in a 4.9% (95% CI: 3.1-6.8%) catastrophic payment rate and 2.5% (95% CI: 0.9-4.1%) catastrophic payment rate for HIV-related health services. About 32% of respondents reported, they were eligible for SHI without copayments. If patients had to pay 20% of costs of ART under social health insurance, the catastrophic payment rate would increase to 8% (95% CI: 5.5-10.0%), and if patients without health insurance had to pay the full costs of ART, the catastrophic payment rate among all patients would be 24% (95% CI: 21.1-27.4%). CONCLUSIONS: Health and catastrophic expenditures were substantially lower than in previous studies, although different methods may explain some of the discrepancy. The 20% copayments required by social health insurance would present a financial burden to an additional 0.6% to 5.1% of ART patients. Ensuring access to health insurance for all ART patients will prevent an even higher level of financial hardship.

NF-κB factors control the induction of NFATc1 in B lymphocytes.

In peripheral lymphocytes, the transcription factors (TFs) NF-κB, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF-κB factors share several properties, such as a similar mode of induction and architecture in their DNA-binding domain, and there is a subgroup of κB-like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP-1 factors that interact and collaborate in binding to DNA, NFAT, and NF-κB seem neither to interact nor to collaborate. We show here that NF-κB1/p50 and c-Rel, the most prominent NF-κB proteins in BCR-induced splenic B cells, control the induction of NFATc1/αA, a prominent short NFATc1 isoform. In part, this is mediated through two composite κB/NFAT-binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/αA by BCR signals. In concert with coreceptor signals that induce NF-κB factors, BCR signaling induces a persistent generation of NFATc1/αA. These data suggest a tight connection between NFATc1 and NF-κB induction in B lymphocytes contributing to the effector function of peripheral B cells.

NFATc1 induction in peripheral T and B lymphocytes.

NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/αA whose generation is induced by immune receptor stimulation supports the proliferation and inhibits the activation-induced cell death of peripheral T and B cells. We will show in this study that in novel bacterial artificial chromosome transgenic mice that express EGFP under the control of entire Nfatc1 locus the Nfatc1/Egfp transgene is expressed as early as in double-negative thymocytes and in nonstimulated peripheral T and B cells. Upon immune receptor stimulation, Nfatc1/Egfp expression is elevated in B, Th1, and Th2 cells, but only weakly in T regulatory, Th9, and Th17 cells in vitro whose generation is affected by TGFß. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/αA RNA levels during primary and secondary stimulation, but a much stronger induction was observed at the protein level. Whereas anti-CD3(+)CD28 stimulation of primary T cells induces both NFATc1/αA and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/αA and proliferation, but activation-induced cell death after 3-d incubation in vitro. The anti-IgM-mediated activation-induced cell death induction of B cells in vitro is suppressed by anti-CD40-, LPS-, and CpG-mediated signals. In addition to inducing NF-κB factors, together with anti-IgM, these signals also support the generation of NFATc1/αA. According to these data and the architecture of its promoter region, the Nfatc1 gene resembles a primary response gene whose induction is affected at the posttranscriptional level.

Cost-effectiveness of methadone maintenance treatment for HIV-positive drug users in Vietnam.

Methadone maintenance treatment (MMT) is efficacious in reducing drug use that may improve HIV/AIDS care and treatment outcomes. This study evaluated the incremental cost-effectiveness of MMT for HIV-positive drug users from the perspective of health service providers. A sample of 370 HIV-positive drug users (age: mean ± SD: 29.5 ± 5.9 years; 95.7% male) taking MMT in multi-sites was assessed at baseline, three, six and nine months. Costs of MMT services were analyzed and converted to the year 2009. Quality-adjusted life years (QALYs) were modeled from changes in health-related quality of life of patients using the modified World Health Organization Quality of Life - Brief Version (WHOQOL-BREF). Inverse probability-of-treatment weights, constructed using propensity score of non-responses, were applied to adjust for potential confounding. Over nine months, MMT substantially improved QALYs of HIV/AIDS patients (0.076 QALY [0.066-0.084]). The increments in QALY were large and stabilized in those patients taking antiretroviral treatment and abstinent to drug use. For one QALY gained, the MMT program would cost US$3745.3, approximately 3.2 times Vietnam GDP per capita in 2009. The cost-effectiveness of MMT intervention was robust against HIV advanced status or co-morbidity, e.g., TB treatment, but it might not be cost-effective for those patients who continued to use drug. Findings of this study indicate that providing MMT for HIV-positive drug users is a cost-effective intervention in Vietnam. Integrating MMT to HIV/AIDS care and treatment services would be beneficial in injection-driven HIV epidemics.

Changes in drug use are associated with health-related quality of life improvements among methadone maintenance patients with HIV/AIDS.

PURPOSE: This longitudinal study assessed the changes in drug use patterns and health-related quality of life (HRQL) among HIV-positive drug users in the first methadone maintenance treatment (MMT) cohort in Vietnam. METHODS: A secondary analysis was conducted on 370 HIV-positive drug users (age: mean ± SD: 29.5 ± 5.9 years; 95.7% men). Modified WHOQOL-BREF, self-report, and opioid confirmatory urine tests were used to assess HRQL and drug use behaviours at baseline, 3, 6, and 9 months. Generalized estimating equations (GEE) models were constructed to adjust for intra-individual correlations. RESULTS: MMT response rate after 9 months was 89.9%. Rates of positive heroin urine tests rapidly decreased at the first trimester (18.1%) and then stabilized during the next 2 trimesters (11.8 and 14.4%). Among patients with continued drug use, frequency of use decreased from 3.4 to 0.7 time/day. Improvements in HRQL were large over the course of the study and highest in the psychological domain. Adjusting for propensity score in GEE models, ongoing heroin use during MMT resulted in large decrements in all HRQL domains. CONCLUSIONS: MMT improved the outcomes of treatment for drug users in ways that might facilitate success of antiretroviral therapy. Integrating MMT to HIV care and treatment services could be beneficial in injection-driven HIV epidemics in resource-scare settings.

Standardization of DNA amount for bisulfite conversion for analyzing the methylation status of LINE-1 in lung cancer.

Highly methylated Long Interspersed Nucleotide Elements 1 (LINE-1) constitute approximately 20% of the human genome, thus serving as a surrogate marker of global genomic DNA methylation. To date, there is still lacking a consensus about the precise location in LINE-1 promoter and its methylation threshold value, making challenging the use of LINE-1 methylation as a diagnostic, prognostic markers in cancer. This study reports on a technical standardization of bisulfite-based DNA methylation analysis, which ensures the complete bisulfite conversion of repeated LINE-1 sequences, thus allowing accurate LINE-1 methylation value. In addition, the study also indicated the precise location in LINE-1 promoter of which significant variance in methylation level makes LINE-1 methylation as a potential diagnostic biomarker for lung cancer. A serial concentration of 5-50-500 ng of DNA from 275 formalin-fixed paraffin-embedded lung tissues were converted by bisulfite; methylation level of two local regions (at nucleotide position 300-368 as LINE-1.1 and 368-460 as LINE-1.2) in LINE-1 promoter was measured by real time PCR. The use of 5 ng of genomic DNA but no more allowed to detect LINE-1 hypomethylation in lung cancer tissue (14.34% versus 16.69% in non-cancerous lung diseases for LINE-1.1, p < 0.0001, and 30.28% versus 32.35% for LINE-1.2, p < 0.05). Our study thus highlighted the optimal and primordial concentration less than 5 ng of genomic DNA guarantees the complete LINE-1 bisulfite conversion, and significant variance in methylation level of the LINE-1 sequence position from 300 to 368 allowed to discriminate lung cancer from non-cancer samples.

Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation.

In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/αA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/αA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/αA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/αA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/αA interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/αA plays an important role in controlling plasmablast/plasma cell formation.

NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells.

Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.

Estimating the Cost-Effectiveness of HIV Prevention Programmes in Vietnam, 2006-2010: A Modelling Study.

INTRODUCTION: Vietnam has been largely reliant on international support in its HIV response. Over 2006-2010, a total of US$480 million was invested in its HIV programmes, more than 70% of which came from international sources. This study investigates the potential epidemiological impacts of these programmes and their cost-effectiveness. METHODS: We conducted a data synthesis of HIV programming, spending, epidemiological, and clinical outcomes. Counterfactual scenarios were defined based on assumed programme coverage and behaviours had the programmes not been implemented. An epidemiological model, calibrated to reflect the actual epidemiological trends, was used to estimate plausible ranges of programme impacts. The model was then used to estimate the costs per averted infection, death, and disability adjusted life-year (DALY). RESULTS: Based on observed prevalence reductions amongst most population groups, and plausible counterfactuals, modelling suggested that antiretroviral therapy (ART) and prevention programmes over 2006-2010 have averted an estimated 50,600 [95% uncertainty bound: 36,300-68,900] new infections and 42,600 [36,100-54,100] deaths, resulting in 401,600 [312,200-496,300] fewer DALYs across all population groups. HIV programmes in Vietnam have cost an estimated US$1,972 [1,447-2,747], US$2,344 [1,843-2,765], and US$248 [201-319] for each averted infection, death, and DALY, respectively. CONCLUSIONS: Our evaluation suggests that HIV programmes in Vietnam have most likely had benefits that are cost-effective. ART and direct HIV prevention were the most cost-effective interventions in reducing HIV disease burden.

Costing analysis of national HIV treatment and care program in Vietnam.

BACKGROUND: Vietnam achieved rapid scale-up of antiretroviral therapy (ART), although external funds are declining sharply. To achieve and sustain universal access to HIV services, evidence-based planning is essential. To date, there had been limited HIV treatment and care cost data available in Vietnam. METHODS: Cost data of outpatient and inpatient HIV care were extracted at 21 sentinel facilities (17 adult and 4 pediatric) that epitomize the national program. Step-down costing for administration costs and bottom-up resource costing for drugs, diagnostics, and labor were used. Records of 1401 adults and 527 pediatric patients were reviewed. RESULTS: Median outpatient care costs per patient-year for pre-ART, first year ART, later year ART, and second-line ART were US $100, US $316, US $303, and US $1557 for adults; and US $171, US $387, US $320, and US $1069 for children, respectively. Median inpatient care cost per episode was US $162 for adults and US $142 for children. Non-antiretroviral (ARV) costs in adults at stand-alone facilities were 44% (first year ART) and 24% (later year ART) higher than those at integrated facilities. Adults who started ART with CD4 count ≤100 cells per cubic millimeter had 47% higher non-ARV costs in the first year ART than those with CD4 count >100 cells per cubic millimeter. Adult ARV drug costs at government sites were from 66% to 85% higher than those at donor-supported sites in the first year ART. CONCLUSIONS: The study found that HIV treatment and care costs in Vietnam are economical, yet there is potential to further promote efficiency through strengthening competitive procurement, integrating HIV services, and promoting earlier ART initiation.

Prevalence and correlates of alcohol use disorders during antiretroviral treatment in injection-driven HIV epidemics in Vietnam.

BACKGROUND: Alcohol use disorders (AUD) negatively affects adherence to and outcomes of antiretroviral treatment (ART) for HIV/AIDS patients. This study determined the prevalence of AUD and identified correlates of alcohol consumption and drinking problems during ART in large injection-driven HIV epidemics in Vietnam. METHODS: We conducted a cross-sectional study of 1016 patients (36.2% women, mean age=35.4) in 7 hospitals in Hanoi, Hai Phong, and Ho Chi Minh City. Alcohol use problems were assessed using the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C). Step-wise multivariate regression analyses determined the correlates of alcohol consumption, hazardous drinking, and binge drinking in HIV/AIDS patients. RESULTS: There were 55.0% patients reported ever drinking, 30.1% had positive hazardous drinking and 22.3% had binge drinking. Patients who were male, drug users, working as free-lancers, asymptomatic stage, and poorer immune status were more likely to have severe alcohol consumption, hazardous drinking and binge drinking. Drug users taking both ART and Methadone Maintenance Treatment (MMT), were less likely to report AUD. In non-drug users, the longer duration of ART was also associated with lower alcohol consumption and likelihood of drinking problems. In drug users, those in the 1st year ART were more likely to be at-risk drinking than other patient groups. CONCLUSION: AUD is highly prevalent in HIV/AIDS patients taking ART in large injection-driven HIV epidemics. ART guidelines should include AUD screening and interventions. Expanding the coverage of current services for drug users, including MMT and ART, might contribute to the reduction of AUD.

Cost-effectiveness of integrating methadone maintenance and antiretroviral treatment for HIV-positive drug users in Vietnam's injection-driven HIV epidemics.

Drug use negatively affects adherence to and outcomes of antiretroviral treatment (ART). This study evaluated the cost-effectiveness of integrating methadone maintenance treatment (MMT) with ART for HIV-positive drug users (DUs) in Vietnam. A decision analytical model was developed to compare the costs and consequences of 3 HIV/AIDS treatment strategies for DUs: (1) only ART, (2) providing ART and MMT in separated sites (ART-MMT), and (3) integrating ART and MMT with direct administration (DAART-MMT). The model was parameterized using empirical data of costs and outcomes extracted from the MMT and ART cohort studies in Vietnam, and international published sources. Probabilistic sensitivity analysis was conducted to examine the model's robustness. The base-case analysis showed that the cost-effectiveness ratio of ART, DAART-MMT, and ART-MMT strategies was USD 1358.9, 1118.0 and 1327.1 per 1 Quality-Adjusted Life Year (QALY), equivalent to 1.22, 1.00, and 1.19 times Gross Domestic Product per capita (GDPpc). The incremental cost-effectiveness ratio for DAART-MMT and ART-MMT versus ART strategy was 569.4 and 1227.8, approximately 0.51 and 1.10 times GDPpc/QALY. At the willingness to pay threshold of 3 times GDPpc, the probability of being cost-effective of DAART-MMT versus ART was 86.1%. These findings indicated that providing MMT along with ART for HIV-positive DUs is a cost-effective intervention in Vietnam. Integrating MMT and ART services could facilitate the use of directly observed therapy that supports treatment adherence and brings about clinically important improvements in health outcomes. This approach is also incrementally cost-effective in this large injection-driven HIV epidemic.

Multilevel predictors of concurrent opioid use during methadone maintenance treatment among drug users with HIV/AIDS.

BACKGROUND: Ongoing drug use during methadone maintenance treatment (MMT) negatively affects outcomes of HIV/AIDS care and treatment for drug users. This study assessed changes in opioid use, and longitudinal predictors of continued opioid use during MMT among HIV-positive drug users in Vietnam, with the aim of identifying changes that might enhance program efficacy. METHODS: We analyze data of 370 HIV-positive drug users (mean age 29.5; 95.7% male) taking MMT at multi-sites. Opioid use was assessed at baseline, 3, 6, and 9 months using interviews and heroin confirmatory urine tests. A social ecological model was applied to explore multilevel predictors of continued opioid use, including individual, interpersonal, community and service influences. Generalized estimating equations (GEE) statistical models were constructed to adjust for intra-individual correlations. RESULTS: Over 9 month follow-up, self-reported opioid use and positive heroin urine test substantially decreased to 14.6% and 14.4%. MMT helped improve referrals and access to health care and social services. However, utilization of social integration services was small. GEE models determined that participants who were older (Adjusted Odd Ratio - AOR = 0.97 for 1 year increase), had economic dependents (AOR = 0.33), or were referred to TB treatment (AOR = 0.53) were less likely to continue opioid use. Significant positive predictors of ongoing opioid use included frequency of opioid use prior to MMT, peer pressure, living with sexual partners, taking antiretroviral treatment, other health concerns and TB treatment. CONCLUSION: These findings show that MMT in the Vietnamese context can dramatically reduce opioid use, which is known to be associated with reduced antiretroviral (ART) adherence. Disease stage and drug interactions between antiretrovirals or TB drugs and MMT could explain some of the observed predictors of ongoing drug use; these findings could inform changes in MMT program design and implementation.

The cost-effectiveness and budget impact of Vietnam's methadone maintenance treatment programme in HIV prevention and treatment among injection drug users.

We analysed the cost-effectiveness and budget impact of the methadone maintenance treatment (MMT) programme in HIV prevention and treatment among injection drug users (DUs) in Vietnam. The costs and health outcomes of providing MMT for opioid-dependent DUs versus non-MMT were estimated using a decision analytical model. Probabilistic sensitivity analysis using Monte Carlo simulation was conducted to justify uncertainties of model parameters simultaneously. The incremental cost-effectiveness ratio (ICER) of MMT in HIV prevention was US$3324 per one averted HIV case. The decision model showed that the cost-effectiveness ratio of MMT and non-MMT strategies was US$480 and US$204 per 1 quality-adjusted life year (QALY), equivalent to 0.43 and 0.18 times the gross domestic product per capita (GDPpc). The ICER for MMT versus non-MMT strategy was US$1964, approximately 1.76 times the GDPpc/QALY, classifying MMT as a cost-effective intervention. At the willingness to pay threshold of three times the GDPpc, the probability of MMT and non-MMT strategies being cost-effective was 80.3 and 19.7%, respectively. The budget impact of scaling up MMT from 2011 to 2015 will be US$97 million for 65% coverage or US$49 million for treating 80,000 DUs. The results indicated that MMT was cost-effective in HIV prevention and treatment among DUs who were opioid dependent.