Cryptococcal Meningitis and Clinical Outcomes in Persons With Human Immunodeficiency Virus: A Global View.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of morbidity and mortality in persons with human immunodeficiency virus (HIV; PWH). Little is known about CM outcomes and availability of diagnostic and treatment modalities globally. METHODS: In this retrospective cohort study, we investigated CM incidence and all-cause mortality in PWH in the International Epidemiology Databases to Evaluate AIDS cohort from 1996 to 2017. We estimated incidence using quasi-Poisson models adjusted for sex, age, calendar year, CD4 cell count (CD4), and antiretroviral therapy (ART) status. Mortality after CM diagnosis was examined using multivariable Cox models. A site survey from 2017 assessed availability of CM diagnostic and treatment modalities. RESULTS: Among 518 852 PWH, there were 3857 cases of CM with an estimated incidence of 1.54 per 1000 person-years. Mortality over a median of 2.6 years of post-CM diagnosis follow-up was 31.6%, with 29% lost to follow-up. In total, 2478 (64%) were diagnosed with CM after ART start with a median of 253 days from ART start to CM diagnosis. Older age (hazard [HR], 1.31 for 50 vs 35 years), lower CD4 (HR, 1.15 for 200 vs 350 cells/mm3), and earlier year of CM diagnosis (HR, 0.51 for 2015 vs 2000) were associated with higher mortality. Of 89 sites, 34% reported access to amphotericin B; 12% had access to flucytosine. CONCLUSIONS: Mortality after CM diagnosis was high. A substantial portion of CM cases occurred after ART start, though incidence and mortality may be higher than reported due to ascertainment bias. Many sites lacked access to recommended CM treatment.

BMI as a predictor of high fasting blood glucose among people living with HIV in the Asia-Pacific region.

BACKGROUND: Non-Asian body mass index (BMI) classifications are commonly used as a risk factor for high fasting blood glucose (FBG). We investigated the incidence and factors associated with high FBG among people living with HIV in the Asia-Pacific region, using a World Health Organization BMI classification specific to Asian populations. METHODS: This study included people living with HIV enrolled in a longitudinal cohort study from 2003 to 2019, receiving antiretroviral therapy (ART), and without prior tuberculosis. BMI at ART initiation was categorized using Asian BMI classifications: underweight (<18.5 kg/m2 ), normal (18.5-22.9 kg/m2 ), overweight (23-24.9 kg/m2 ), and obese (≥25 kg/m2 ). High FBG was defined as a single post-ART FBG measurement ≥126 mg/dL. Factors associated with high FBG were analyzed using Cox regression models stratified by site. RESULTS: A total of 3939 people living with HIV (63% male) were included. In total, 50% had a BMI in the normal weight range, 23% were underweight, 13% were overweight, and 14% were obese. Median age at ART initiation was 34 years (interquartile range 29-41). Overall, 8% had a high FBG, with an incidence rate of 1.14 per 100 person-years. Factors associated with an increased hazard of high FBG included being obese (≥25 kg/m2 ) compared with normal weight (hazard ratio [HR] = 1.79; 95% confidence interval [CI] 1.31-2.44; p < 0.001) and older age compared with those aged ≤30 years (31-40 years: HR = 1.47; 95% CI 1.08-2.01; 41-50 years: HR = 2.03; 95% CI 1.42-2.90; ≥51 years: HR = 3.19; 95% CI 2.17-4.69; p < 0.001). CONCLUSION: People living with HIV with BMI >25 kg/m2 were at increased risk of high FBG. This indicates that regular assessments should be performed in those with high BMI, irrespective of the classification used.

Factors associated with high alanine aminotransferase (ALT) and cirrhosis in people living with HIV on combination antiretroviral treatment (cART) in the Asia-Pacific.

Liver disease is a growing burden among people living with HIV (PLHIV) in resource-limited settings. As an indicator of liver disease, risk factors of high alanine aminotransferase (ALT) and cirrhosis were assessed among PLHIV in the TREAT Asia HIV Observational Database (TAHOD). Patients on combination antiretroviral therapy (cART) with a pre-cART ALT measurement and at least one follow-up ALT measurement were included. Factors associated with high ALT (ALT levels > 5 times its upper limit of normal) were analyzed using repeated measure logistic regression over a 10-year follow-up period. Liver cirrhosis was defined as having an AST to Platelet Ratio Index score > 1.5, fibrosis-4 score > 3.25, or a clinical diagnosis of cirrhosis. Cox regression analysis stratified by site was used to analyze factors associated with cirrhosis among those in follow-up after 2015. Of 5182 patients, 101 patients (1.9%) had high ALT levels with hepatitis C virus (HCV) antibody positive (odds ratio [OR]: 4.98, 95% confidence interval [CI]: 2.82-8.77, p < 0.001) and ever high alcohol consumption (OR: 2.33, 95% CI: 1.00-5.46, p = 0.050) as likely factors. Among 6318 PLHIV in the liver cirrhosis analysis, 151 (2%) developed cirrhosis (incidence rate = 0.82 per 100 person-years). Those HCV-antibody positive (hazard ratio [HR]: 5.54, 95% CI: 3.75-8.18, p < 0.001) and had high alcohol consumption (HR: 2.06, 95% CI: 1.23-3.45, p = 0.006) were associated with liver cirrhosis. HCV-antibody positive and high alcohol consumption are factors associated with high ALT. With raised ALT levels as a known factor associated with liver cirrhosis, greater efforts are required in managing ALT levels and reducing the risk of developing liver cirrhosis among those positive for HCV-antibody and those who consume alcohol.

Understanding the epidemiology, clinical characteristics, knowledge and barriers to treatment and prevention of malaria among returning international laborers in northern Vietnam: a mixed-methods study.

BACKGROUND: With the decline in local malaria transmission in Vietnam as a result of the National Malaria Control Program (NMCP) elimination activities, a greater focus on the importation and potential reintroduction of transmission are essential to support malaria elimination objectives. METHODS: We conducted a multi-method assessment of the demographics, epidemiology, and clinical characteristics of imported malaria among international laborers returning from African or Southeast Asian countries to Vietnam. Firstly, we conducted a retrospective review of hospital records of patients from January 2014 to December 2016. Secondly, we conducted a mixed-methods prospective study for malaria patients admitted to the study sites from January 2017 to May 2018 using a structured survey with blood sample collection for PCR analysis and in-depth interviews. Data triangulation of the qualitative and quantitative data was used during analysis. RESULTS: International laborers were young (median age 33.0 years IQR 28.0-39.5 years), predominantly male (92%) adults returning mostly from the African continent (84%) who stayed abroad for prolonged periods (median time 13.5 months; IQR 6.0-331.5 months) and were involved in occupations that exposed them to a higher risk of malaria infection. Epidemiological trends were also similar amongst study strands and included the importation of Plasmodium falciparum primarily from African countries and P. vivax from Southeast Asian countries. Of 11 P. malariae and P. ovale infections across two study strands, 10 were imported from the African continent. Participants in the qualitative arm demonstrated limited knowledge about malaria prior to travelling abroad, but reported knowledge transformation through personal or co-worker's experience while abroad. Interestingly, those who had a greater understanding of the severity of malaria presented to the hospital for treatment sooner than those who did not; median of 3 days (IQR 2.0-7.0 days) versus 5 days (IQR 4.0-9.5 days) respectively. CONCLUSION: To address the challenges to malaria elimination raised by a growing Vietnamese international labor force, consideration should be given to appropriately targeted interventions and malaria prevention strategies that cover key stages of migration including pre-departure education and awareness, in-country prevention and prophylaxis, and malaria screening upon return.

The patient voice: a survey of worries and anxieties during health system transition in HIV services in Vietnam.

BACKGROUND: Vietnam is shifting toward integrating HIV services into the public health system using social health insurance (SHI), and the HIV service delivery system is becoming decentralized. The study aim was to investigate current SHI coverage and patients' perspectives on this transition. METHODS: A survey of 1348 HIV-positive patients on antiretroviral therapy (aged ≥18 years) was conducted at an HIV outpatient clinic at a central-level hospital in Hanoi, Vietnam, in October and November 2018. Insurance coverage, reasons for not having a SHI card, perceived concerns about receiving HIV services in SHI-registered local health facilities, and willingness to continue regularly visiting the current hospital were self-reported. Logistic regression analyses were performed to analyze factors associated with not having a SHI card and having concerns about receiving HIV services in SHI-registered hospitals/clinics. RESULTS: SHI coverage was 78.0%. The most frequently reported reason for not having a SHI card was that obtaining one was burdensome, followed by lack of information on how to obtain a card, and financial problems. Most patients (86.6%) had concerns about receiving HIV services at SHI-registered local health facilities, and disclosure of HIV status to neighbors and low quality of HIV services were the main concerns reported. Participants aged < 40 years old and unmarried were more likely to report lack of SHI cards, and women and those aged ≥40 years were more likely to have concerns. However, 91.4% of patients showed willingness to continue regular visits to the current hospital. CONCLUSIONS: Although SHI coverage has been rapidly improving among HIV patients, most participants had concerns about the current system transition in Vietnam. In response to their voiced concerns, strengthening the link between higher-level and lower-level facilities may help to ensure good quality HIV services at all levels while mitigating patients' worries and anxieties.

HIV treatment eligibility expansion and timely antiretroviral treatment initiation following enrollment in HIV care: A metaregression analysis of programmatic data from 22 countries.

BACKGROUND: The effect of antiretroviral treatment (ART) eligibility expansions on patient outcomes, including rates of timely ART initiation among those enrolling in care, has not been assessed on a large scale. In addition, it is not known whether ART eligibility expansions may lead to "crowding out" of sicker patients. METHODS AND FINDINGS: We examined changes in timely ART initiation (within 6 months) at the original site of HIV care enrollment after ART eligibility expansions among 284,740 adult ART-naïve patients at 171 International Epidemiology Databases to Evaluate AIDS (IeDEA) network sites in 22 countries where national policies expanding ART eligibility were introduced between 2007 and 2015. Half of the sites included in this analysis were from Southern Africa, one-third were from East Africa, and the remainder were from the Asia-Pacific, Central Africa, North America, and South and Central America regions. The median age of patients enrolling in care at contributing sites was 33.5 years, and the median percentage of female patients at these clinics was 62.5%. We assessed the 6-month cumulative incidence of timely ART initiation (CI-ART) before and after major expansions of ART eligibility (i.e., expansion to treat persons with CD4 ≤ 350 cells/µL [145 sites in 22 countries] and CD4 ≤ 500 cells/µL [152 sites in 15 countries]). Random effects metaregression models were used to estimate absolute changes in CI-ART at each site before and after guideline expansion. The crude pooled estimate of change in CI-ART was 4.3 percentage points (95% confidence interval [CI] 2.6 to 6.1) after ART eligibility expansion to CD4 ≤ 350, from a baseline median CI-ART of 53%; and 15.9 percentage points (pp) (95% CI 14.3 to 17.4) after ART eligibility expansion to CD4 ≤ 500, from a baseline median CI-ART of 57%. The largest increases in CI-ART were observed among those newly eligible for treatment (18.2 pp after expansion to CD4 ≤ 350 and 47.4 pp after expansion to CD4 ≤ 500), with no change or small increases among those eligible under prior guidelines (CD4 ≤ 350: -0.6 pp, 95% CI -2.0 to 0.7 pp; CD4 ≤ 500: 4.9 pp, 95% CI 3.3 to 6.5 pp). For ART eligibility expansion to CD4 ≤ 500, changes in CI-ART were largest among younger patients (16-24 years: 21.5 pp, 95% CI 18.9 to 24.2 pp). Key limitations include the lack of a counterfactual and difficulty accounting for secular outcome trends, due to universal exposure to guideline changes in each country. CONCLUSIONS: These findings underscore the potential of ART eligibility expansion to improve the timeliness of ART initiation globally, particularly for young adults.

Changes in renal function with long-term exposure to antiretroviral therapy in HIV-infected adults in Asia.

PURPOSE: Renal disease is common among people living with human immunodeficiency virus (HIV). However, there is limited information on the incidence and risk factors associated with renal dysfunction among this population in Asia. METHODS: We used data from the TREAT Asia HIV Observational Database. Patients were included if they started antiretroviral therapy during or after 2003, had a serum creatinine measurement at antiretroviral therapy initiation (baseline), and had at least 2 follow-up creatinine measurements taken ≥3 months apart. Patients with a baseline estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 were excluded. Chronic kidney disease was defined as 2 consecutive eGFR values ≤60 mL/min/1.73 m2 taken ≥3 months apart. Generalized estimating equations were used to identify factors associated with eGFR change. Competing risk regression adjusted for study site, age and sex, and cumulative incidence plots were used to evaluate factors associated with chronic kidney disease (CKD). RESULTS: Of 2547 patients eligible for this analysis, tenofovir was being used by 703 (27.6%) at baseline. Tenofovir use, high baseline eGFR, advanced HIV disease stage, and low nadir CD4 were associated with a decrease in eGFR during follow-up. Chronic kidney disease occurred at a rate of 3.4 per 1000 patient/years. Factors associated with CKD were tenofovir use, old age, low baseline eGFR, low nadir CD4, and protease inhibitor use. CONCLUSIONS: There is an urgent need to enhance renal monitoring and management capacity among at-risk groups in Asia and improve access to less nephrotoxic antiretrovirals.

Bacterial bloodstream infections in a tertiary infectious diseases hospital in Northern Vietnam: aetiology, drug resistance, and treatment outcome.

BACKGROUND: Bloodstream infections (BSIs) are associated with high morbidity and mortality worldwide. However their aetiology, antimicrobial susceptibilities and associated outcomes differ between developed and developing countries. Systematic data from Vietnam are scarce. Here we present aetiologic data on BSI in adults admitted to a large tertiary referral hospital for infectious diseases in Hanoi, Vietnam. METHODS: A retrospective study was conducted at the National Hospital for Tropical Diseases between January 2011 and December 2013. Cases of BSI were determined from records in the microbiology department. Case records were obtained where possible and clinical findings, treatment and outcome were recorded. BSI were classified as community acquired if the blood sample was drawn ≤48 h after hospitalization or hospital acquired if >48 h. RESULTS: A total of 738 patients with BSI were included for microbiological analysis. The predominant pathogens were: Klebsiella pneumoniae (17.5%), Escherichia coli (17.3%), Staphylococcus aureus (14.9%), Stenotrophomonas maltophilia (9.6%) and Streptococcus suis (7.6%). The overall proportion of extended spectrum beta-lactamase (ESBL) production among Enterobacteriaceae was 25.1% (67/267 isolates) and of methicillin-resistance in S. aureus (MRSA) 37% (40/108). Clinical data was retrieved for 477 (64.6%) patients; median age was 48 years (IQR 36-60) with 27.7% female. The overall case fatality rate was 28.9% and the highest case fatality was associated with Enterobacteriaceae BSI (34.7%) which accounted for 61.6% of all BSI fatalities. CONCLUSIONS: Enterobacteriaceae (predominantly K. pneumoniae and E. coli) are the most common cause of both community and hospital acquired bloodstream infections in a tertiary referral clinic in northern Vietnam.

Effects of unplanned treatment interruptions on HIV treatment failure - results from TAHOD.

OBJECTIVES: Treatment interruptions (TIs) of combination antiretroviral therapy (cART) are known to lead to unfavourable treatment outcomes but do still occur in resource-limited settings. We investigated the effects of TI associated with adverse events (AEs) and non-AE-related reasons, including their durations, on treatment failure after cART resumption in HIV-infected individuals in Asia. METHODS: Patients initiating cART between 2006 and 2013 were included. TI was defined as stopping cART for >1 day. Treatment failure was defined as confirmed virological, immunological or clinical failure. Time to treatment failure during cART was analysed using Cox regression, not including periods off treatment. Covariables with P < 0.10 in univariable analyses were included in multivariable analyses, where P < 0.05 was considered statistically significant. RESULTS: Of 4549 patients from 13 countries in Asia, 3176 (69.8%) were male and the median age was 34 years. A total of 111 (2.4%) had TIs due to AEs and 135 (3.0%) had TIs for other reasons. Median interruption times were 22 days for AE and 148 days for non-AE TIs. In multivariable analyses, interruptions >30 days were associated with failure (31-180 days HR = 2.66, 95%CI (1.70-4.16); 181-365 days HR = 6.22, 95%CI (3.26-11.86); and >365 days HR = 9.10, 95% CI (4.27-19.38), all P < 0.001, compared to 0-14 days). Reasons for previous TI were not statistically significant (P = 0.158). CONCLUSIONS: Duration of interruptions of more than 30 days was the key factor associated with large increases in subsequent risk of treatment failure. If TI is unavoidable, its duration should be minimised to reduce the risk of failure after treatment resumption.

Critical effect of Pol escape mutations associated with detrimental allele HLA-C*15: 05 on clinical outcome in HIV-1 subtype A/E infection.

OBJECTIVE: The mechanism explaining the role of detrimental HLA alleles in HIV-1 infections has been investigated in very few studies. HLA-A*29:01-B*07:05-C*15:05 is a detrimental haplotype in HIV-1 subtype A/E-infected Vietnamese individuals. The accumulation of mutations at Pol 653/657 is associated with a poor clinical outcome in these individuals. However, the detrimental HLA allele and the mechanism responsible for its detrimental effect remains unknown. Therefore, in this current study we identified the detrimental HLA allele and investigated the mechanism responsible for the detrimental effect. DESIGN AND METHODS: A T-cell epitope including Pol 653/657 and its HLA restriction were identified by using overlapping HIV-1 peptides and cell lines expressing a single HLA. The effect of the mutations on the T-cell recognition of HIV-1-infected cells was investigated by using target cells infected with the mutant viruses. The effect of these mutations on the clinical outcome was analyzed in 74 HLA-C*15:05 Vietnamese infected with the subtype A/E virus. RESULTS: We identified HLA-C*15:05-restricted SL9 epitope including Pol 653/657. PolS653A/T/L mutations within this epitope critically impaired the T-cell recognition of HIV-1-infected cells, indicating that these mutations had escaped from the T cells. T-cell responders infected with these mutants showed significantly lower CD4 T-cell counts than those with the wild-type virus or Pol S653K/Q mutants, which are not associated with HLA-C*15:05. CONCLUSION: The accumulation of Pol S653A/T/L escape mutants critically affected the control of HIV-1 by SL9-specific T cells and led to a poor clinical outcome in the subtype A/E-infected individuals having the detrimental HLA-C*15:05 allele.

An expanded HIV care cascade: ART uptake, viral load suppression and comorbidity monitoring among adults living with HIV in Asia.

BACKGROUND: Comprehensive treatment and clinical management are central to improving outcomes for people living with HIV (PLHIV). We explored trends in HIV clinical care, treatment outcomes, and chronic kidney disease (CKD) and diabetes monitoring. METHODS: We included patients ≥18 years in care at ten clinical sites in eight Asian countries. Proportions of patients on antiretroviral therapy (ART), with annual viral load, and with viral load suppression (VLS; <1,000 copies/ml) were estimated by year for 2011-2016, stratified by country income level (lower-middle income [LMIC] and high-income countries [HIC]). Among those on ART in 2016 we evaluated factors associated with annual CKD and diabetes monitoring. RESULTS: Among 31,346 patients (67% male), the proportions of patients on ART (median ART initiation year 2011, IQR 2007-2013), with annual viral load and VLS had substantially increased by 2016 (to 94%, 42% and 92%, respectively, in LMIC and 95%, 97% and 93%, respectively, in HIC) with the larger increases over time seen in LMIC. Among those on ART in 2016, monitoring proportions in LMIC were 53% for CKD and 26% for diabetes compared with 83% and 59%, respectively, in HIC. Overall, a decreased odds of monitoring was observed for male gender, heterosexual HIV exposure, no viral load and LMIC. Diabetes monitoring was also decreased in those with viral failure. CONCLUSIONS: Our findings highlight suboptimal monitoring of viral load, CKD and diabetes in PLHIV in Asia. There is a need for affordable and scalable monitoring options to improve the joint care for HIV and non-communicable diseases.

Validation of the D: A: D Chronic Kidney Disease Risk Score Model Among People Living With HIV in the Asia-Pacific.

BACKGROUND: We validated the Data collection on Adverse events of anti-HIV Drugs (D:A:D) full-risk and short-risk score models for chronic kidney disease (CKD) in the Asian HIV cohorts. SETTINGS: A validation study among people living with HIV (PLHIV) aged ≥18 years among the cohorts in the Asia-Pacific region. METHODS: PLHIV with a baseline estimated glomerular filtration rate > 60 mL/min/1.73 m were included for validation of the D:A:D CKD full version and short version without cardiovascular risk factors. Those with <3 estimated glomerular filtration rate measurements from baseline or previous exposure to potentially nephrotoxic antiretrovirals were excluded. Kaplan-Meier methods were used to estimate the probability of CKD development. The area under the receiver operating characteristics was also used to validate the risk score. RESULTS: We included 5701 participants in full model {median 8.1 [interquartile range (IQR) 4.8-10.9] years follow-up} and 9791 in short model validation [median 4.9 (IQR 2.5-7.3) years follow-up]. The crude incidence rate of CKD was 8.1 [95% confidence interval (CI): 7.3 to 8.9] per 1000 person-years in the full model cohort and 10.5 (95% CI: 9.6 to 11.4) per 1000 person-years in the short model cohort. The progression rates for CKD at 10 years in the full model cohort were 2.7%, 8.9%, and 26.1% for low-risk, medium-risk, and high-risk groups, and 3.5%, 11.7%, and 32.4% in the short model cohort. The area under the receiver operating characteristics for the full-risk and short-risk score was 0.81 (95% CI: 0.79 to 0.83) and 0.83 (95% CI: 0.81 to 0.85), respectively. CONCLUSION: The D:A:D CKD full-risk and short-risk score performed well in predicting CKD events among Asian PLHIV. These risk prediction models may be useful to assist clinicians in identifying individuals at high risk of developing CKD.

Diabetes mellitus burden among people living with HIV from the Asia-Pacific region.

INTRODUCTION: Comorbidities including diabetes mellitus (DM) among people living with HIV (PLHIV) are of increasing clinical concerns in combination antiretroviral therapy (cART) era. We aimed to determine the incidence and risk factors of new-onset DM among PLHIV in Asian settings. METHODS: PLHIV from a regional observational cohort without DM prior to antiretroviral therapy (ART) initiation were included in the analysis. DM was defined as having a fasting blood glucose ≥126 mg/dL, glycated haemoglobin ≥6.5%, a two-hour plasma glucose ≥200 mg/dL, or a random plasma glucose ≥200 mg/dL. A Cox regression model, stratified by site, was used to identify risk factors associated with DM. RESULTS AND DISCUSSION: Of the 1927 participants included, 127 were diagnosed with DM after ART initiation. Median follow-up time from ART initiation to DM diagnosis was 5.9 years (interquartile range (IQR): 2.8 to 8.9 years). The crude incidence rate of DM was 1.08 per 100 person-years (100 PYS), 95% confidence interval (CI) (0.9 to 1.3). In the multivariate analysis, later years of follow-up (2011 to 2013: HR = 2.34, 95% CI 1.14 to 4.79, p = 0.02; and 2014 to 2017: HR = 7.20, 95% CI 3.27 to 15.87, p < 0.001) compared to <2010, older age (41 to 50 years: HR = 2.46, 95% CI 1.39 to 4.36, p  = 0.002; and >50 years: HR = 4.19, 95% CI 2.12 to 8.28, p < 0.001) compared to <30 years, body mass index (BMI) >30 kg/m2 (HR = 4.3, 95% CI 1.53 to 12.09, p = 0.006) compared to BMI <18.5 kg/m2 , and high blood pressure (HR = 2.05, 95% CI 1.16 to 3.63, p = 0.013) compared to those without high blood pressure, were associated with developing DM. The hazard was reduced for females (HR = 0.47, 95% CI 0.28 to 0.80, p = 0.006). CONCLUSIONS: Type 2 DM in HIV-infected Asians was associated with later years of follow-up, high blood pressure, obesity and older age. This highlights the importance of monitoring and routine screening for non-communicable diseases including DM as PLHIV age.

Brief Report: Malignancies in Adults Living With HIV in Asia.

BACKGROUND: Hematological malignancies have continued to be highly prevalent among people living with HIV (PLHIV). This study assessed the occurrence of, risk factors for, and outcomes of hematological and nonhematological malignancies in PLHIV in Asia. METHODS: Incidence of malignancy after cohort enrollment was evaluated. Factors associated with development of hematological and nonhematological malignancy were analyzed using competing risk regression and survival time using Kaplan-Meier. RESULTS: Of 7455 patients, 107 patients (1%) developed a malignancy: 34 (0.5%) hematological [0.08 per 100 person-years (/100PY)] and 73 (1%) nonhematological (0.17/100PY). Of the hematological malignancies, non-Hodgkin lymphoma was predominant (n = 26, 76%): immunoblastic (n = 6, 18%), Burkitt (n = 5, 15%), diffuse large B-cell (n = 5, 15%), and unspecified (n = 10, 30%). Others include central nervous system lymphoma (n = 7, 21%) and myelodysplastic syndrome (n = 1, 3%). Nonhematological malignancies were mostly Kaposi sarcoma (n = 12, 16%) and cervical cancer (n = 10, 14%). Risk factors for hematological malignancy included age >50 vs. ≤30 years [subhazard ratio (SHR) = 6.48, 95% confidence interval (CI): 1.79 to 23.43] and being from a high-income vs. a lower-middle-income country (SHR = 3.97, 95% CI: 1.45 to 10.84). Risk was reduced with CD4 351-500 cells/µL (SHR = 0.20, 95% CI: 0.05 to 0.74) and CD4 >500 cells/µL (SHR = 0.14, 95% CI: 0.04 to 0.78), compared to CD4 ≤200 cells/µL. Similar risk factors were seen for nonhematological malignancy, with prior AIDS diagnosis showing a weak association. Patients diagnosed with a hematological malignancy had shorter survival time compared to patients diagnosed with a nonhematological malignancy. CONCLUSIONS: Nonhematological malignancies were common but non-Hodgkin lymphoma was more predominant in our cohort. PLHIV from high-income countries were more likely to be diagnosed, indicating a potential underdiagnosis of cancer in low-income settings.

Durability of antiretroviral therapy regimens and determinants for change in HIV-1-infected patients in the TREAT Asia HIV Observational Database (TAHOD-LITE).

BACKGROUND: The durability of first-line regimen is important to achieve long-term treatment success for the management of HIV infection. Our analysis describes the duration of sequential ART regimens and identifies the determinants leading to treatment change in HIV-positive patients initiating in Asia. METHODS: All HIV-positive adult patients initiating first-line ART in 2003-2013, from eight clinical sites among seven countries in Asia. Patient follow-up was to May 2014. Kaplan-Meier curves were used to estimate the time to second-line ART and third-line ART regimen. Factors associated with treatment durability were assessed using Cox proportional hazards model. RESULTS: A total of 16,962 patients initiated first-line ART. Of these, 4,336 patients initiated second-line ART over 38,798 person-years (pys), a crude rate of 11.2 (95% CI 10.8, 11.5) per 100 pys. The probability of being on first-line ART increased from 83.7% (95% CI 82.1, 85.1%) in 2003-2005 to 87.9% (95% CI 87.1, 88.6%) in 2010-2013. Third-line ART was initiated by 1,135 patients over 8,078 pys, a crude rate of 14.0 (95% CI 13.3, 14.9) per 100 pys. The probability of continuing second-line ART significantly increased from 64.9% (95% CI 58.5, 70.6%) in 2003-2005 to 86.2% (95% CI 84.7, 87.6%) in 2010-2013. CONCLUSIONS: Rates of discontinuation of first- and second-line regimens have decreased over the last decade in Asia. Subsequent regimens were of shorter duration compared to the first-line regimen initiated in the same year period. Lower CD4+ T-cell count and the use of suboptimal regimens were important factors associated with higher risk of treatment switch.

Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.

OBJECTIVE: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. METHODS: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. RESULTS: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. CONCLUSIONS: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Improved survival in HIV treatment programmes in Asia.

BACKGROUND: Antiretroviral treatment (ART) for HIV-positive patients has expanded rapidly in Asia over the last 10 years. Our study aimed to describe the time trends and risk factors for overall survival in patients receiving first-line ART in Asia. METHODS: We included HIV-positive adult patients who initiated ART between 2003-2013 (n=16,546), from seven sites across six Asia-Pacific countries. Patient follow-up was to May 2014. We compared survival for each country and overall by time period of ART initiation using Kaplan-Meier curves. Factors associated with mortality were assessed using Cox regression, stratified by site. We also summarized first-line ART regimens, CD4+ T-cell count at ART initiation, and CD4+ T-cell and HIV viral load testing frequencies. RESULTS: There were 880 deaths observed over 54,532 person-years of follow-up, a crude rate of 1.61 (95% CI 1.51, 1.72) per 100 person-years. Survival significantly improved in more recent years of ART initiation. The survival probability at 4 years follow-up for those initiating ART in 2003-2005 was 92.1%, 2006-2009 was 94.3% and 2010-2013 was 94.5% (P<0.001). Factors associated with higher mortality risk included initiating ART in earlier time periods, older age, male sex, injecting drug use as HIV exposure and lower pre-ART CD4+ T-cell count. Concurrent with improved survival was increased tenofovir use, ART initiation at higher CD4+ T-cell counts and greater monitoring of CD4+ T-cells and HIV viral load. CONCLUSIONS: Our results suggest that HIV-positive patients from Asia have improved survival in more recent years of ART initiation. This is likely a consequence of improvements in treatment, patient management and monitoring over time.

A strong association of human leukocyte antigen-associated Pol and Gag mutations with clinical parameters in HIV-1 subtype A/E infection.

OBJECTIVES: Identification of human leukocyte antigen-associated HIV-1 polymorphisms (HLA-APs) in different global populations furthers our understanding of HIV-1 pathogenesis and may help identify candidate immunogens for HIV vaccines targeted to these populations. Although numerous population-based studies identifying HLA-APs have been conducted in HIV-1 subtype B- and subtype C-infected cohorts, few have focused on subtype A/E. DESIGN: We investigated HLA-APs in a cohort of chronically HIV-1 subtype A/E-infected Vietnamese individuals. METHODS: HLA-APs in HIV-1 Gag, Pol, and Nef regions from 388 treatment-naive individuals chronically infected with HIV-1 subtype A/E were analyzed using phylogenetically informed approaches. RESULTS: A total of 303 HLA-APs were identified. HLA-APs occurring at six positions in Gag and six positions in Pol were significantly associated with higher plasma viral load (pVL), whereas HLA-APs occurring at two positions in Gag and 13 positions in Pol were significantly associated with lower CD4 T-cell counts. Furthermore, the proportion of Pol codons harboring an HLA-AP specific to the host's HLA correlated positively with HIV-1 pVL (R = 0.22; P < 0.0001) and inversely with CD4 T-cell counts (R = -0.32; P < 0.0001). Similarly, the proportion of HLA-associated Gag codons harboring host-specific HLA-AP correlated inversely with CD4 T-cell counts (R = -0.13; P = 0.01). CONCLUSION: These significant associations between HIV-1 amino acids adapted to Vietnamese HLA alleles and higher pVL and lower CD4 T-cell counts suggests that accumulation of cytotoxic T cells escape mutations may influence clinical outcomes in HIV-1 subtype A/E-infected Vietnamese individuals.

Population structure of colonizing and invasive Staphylococcus aureus strains in northern Vietnam.

Staphylococcus aureus is an important global health problem worldwide. There is still scarce information on the population structure of S. aureus strains in Asia, where the majority of the world population lives. This study characterized the diversity of S. aureus strains in northern Vietnam through multilocus sequence typing (MLST). Eighty-five carriage isolates from the community and 77 invasive isolates from the clinical setting were selected and tested for meticillin resistance and the presence of Panton-Valentine leukocidin (PVL). MLST was performed on these isolates, of which CC59 (25.4 %), CC188 (17.3 %) and CC45 (16.7 %) were the predominant clonal complexes (CCs). CC59 carriage isolates had significantly lower rates of meticillin-resistant S. aureus (MRSA) than their corresponding clinical group isolates (32 vs 83 %). There were no significant differences in rates of MRSA between carriage isolates and clinical isolates of CC45 and CC188. CC59 carriage isolates were significantly lower in rates of PVL+ than CC59 clinical isolates (32 vs 83 %), but the converse was shown in CC45 isolates (14 vs 0 %, respectively). This study revealed vast differences in the molecular epidemiology and population structure of S. aureus in community and clinical settings in Vietnam. Nevertheless, the data underline the spread of virulent and/or resistant strains (MRSA and/or PVL+) in the community, suggesting the necessity for further surveillance to determine the mechanism of transmission of these strains (i.e. MRSA/PVL+) outside clinical settings.

Elevated CD8 T-cell counts and virological failure in HIV-infected patients after combination antiretroviral therapy.

Elevated CD8 counts with combination antiretroviral therapy (cART) initiation may be an early warning indicator for future treatment failure. Thus, we investigated whether elevated CD8 counts were associated with virological failure (VF) in the first 4 years of cART in Asian HIV-infected patients in a multicenter regional cohort.We included patients from the TREAT Asia HIV Observational Database (TAHOD). Patients were included in the analysis if they started cART between 1996 and 2013 with at least one CD8 measurement within 6 months prior to cART initiation and at least one CD8 and viral load (VL) measurement beyond 6 months after starting cART. We defined VF as VL ≥400 copies/mL after 6 months on cART. Elevated CD8 was defined as CD8 ≥1200 cells/µL. Time to VF was modeled using Cox regression analysis, stratified by site.In total, 2475 patients from 19 sites were included in this analysis, of whom 665 (27%) experienced VF in the first 4 years of cART. The overall rate of VF was 12.95 per 100 person-years. In the multivariate model, the most recent elevated CD8 was significantly associated with a greater hazard of VF (HR = 1.35, 95% CI 1.14-1.61; P = 0.001). However, the sensitivity analysis showed that time-lagged CD8 measured at least 6 months prior to our virological endpoint was not statistically significant (P = 0.420).This study indicates that the relationship between the most recent CD8 count and VF was possibly due to the CD8 cells reacting to the increase in VL rather than causing the VL increase itself. However, CD8 levels may be a useful indicator for VF in HIV-infected patients after starting cART.