Publications by authors named "Anchalee Avihingsanon"

151 Publications

Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features.

mBio 2021 03 9;12(2). Epub 2021 Mar 9.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA

Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. The kinetics of viral rebound, specifically the time until plasma virus becomes detectable, differ quite substantially between individuals, and associations with virological and immunological factors have been suggested. Standard clinical measures, like CD4 T-cell counts and plasma HIV RNA levels, however, are poor predictive markers. Antibody features, including Fc functionality and Fc glycosylation have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we analyzed HIV-specific antibody quantities and qualitative differences like antibody-mediated functions, Fc gamma receptor (FcγR) binding, and IgG Fc glycosylation as well as cytokine profiles and cellular HIV DNA and RNA levels in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders (≤4 weeks versus >4 weeks) and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. Specifically, individuals with early viral rebound exhibited higher levels of total HIV-specific IgGs carrying inflammatory Fc glycans, while delayed rebounders showed an enrichment of highly functional antibodies. Overall, only four features, including enhanced antibody-mediated NK cell activation in delayed rebounders, were necessary to discriminate the groups. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future ATI studies. Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy is interrupted, and interindividual differences in the kinetics of viral rebound have been associated with virological and immunological factors. Antibody features, including Fc functionality and Fc glycosylation, have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we systematically analyzed HIV-specific antibody quantities and qualitative differences in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future HIV eradication studies.
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http://dx.doi.org/10.1128/mBio.00170-21DOI Listing
March 2021

Liver fibrosis improvement assessed by magnetic resonance elastography and Mac-2-binding protein glycosylation isomer in patients with hepatitis C virus infection receiving direct-acting antivirals.

Hepatol Res 2021 Feb 21. Epub 2021 Feb 21.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Aim: Fibrosis regression has been observed in patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antivirals. This study was aimed at evaluating dynamic changes of serum Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with HCV genotype 1 receiving elbasvir/grazoprevir.

Methods: M2BPGi were serially measured at baseline, during and after therapy. Its diagnostic performance at baseline and sustained virological response at 24 weeks after treatment (SVR24) were compared with transient elastography (TE) and the aspartate aminotransferase/platelet ratio index (APRI) using magnetic resonance elastography (MRE) as a reference.

Results: Overall, 60 HCV mono-infected and 36 HCV/HIV co-infected patients were included with SVR24 rates of 93.3% and 97.2%, respectively. At baseline, TE, M2BPGi and APRI were correlated with MRE (r = 0.788, r = 0.703 and r = 0.564, respectively, p < 0.001). The area under the receiver operator characteristics curves for TE, M2BPGi and APRI in differentiating significant fibrosis were 0.88 (95% confidence interval; 0.81-0.95, p < 0.001), 0.86 (0.79-0.94, p < 0.001) and 0.74 (0.64-0.83, p < 0.001), respectively. The corresponding figures for cirrhosis were 0.95 (0.90-1.00, p < 0.001), 0.96 (0.92-1.00, p < 0.001) and 0.88 (0.79-0.97, p < 0.001), respectively. Compared with baseline, all fibrosis markers significantly declined after achieving SVR24. The correlations of TE, M2BPGi and APRI with MRE at time of SVR24 were r = 0.587 (p < 0.001), r = 0.457 (p < 0.001) and r = 0.293 (p = 0.004), respectively. In multivariate analysis, high baseline alanine aminotransferase level, HCV mono-infection and advanced fibrosis were factors associated with M2BPGi reduction.

Conclusions: HCV eradication is associated with liver fibrosis improvement. M2BPGi has a better performance than APRI in monitoring liver fibrosis in patients treated with direct-acting antivirals. This marker is applicable in resource-limited settings where imaging-based modalities are not widely accessible.
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http://dx.doi.org/10.1111/hepr.13630DOI Listing
February 2021

Improvement of Gut Diversity and Composition after Direct-Acting Antivirals in HCV-Infected Patients with or without HIV Coinfection.

J Infect Dis 2021 Feb 17. Epub 2021 Feb 17.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: The influence of direct-acting antivirals (DAAs) on the composition of gut microbiota in hepatitis C virus (HCV)-infected patients with or without human immunodeficiency virus (HIV) is unclear.

Methods: We enrolled 62 patients with HCV monoinfection and 24 patients with HCV/HIV coinfection receiving elbasvir/grazoprevir from a clinical trial. Fecal specimens collected at pre-treatment and 12 weeks post-treatment were analyzed using amplicon-based 16S rRNA sequencing.

Results: Sustained virological response (SVR12) rates in the mono- and co-infection groups were similar (98.4%vs.95.8%). Pre-treatment bacterial communities in the patient groups were less diverse and distinct from those of healthy controls. Compared with HCV-monoinfected patients, HCV/HIV-coinfected individuals showed comparable microbial alpha-diversity but displayed declined Firmicutes/Bacteroidetes ratio. The improvement of microbial dysbiosis was observed in responders achieving SVR12 across fibrosis stages but was not found in non-responders. Responders with low degree of fibrosis exhibited a recovery in alpha-diversity to level comparable with healthy controls. Reciprocal alterations of increased beneficial bacteria and reduced pathogenic bacteria were also observed in responders.

Conclusions: This study indicates short-term effect of DAAs in restoration of microbial dysbiosis. The favorable changes in gut microbiota profiles after viral eradication might potentially contribute towards the reduction of HCV-related complications among infected individuals.
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http://dx.doi.org/10.1093/infdis/jiab094DOI Listing
February 2021

Successful direct-acting antiviral therapy improves circulating mucosal-associated invariant T cells in patients with chronic HCV infection.

PLoS One 2020 31;15(12):e0244112. Epub 2020 Dec 31.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Objectives: Mucosal-associated invariant T (MAIT) cells have been shown to contribute in the pathogenesis of various liver diseases, including chronic hepatitis C virus (HCV) infection. This study was aimed at investigating the frequency, phenotype, and function of circulating MAIT cells, as well as their alterations after successful direct-acting antivirals (DAAs) in HCV-infected patients with or without HIV infection.

Methods: A total 85 patients (51 HCV-monoinfection and 34 HCV/HIV-coinfection), who received elbasvir/grazoprevir from a clinical trial and 20 healthy controls were included. MAIT cells in blood were characterized using flow cytometry at baseline and 24 weeks post-treatment.

Results: HCV-monoinfected and HCV/HIV-coinfected patients achieved similar sustained virological response rates (SVR24, 94.1% vs. 97.1%). Circulating MAIT cells in the monoinfection and coinfection groups were presented at low frequencies in comparison with healthy controls (median, 1.1% vs. 1.1% vs. 2.4%, P<0.001) and exhibited features of chronic activation and impaired functional capacity. A negative correlation between circulating MAIT cell frequency and liver stiffness assessed by magnetic resonance elastography was observed. Compared with baseline, increased in circulating MAIT cells after successful DAA therapy was mainly detected in HCV-monoinfected patients compared with HCV/HIV-coinfected individuals. Moreover, MAIT cell restoration was predominantly observed among patients with significant fibrosis to cirrhosis (F2-F4).

Conclusions: These data indicated that dysregulation of MAIT cells might play a role in the progression of chronic HCV infection. Partial restoration of MAIT cell frequency and function was observed after successful DAA therapy, particularly in HCV-monoinfected patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244112PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775079PMC
March 2021

Incident Liver Cirrhosis, Associated Factors, and Cardiovascular Disease Risks Among People Living With HIV: A Longitudinal Study.

J Acquir Immune Defic Syndr 2021 Apr;86(4):463-472

HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objectives: We investigated the incidence and associated factors of liver cirrhosis and cardiovascular disease risks among people living with HIV (PLHIV) in a Thai cohort.

Design: A prospective cohort analysis.

Methods: Participants with at least one reliable transient elastography measurement during follow-up, who had pretreatment alanine transaminase, AST, and platelet count at HIV treatment initiation were included. Liver cirrhosis was defined as AST to Platelet Ratio Index >1.5 or fibrosis-4 (FIB-4) >3.25 or liver stiffness by transient elastography >12.5 kPa and confirmed by imaging or liver biopsy. Competing-risk regression was used to identify factors associated with liver cirrhosis. Time-updated 10-year atherosclerotic CVD (ASCVD) risks were compared between PLHIV with or without liver cirrhosis.

Results: A total of 1069 participants (33% women, 9% hepatitis C virus, and 16% hepatitis B virus) with the median age and CD4 at cART initiation of 32 years and 240 cells/mm3 were included. During 8232 person-years, 124 (12%) developed liver cirrhosis after a median of 6.9 (2.4-13.7) follow-up years [incidence, 1.5 (95% confidence interval: 1.3 to 1.8) per 100 person-years]. In multivariable analysis, the factors independently associated with liver cirrhosis were time-updated HIV viremia, hepatitis B virus, and hepatitis C virus coinfection, diabetes mellitus, high-density lipoproteins <40 mg/mL, and d4T exposure. The median time-updated 10-year ASCVD risk score was statistically higher among cirrhotic PLHIV vs. noncirrhosis [4.9% (interquartile range, 2.3-9.7) vs. 2.4% (interquartile range, 1.3-4.9), P < 0.001].

Conclusion: PLHIV with metabolic diseases were more likely to develop liver cirrhosis, independent of hepatitis coinfections, and ASCVD risks were higher among cirrhotic individuals.
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http://dx.doi.org/10.1097/QAI.0000000000002585DOI Listing
April 2021

Performance of a simple flow cytometric assay in diagnosing active tuberculosis.

Tuberculosis (Edinb) 2021 01 11;126:102017. Epub 2020 Nov 11.

The Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, Australia.

A flow cytometric assay measuring Mycobacterium tuberculosis-specific CD4 T-cell responses using co-expression of CD25/CD134 (OX40 assay) was explored as a diagnostic tool for active tuberculosis (TB) in a Thai population with and without HIV infection. Peripheral blood mononuclear cells (PBMC) obtained from 133 participants at TB diagnosis were cryopreserved. Seventy-six participants had a clinical diagnosis of TB which were confirmed by a positive culture. CD4 T-cell responses were measured after stimulation with a pool of overlapping peptides covering RD-1 antigens: CFP-10 + ESAT-6. The performance of the assay was also compared to the Xpert MTB/RIF assay. The overall sensitivity of the OX40 assay was 94.7% (95%CI 87.1-98.5); its specificity was 71.9% (95%CI, 58.5-83). The sensitivity of the OX40 assay among HIV-infected participants was 100% (95%CI, 88.8-100) with a specificity of 92.9% (95%CI, 66.1-99.8). OX40 assay performed particularly well in those with active TB and HIV infection.
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http://dx.doi.org/10.1016/j.tube.2020.102017DOI Listing
January 2021

Maintenance of statin therapy among people living with HIV.

AIDS 2021 03;35(4):567-574

HIV-NAT Research Collaboration/Thai Red Cross AIDS Research Centre.

Objective: Statins play a critical role in reducing the elevated risk of atherosclerotic cardiovascular disease (ASCVD) among people living with HIV (PLHIV). However, maintaining statin therapy is difficult and may be impeded further in PLHIV due to the risk of antiretroviral therapy (ART)/statin interactions. We estimated rates of statin discontinuation and reinitiation, and the percentage of days covered by statin use among PLHIV on ART, and investigated factors associated with these outcomes.

Design: Observational cohort study.

Methods: Clinical data from individuals attending the HIV-NAT Centre in Bangkok, Thailand between 2001 and 2020 were analyzed using Kaplan-Meier curves, competing-risk regression, and generalized estimating equations. Discontinuation was defined as statin cessation lasting 90 days.

Results: Data on 318 PLHIV were included. After 1, 3, and 5 years, 22.3, 50.8, and 61.1% had discontinued statin use, respectively. Among those who discontinued (n = 178), 52.0% reinitiated statin use within 5 years. Factors associated with statin discontinuation were low education level, fewer concomitant medications, and lack of ASCVD. Factors associated with statin reinitiation were older age, diabetes, and high levels of LDL cholesterol. The adjusted mean percentage of days covered by a statin was 86.7, 61.1, and 58.1% in the 6 months prior to 1, 3, and 5 years of follow-up, respectively.

Conclusion: Maintenance of statin therapy is poor among PLHIV on ART but is not associated with using contraindicated antiretroviral/statin combinations. A better understanding of statin use in PLHIV will aid clinicians treating individuals and policy makers designing interventions for population-level ASCVD risk reduction.
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http://dx.doi.org/10.1097/QAD.0000000000002769DOI Listing
March 2021

Characteristics of suboptimal immune response after initiating antiretroviral therapy among people living with HIV with a pre-treatment CD4 T cell count <200 ​cells/mm in Thailand.

J Virus Erad 2020 Sep 19;6(3):100005. Epub 2020 Jul 19.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Background: Complete recovery of the CD4 T cell count is uncommon among chronically HIV-infected individuals with very low pre-treatment CD4 count. We studied the prevalence of chronically immune recovery and its associated factors including immune characteristics chronic HIV-infected Thais.

Methods: Treatment-naïve participants (n ​= ​375) from the HIV-NAT 006 cohort with a pre-treatment CD4 T cell count after initiating antiretroviral therapy (ART) and having achieved a suppressed viremia (HIV-RNA level ​< ​400 copies/mL) were retrospectively followed at the Thai Red Cross AIDS Research Centre, Bangkok, Thailand. Suboptimal immune recovery (SIR) was defined as having a CD4 T cell count <200 ​cells/mm for 3 years after ART initiation. A case-control sub-study matched for age, sex and pre-ART CD4 T cell count was conducted to compare immunological characteristics between SIR (n ​= ​17) and non-SIR (n ​= ​24) participants. Immunological biomarkers such as interleukin-7 (IL-7) and soluble CD14 (sCD14) and other covariates including cytomegalovirus (CMV) DNA level, baseline hemoglobin level, hepatitis B and C co-infections, and T cell subsets associated with immune activation and exhaustion were evaluated.

Results: Among 375 participants with pre-ART CD4 T cell counts < 200 ​cells/mm, the prevalence of SIR was 39.7%, 19.7% and 7.7% at years 1, 2 and 3 after starting ART, respectively. In a multivariate analysis, a pre-ART CD4 T cell count ≤100 ​cells/mm (adjusted odds ratio [aOR] 9.45, 95% CI 2.92-30.61, p ​< ​0.001), older age (aOR 1.07, 95% CI 1.01-1.13, p ​= ​0.029) and baseline HIV-RNA level (aOR 0.36, 95% CI 0.21-0.59, p ​< ​0.001) were independently associated with SIR at year 3 after ART initiation. In the matched case-control sub-study (cases ​= ​17, controls ​= ​24), there was a higher prevalence of hepatitis C co-infection (18.8% vs. 0%, p ​= ​0.05), lower sCD14 levels (mean, 6.23 vs. 6.27 log ​pg/mL, p ​= ​0.04), lower CD8 T cell counts (mean, 514 vs. 876, p ​= ​0.0003), lower CD4/CD8 T cell ratio (mean, 0.27 vs. 0.41, p ​= ​0.01) and higher expression of PD1 on CD8 T cells (74.2% vs. 65.1%, p ​= ​0.02) observed in SIR participants compared to their non-SIR counterparts at year 3 after ART initiation.

Conclusions: Nearly 10% of the study participants who had achieved virological suppression failed to recover a CD4 T cell count > 200 cells/mm after 3 years of ART which was with a very low pre-ART CD4 T cell count and older age. The long-term clinical outcomes of SIR participants need to be further explored.
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http://dx.doi.org/10.1016/j.jve.2020.100005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646671PMC
September 2020

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

J Acquir Immune Defic Syndr 2020 12;85(4):489-497

HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

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.
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http://dx.doi.org/10.1097/QAI.0000000000002464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018533PMC
December 2020

Human immunodeficiency virus type-1 Vpu inhibitor, BIT225, in combination with 3-drug antiretroviral therapy modulates inflammation and immune cells functions.

J Infect Dis 2020 Oct 10. Epub 2020 Oct 10.

Northwestern University, Chicago, USA.

BIT225 is a first in class inhibitor of HIV-1 Vpu. A phase II trial enrolled 36 HIV-1-infected, treatment-naïve participants in Thailand to receive standard of care antiretroviral therapy (ART) Atripla®, with 100 mg or 200 mg of BIT225 or placebo for 12 weeks. Combined treatment with BIT225 and ART was found to be generally safe and well tolerated, with comparable antiviral efficacy to ART alone. The secondary endpoint sCD163, a marker of monocyte/macrophage inflammation, was noted to be significantly decreased in the BIT225 arm. Plasma derived activated CD4 + and CD8 + T cells, NK cells and IL-21 were increased in those treated with BIT225. These findings are consistent with inhibition of the known effects of HIV Vpu, and may reflect clinically important modulation of inflammatory and immune function. Further clinical study is planned to both confirm and extend these important findings in treatment naïve, and treatment experienced individuals.
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http://dx.doi.org/10.1093/infdis/jiaa635DOI Listing
October 2020

Reclassification of Statin Indication Among People Living With HIV Using Coronary Artery Calcium Scoring.

J Acquir Immune Defic Syndr 2020 10;85(2):e26-e29

HIV-Netherlands Australia Thailand/Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

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http://dx.doi.org/10.1097/QAI.0000000000002430DOI Listing
October 2020

Efficacy of elbasvir/grazoprevir therapy in HCV genotype-1 with or without HIV infection: role of HCV core antigen monitoring and improvement of liver stiffness and steatosis.

Antivir Ther 2020 Sep 10. Epub 2020 Sep 10.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: The combination of elbasvir and grazoprevir (EBR/GZR) has been approved for treating HCV infection. This study aimed to evaluate the efficacy of EBR/GZR in terms of sustained virological response (SVR) and improvement of liver fibrosis in Thai patients with HCV genotype-1 (GT1). The utility of serum HCV core antigen (HCVcAg) as an alternative to HCV RNA in assessing SVR was also investigated.

Methods: A total of 101 HCV GT1-infected patients (65 monoinfection and 36 HIV coinfection) who received EBR/GZR for 12-16 weeks were included. Liver stiffness (LS) and controlled attenuation parameter (CAP) were measured by transient elastography. Serum HCVcAg was measured in parallel with HCV RNA.

Results: The overall SVR12 and SVR24 rates in the cohort were 98.0% and 95.0%, respectively. SVR24 rates were consistently high (90.0% to 100%) across all subgroups of patients. A significant LS decline ³30% was observed more frequently in cirrhotic than non-cirrhotic individuals who achieved SVR (63.3% versus 30.3%; P=0.003). The magnitude of LS decline following HCV eradication was comparable between HCV monoinfection and HCV-HIV coinfection. The reduction of CAP was also observed in responders who had significant steatosis at baseline. Compared with HCV RNA, HCVcAg testing displayed high sensitivity (100%) and specificity (99.0-100%) in determining SVR12 and SVR24.

Conclusions: This study confirms that EBR/GZR is effective for HCV GT1-infected Thai patients with or without HIV infection. HCV eradication is associated with LS and CAP improvement regardless of HIV status. HCVcAg testing could be a potential replacement for HCV RNA for assessing SVR in resource-limited settings.
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http://dx.doi.org/10.3851/IMP3370DOI Listing
September 2020

Intrahepatic CXCL10 is strongly associated with liver fibrosis in HIV-Hepatitis B co-infection.

PLoS Pathog 2020 09 8;16(9):e1008744. Epub 2020 Sep 8.

The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia.

In HIV-hepatitis B virus (HBV) co-infection, adverse liver outcomes including liver fibrosis occur at higher frequency than in HBV-mono-infection, even following antiretroviral therapy (ART) that suppresses both HIV and HBV replication. To determine whether liver disease was associated with intrahepatic or circulating markers of inflammation or burden of HIV or HBV, liver biopsies and blood were collected from HIV-HBV co-infected individuals (n = 39) living in Bangkok, Thailand and naïve to ART. Transient elastography (TE) was performed. Intrahepatic and circulating markers of inflammation and microbial translocation were quantified by ELISA and bead arrays and HIV and HBV infection quantified by PCR. Liver fibrosis (measured by both transient elastography and liver biopsy) was statistically significantly associated with intrahepatic mRNA for CXCL10 and CXCR3 using linear and logistic regression analyses adjusted for CD4 T-cell count. There was no evidence of a relationship between liver fibrosis and circulating HBV DNA, qHBsAg, plasma HIV RNA or circulating cell-associated HIV RNA or DNA. Using immunohistochemistry of liver biopsies from this cohort, intrahepatic CXCL10 was detected in hepatocytes associated with inflammatory liver infiltrates in the portal tracts. In an in vitro model, we infected an HBV-infected hepatocyte cell line with HIV, followed by interferon-γ stimulation. HBV-infected cells lines produced significantly more CXCL10 than uninfected cells lines and this significantly increased in the presence of an increasing multiplicity of HIV infection. Conclusion: Enhanced production of CXCL10 following co-infection of hepatocytes with both HIV and HBV may contribute to accelerated liver disease in the setting of HIV-HBV co-infection.
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http://dx.doi.org/10.1371/journal.ppat.1008744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521747PMC
September 2020

Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland

Mutations in the genes of the F signaling pathway of complex, including , , , , , and , can lead to delamanid resistance. We searched for such mutations among 129 strains from Asia, South America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For 10 strains with mutations, we determined the MIC of delamanid. We found one strain from a delamanid-naive patient carrying the natural polymorphism Tyr29del () that was associated with a critical delamanid MIC.
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http://dx.doi.org/10.1128/AAC.00513-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577131PMC
October 2020

HIV Coinfection Is Associated with Low-Fitness Variants in Rifampicin-Resistant Mycobacterium tuberculosis.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

Swiss Tropical and Public Health Institute, Basel, Switzerland

We analyzed 312 drug-resistant genomes of isolates collected from HIV-coinfected and HIV-negative TB patients from nine countries with a high tuberculosis burden. We found that rifampicin-resistant strains isolated from HIV-coinfected patients carried disproportionally more resistance-conferring mutations in that are associated with a low fitness in the absence of the drug, suggesting these low-fitness variants can thrive in the context of reduced host immunity.
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http://dx.doi.org/10.1128/AAC.00782-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508592PMC
September 2020

Echocardiographic Findings Among Virally Suppressed HIV-Infected Aging Asians Compared with HIV-Negative Individuals.

J Acquir Immune Defic Syndr 2020 11;85(3):379-386

The HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objectives: Prevalence of cardiovascular disease increases with age. Little is known about the prevalence and risk factors for echocardiographic abnormalities among older people living with HIV (PLHIV) from Asia.

Design: A cross-sectional study was conducted among PLHIV aged >50 years (N = 298) on antiretroviral treatment (ART) and HIV-negative controls (N = 100) frequency matched by sex and age in Thailand.

Methods: All participants underwent standard 2-dimensional transthoracic echocardiography performed by trained cardiologists who were blinded to the participant's care and HIV status. Logistic regression was used to examine the association between cardiac abnormalities and risk factors.

Results: The median age was 54.7 years (60.8% men) with 37.2% having hypertension and 16.6% having diabetes mellitus. PLHIV was on ART for a median of 16.2 years with current CD4 cell counts of 616 cells per cubic millimeter. Echocardiogram abnormalities did not differ among PLHIV (55%) and the controls (60%). The major abnormalities in PLHIV were following: left ventricular (LV) hypertrophy: 37% men and 42.2% women, LV systolic dysfunction (0.7%), diastolic dysfunction (24.2%), and pulmonary hypertension (3.9%). From the multivariate analyses in PLHIV, being aged >60 years was independently associated with diastolic dysfunction, whereas female sex and left atrial volume index of >34 mL/m were associated with pulmonary hypertension (P < 0.05). None of the ART was significantly associated with any major echocardiographic abnormalities.

Conclusions: In this long-term, well-suppressed, older, Asian PLHIV cohort, the prevalence of asymptomatic LV systolic dysfunction and pulmonary hypertension were relatively low, whereas the diastolic dysfunction and LV hypertrophy were common. Echocardiographic findings did not differ between PLHIV and HIV-uninfected controls.
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http://dx.doi.org/10.1097/QAI.0000000000002456DOI Listing
November 2020

Long-Term TDF-Inclusive ART and Progressive Rates of HBsAg Loss in HIV-HBV Coinfection-Lessons for Functional HBV Cure?

J Acquir Immune Defic Syndr 2020 08;84(5):527-533

Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, Australia.

Background: Tenofovir disoproxil fumarate (TDF) is effective in suppressing HIV and hepatitis B virus (HBV) replication in HIV-HBV coinfection although HBV DNA can persist in some individuals on TDF-containing antiretroviral therapy (ART). We initiated a prospective longitudinal study to determine durability of HBV virological control and clinical outcomes after prolonged TDF-based ART in HIV-HBV coinfection.

Methods: Ninety-two HIV-HBV coinfected participants on, or about to commence, TDF-containing ART from Australia (n = 41) and Thailand (n = 52) were enrolled. Participants were followed 6-monthly for 2 years, then annually to 5 years. Laboratory and clinical assessments and a serum sample were collected at each study visit. These analyses compare follow-up at 2 and 5 years.

Results: 12.0% (95% confidence interval 6.8 to 20.2) of total study entry cohort (n = 92) or 15.3% (95% confidence interval: 8.8 to 25.3) of those with data to year 5 (n = 72) lost hepatitis B surface antigen (HBsAg). The only statistically significant association with HBsAg loss was lower study entry quantitative HBsAg. CD4 T-cell count increased by a median 245 cells/mm3 between the preTDF sample and 5 years of follow-up. By year 5, 98.5% of the cohort had undetectable HBV DNA (<15 IU/mL) and 91.4% had undetectable HIV RNA (<20 copies/mL).

Conclusions: HBsAg loss was high and ongoing over 5 years of follow-up in HIV-HBV coinfected individuals on TDF-containing ART and undetectable HBV was almost universal. Although the pattern of HBsAg loss temporarily parallels immune reconstitution, we could not identify predictive immune markers. The high rate of HBsAg loss in HIV-HBV coinfection may offer valuable insights into the search for a functional HBV cure.
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http://dx.doi.org/10.1097/QAI.0000000000002386DOI Listing
August 2020

Large transmission cluster of acute hepatitis C identified among HIV-positive men who have sex with men in Bangkok, Thailand.

Liver Int 2020 09 20;40(9):2104-2109. Epub 2020 Jul 20.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

A rapidly emerging and highly concentrated hepatitis C virus (HCV) outbreak has recently been observed among both acute and chronic HIV-positive men who have sex with men (MSM) in Bangkok, Thailand. NS5B regions of the HCV genome were amplified using nested PCR and sequenced. Phylogenetic inference was constructed by Maximum Likelihood methods and clusters were identified with support and genetic distance thresholds of 85% and of 4.5%. Forty-eight (25 acute HIV and 23 chronic HIV) MSM with incident HCV infection were included in the analysis. HCV genotype (GT) was 85% GT 1a and 15% GT 3a or 3b. Median age at HCV diagnosis was 34 (interquartile range, 28-41) years. 83.3% (40/48) had history of syphilis infection and 36% (16/44) reported crystal methamphetamine use. Only 2 (4%) reported ever injecting drugs, both crystal methamphetamine. In the phylogenetic clustering analysis, 83% belonged to one of two clusters: one large (75%) and one small (8%) cluster. All clusters were GT 1a. MSM with acute HIV infection were more likely to be in a cluster (92%) than those with chronic infection (74%). HCV screening should be regularly performed for MSM in ART clinics, and offering direct-acting antiviral agents to all MSM with HCV infection might contain the HCV epidemic from expanding further.
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http://dx.doi.org/10.1111/liv.14578DOI Listing
September 2020

Statins for atherosclerotic cardiovascular disease prevention in people living with HIV in Thailand: a cost-effectiveness analysis.

J Int AIDS Soc 2020 06;23 Suppl 1:e25494

Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

Introduction: People living with HIV (PLHIV) have an elevated risk of atherosclerotic cardiovascular disease (CVD) compared to their HIV-negative peers. Expanding statin use may help alleviate this burden. However, the choice of statin in the context of antiretroviral therapy is challenging. Pravastatin and pitavastatin improve cholesterol levels in PLHIV without interacting substantially with antiretroviral therapy. They are also more expensive than most statins. We evaluated the cost-effectiveness of pravastatin and pitavastatin for the primary prevention of CVD among PLHIV in Thailand who are not currently using lipid-lowering therapy.

Methods: We developed a discrete-state microsimulation model that randomly selected (with replacement) individuals from the TREAT Asia HIV Observational Database cohort who were aged 40 to 75 years, receiving antiretroviral therapy in Thailand, and not using lipid-lowering therapy. The model simulated each individual's probability of experiencing CVD. We evaluated: (1) treating no one with statins; (2) treating everyone with pravastatin 20mg/day (drug cost 7568 Thai Baht ($US243)/year) and (3) treating everyone with pitavastatin 2 mg/day (drug cost 8182 Baht ($US263)/year). Direct medical costs and quality-adjusted life-years (QALYs) were assigned in annual cycles over a 20-year time horizon and discounted at 3% per year. We assumed the Thai healthcare sector perspective.

Results: Pravastatin was estimated to be less effective and less cost-effective than pitavastatin and was therefore dominated (extended) by pitavastatin. Patients receiving pitavastatin accumulated 0.042 additional QALYs compared with those not using a statin, at an extra cost of 96,442 Baht ($US3095), giving an incremental cost-effectiveness ratio of 2,300,000 Baht ($US73,812)/QALY gained. These findings were sensitive to statin costs and statin efficacy, pill burden, and targeting of PLHIV based on CVD risk. At a willingness-to-pay threshold of 160,000 Baht ($US5135)/QALY gained, we estimated that pravastatin would become cost-effective at an annual cost of 415 Baht ($US13.30)/year and pitavastatin would become cost-effective at an annual cost of 600 Baht ($US19.30)/year.

Conclusions: Neither pravastatin nor pitavastatin were projected to be cost-effective for the primary prevention of CVD among PLHIV in Thailand who are not currently using lipid-lowering therapy. We do not recommend expanding current use of these drugs among PLHIV in Thailand without substantial price reduction.
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http://dx.doi.org/10.1002/jia2.25494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305414PMC
June 2020

Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand.

Clin Ther 2020 07 22;42(7):1234-1245. Epub 2020 May 22.

Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand. Electronic address:

Purpose: Efavirenz exhibits high interindividual variability in plasma concentrations, leading to unpredictable efficacy and toxicity. Polymorphism of CYP2B6 516G > T has been found to predominantly contribute to efavirenz variability. However, dosage recommendations incorporating CYP2B6 516G > T polymorphism have not been investigated in the Thai population. This study aimed to develop a population model of the pharmacokinetic properties of efavirenz, and to investigate the impact of patients' characteristics and CYP2B6 516G > T polymorphism on the pharmacokinetic properties of efavirenz. Model-based simulations were performed to provide genotype-based dosage optimization in a Thai population.

Methods: Plasma efavirenz concentrations measured at 12 h post-dose in 360 Thai HIV-infected patients with and without tuberculosis were analyzed by the nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was used for describing the pharmacokinetic properties of efavirenz.

Findings: The allele frequency of CYP2B6 516G > T was 34.17%. The efavirenz oral clearance were 11.9, 8.0, and 2.8 L/h in patients weighing 57 kg and having the CYP2B6 516 GG, 516 GT, and 516 TT genotypes, respectively. The use of rifampicin increased efavirenz oral clearance by 28%. The results from the simulations suggest that efavirenz dosages of 400, 300, and 100 mg once daily in Thai HIV mono-infected patients, and 800, 600, and 200 mg once daily in HIV/tuberculosis co-infected patients carrying CYP2B6 516 GG, 516 GT, and 516 TT, respectively.

Implication: The results from this study provide a rationale for efavirenz dose adjustment based on CYP2B6 516G > T polymorphism in Thai HIV-infected patients, which could help to improve treatment outcomes in this population. ClinicalTrials.gov identifier: NCT01138267.
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http://dx.doi.org/10.1016/j.clinthera.2020.04.013DOI Listing
July 2020

Bone mineral density changes among people living with HIV who have started with TDF-containing regimen: A five-year prospective study.

PLoS One 2020 25;15(3):e0230368. Epub 2020 Mar 25.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

There are limited data regarding long-term BMD changes over time among treatment-naïve people living with HIV (PLHIV) after initiating combined antiretroviral therapy (cART) in Asia. We aimed to study bone mineral density (BMD) changes among treatment-naïve PLHIV started treatment with tenofovir disoproxil fumarate (TDF)- or non-TDF-containing regimen and HIV-uninfected controls in an Asian setting. The study was a five-year prospective study. BMD at lumbar spine (LS) (L1 to L4), total hip (TH), and femoral neck (FN) were measured by dual energy X-ray absorptiometry (DEXA) scans at baseline, months 12, 24 and 60. Multivariate logistic regression models were used to explore factors associated with mean BMD ≥5% reduction after 5 years of cART. A total of 106 PLHIV (75 and 31 started TDF- and non-TDF-containing regimen, respectively) and 66 HIV-uninfected individuals were enrolled. The mean percent changes of BMD were significantly different longitudinally between TDF and non-TDF users (p<0.001 for LS, p = 0.006 for TH and p = 0.02 for FN). HIV-positive status and on TDF-containing regimen was independently associated with BMD loss ≥5% at month 60 (adjusted odds ratio [aOR] 7.0, 95% confidence interval [95%CI] 2.3-21.0, P = 0.001 for LS; aOR 4.9, 95%CI 1.7-14.3, P = 0.003 for TH and aOR 4.3, 95%CI 1.6-11.2, P = 0.003 for FN) compared to HIV-uninfected individuals. In a multivariate model for PLHIV only, TDF use (vs. non-TDF, P = 0.005) and pre-treatment CD4+ count <350 cells/mm3 (vs. ≥350 cells/mm3, P = 0.02) were independently associated with ≥5% BMD loss in TH at month 60. Treatment-naïve PLHIV initiating treatment with TDF-containing regimen have higher BMD loss in a Thai cohort. TDF use and low pre-treatment CD4 count were independently associated with BMD loss at month 60 at TH. Earlier treatment initiation and interventions to prevent bone loss could improve skeletal health among PLHIV. Clinicaltrials.gov: NCT01634607.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230368PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094833PMC
June 2020

CD4/CD8 Ratio Recovery of Children and Adolescents Living With HIV With Virological Suppression: A Prospective Cohort Study.

J Pediatric Infect Dis Soc 2021 Mar;10(2):88-96

Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: There are limited data on immune restoration of young adults living with virologically suppressed human immunodeficiency virus (HIV). We investigated recovery rates of CD4/CD8 ratio among Thai children and adolescents after they initiated combination antiretroviral therapy (cART).

Methods: Children and adolescents who started cART at age of ≥ 5 years were eligible in this study if they achieved HIV RNA < 50 copies/mL and had a CD4/CD8 ratio < 0.8 at the time of virological suppression. Normalization of CD4/CD8 ratio was defined as 2 consecutive values ≥ 1. Using group-based trajectory analysis, low- and high-recovery groups were identified in terms of CD4/CD8 ratio recovery.

Results: One hundred thirty-eight children and adolescents (101 perinatally infected and 37 behaviorally infected) with median age of 10.6 years at cART treatment initiation were included. After 559 person-years of follow-up (PYFU), overall incidence rate of CD4/CD8 ratio normalization was 4.1 (95% confidence interval, 2.7-6.2) per 100 PYFU. The probabilities of normalization at 2, 5, and 10 years after HIV suppression were 5.2%, 22.6%, and 35.6%, respectively. The low-recovery group had lower median pre-cART CD4 count (146 vs 304 cells/μL, P = .01), pre-cART CD4/CD8 ratio (0.15 vs 0.23, P = .03) and at first viral suppression (0.38 vs 0.65, P = .0001), compared to the high-recovery group.

Conclusions: Less than half of children and adolescents living with HIV on cART with viral suppression had CD4/CD8 ratio normalization. Those with older age at cART initiation, lower pre-cART CD4 count, or CD4/CD8 ratio had slower ratio recovery. Long-term prognoses such as ongoing immune activation and clinical outcomes among children and adolescents on suppressive cART without CD4/CD8 ratio normalization need to be further investigated.
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http://dx.doi.org/10.1093/jpids/piaa020DOI Listing
March 2021

Successful recruitment of a multi-site international randomized placebo-controlled trial in people with HIV with attention to diversity of race and ethnicity: critical role of central coordination.

HIV Res Clin Pract 2020 02 11;21(1):11-23. Epub 2020 Mar 11.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is a multicenter, randomized, placebo-controlled trial, designed to test whether a statin medication can prevent cardiovascular disease in people with HIV. REPRIEVE recently completed enrollment of 7557 participants at over 100 clinical sites globally. Participant groups of focus were women, and racial and ethnic minorities. To describe recruitment methods and strategies developed by the REPRIEVE Clinical Coordinating Center (CCC) and share best practices learned from the recruitment process. Enrollment targets were agreed upon with the primary funder, the National Heart, Lung, and Blood Institute (NHLBI) and were milestone driven. Milestones included number of sites activated, number of participants enrolled within specific time frames, and proportion of women and minorities enrolled. Strategies to achieve these milestones included structured interviews with site-designated REPRIEVE Recruitment Champions to develop best practices, development of a multimedia campaign, and site level recruitment support. Recruitment initiated March, 2015 and completed March, 2019. The final accrual target was 7500 participants over 48 months. The trial met this target within the time specified. Overall, 10,613 screens were completed, 48% of participants enrolled from sites outside of North America, 32% were female, 44% were Black or African American, and 25% were Hispanic or Latino. REPRIEVE met its overall projected recruitment goal by using multiple, simultaneous strategies to specifically target a diverse population including minority subgroups. REPRIEVE benefited from the development of recruitment strategies with clear targets and communication of accrual targets to study teams.
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http://dx.doi.org/10.1080/25787489.2020.1733794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664829PMC
February 2020

Higher Proportion of Abnormal Nutritional Status Among Well-Suppressed HIV-Infected Elderly Asians Compared to HIV-Negative Individuals.

AIDS Res Hum Retroviruses 2020 07 25;36(7):590-596. Epub 2020 Mar 25.

HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Older adults face physiological, psychological, social, and economic changes, which may impair nutritional status, making the body vulnerable to illness and adverse clinical outcomes. Little is known regarding the nutritional status among elderly people living with HIV (PLHIV). We aimed to study the prevalence of malnutrition and the associated factors in a Thai aging cohort. A cross-sectional study was conducted among PLHIV >50 years of age on long-term antiretroviral therapy and HIV-negative controls, frequency matched by sex and age in Bangkok, Thailand. Nutritional status was assessed by the Mini Nutrition Assessment (MNA) tool. Abnormal nutritional status was defined as MNA score <24 (malnutrition and at risk of malnutrition). Body composition was measured by bioelectrical impedance analysis using Body Composition Analyzer. Demographic and disease-related factors were assessed for their association with abnormal nutrition status using multivariable logistic regression. There were 349 PLHIV and 103 HIV-uninfected controls, with median age 55 years. The majority were male (63%) with median body mass index (BMI) of 23.4 kg/m. PLHIV had lower BMI [median, 23.1 (IQR, 20.8-25.2) vs. 25.3 (22.3-28.7) kg/m,  < .001], lower fat percent [22.8% vs. 26.3%,  < .001] and lower fat mass [14.2 vs. 16.9 kg,  < .001] and higher abnormal nutritional status (18.05% vs. 6.8%,  = .005) than controls. In the multivariate model, older age (adjusted odds ratio [aOR], 1.06, 95% confident interval [CI]: 1.01-1.12,  = .03), positive HIV status (aOR, 2.67, 95% CI: 1.07-6.65,  = .036), diabetes mellitus (aOR, 2.21, 95% CI: 1.003-4.87,  = .049), lower fat mass (aOR, 0.70, 95%CI: 0.57-0.86,  < .001), and lower BMI (aOR, 0.63, 95% CI: 0.51-0.78,  < .001) were independently associated with abnormal nutritional status. PLHIV had higher risks for abnormal nutritional status compared with HIV-uninfected individuals. Regular screening and monitoring of nutritional status among PLHIV may promote better health outcomes.
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http://dx.doi.org/10.1089/AID.2019.0285DOI Listing
July 2020

Treatment outcomes and factors associated with mortality among individuals with both TB and HIV in the antiretroviral era in Thailand.

J Virus Erad 2019 Nov 4;5(4):225-230. Epub 2019 Nov 4.

HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objective: This study aimed to compare treatment outcomes and factors associated with mortality in HIV-1-positive and HIV-1-negative individuals.

Methods: We conducted a cohort study between July 2008 and December 2016. Logistic regression was used to determine factors associated with outcomes and death after tuberculosis (TB) treatment.

Results: A total of 996 individuals with TB, 228 (22.9%) with HIV-1 co-infection and 770 (77.1%) who were HIV-1 negative were reviewed. The overall treatment success rate was 74.3%. The HIV-1-negative individuals with TB had significantly higher treatment success rates (77.2% 64.5%,  < 0.001). Using logistic regression analysis, age >50 years (adjusted odds ratio [aOR] 3.89, 95% confidence interval [CI] 2.24-6.76;  < 0.001), body weight ≤45 kg (aOR 2.19, 95% CI 1.14-4.19;  = 0.02) and HIV-1-positive status (aOR 3.31, 95% CI 1.84-5.91;  < 0.001) were independently associated with death during TB treatment. Among HIV-1-positive individuals, not undergoing antiretroviral therapy (ART), having diabetes and a CD4 T cell count of <50 cells/mm were significantly associated with death.

Conclusion: Individuals who had both TB and HIV-1 in Thailand had lower TB treatment success and higher mortality rates compared with individuals with TB without HIV-1. Strategies to improve ART uptake and to reduce risk of developing active TB among individuals with advanced HIV-1 infection should be scaled up.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844402PMC
November 2019

Switching to Fixed-Dose Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) in Virologically Suppressed HIV-1 Infected Women: A Randomized, Open-Label, Multicenter, Active-Controlled, Phase 3, Noninferiority Trial.

J Acquir Immune Defic Syndr 2019 11;82(3):321-328

Gilead Sciences Inc., Foster City, CA.

Background: Bictegravir, coformulated with emtricitabine/tenofovir alafenamide as a fixed-dose combination (B/F/TAF), is recommended for treatment of HIV-1-infection. Multiple studies of B/F/TAF in treatment-naive and virologically suppressed cohorts have shown high efficacy and tolerability with no treatment-emergent resistance through 48 weeks. Participants in these studies have been predominantly men. We report 48-week results from a phase 3 study evaluating switching to B/F/TAF, specifically in a globally distributed trial population of women.

Methods: In this multicenter, randomized, open-label, active-controlled, noninferiority trial (ClinicalTrials.gov NCT02652624), women living with HIV who were virologically suppressed (HIV-1 RNA levels <50 copies/mL) on a regimen containing either TAF or tenofovir disoproxil fumarate were randomly assigned (1:1) to switch to B/F/TAF (50/200/25 mg) or stay on baseline regimen (SBR) once daily for 48 weeks. Primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (U.S. Food and Drug Administration snapshot algorithm); prespecified noninferiority margin was 4%.

Findings: We randomized 472 participants and treated 470 (234 B/F/TAF, 236 SBR). Switching to B/F/TAF was noninferior to SBR for the primary outcome, as 1.7% (4/234) vs 1.7% (4/236) had HIV-1 RNA ≥50 copies/mL at week 48 (difference 0.0%, 95.001% confidence interval: -2.9% to 2.9%). No individual receiving B/F/TAF developed treatment-emergent resistance. Both treatments were well-tolerated; no participant discontinued treatment because of an adverse event.

Interpretation: Fixed-dose combination B/F/TAF provides a safe and efficacious option for ongoing treatment of HIV in women. This study contributes important data on safety, tolerability, and outcomes of antiretroviral therapy among women living with HIV.
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http://dx.doi.org/10.1097/QAI.0000000000002137DOI Listing
November 2019

Short Communication: Carotid Intima-Media Thickness Is Not Associated with Neurocognitive Impairment Among People Older than 50 Years With and Without HIV Infection from Thailand.

AIDS Res Hum Retroviruses 2019 Nov/Dec;35(11-12):1170-1173

HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross - AIDS Research Centre, Bangkok, Thailand.

Neurocognitive impairment (NCI) contributes to poor quality of life among HIV-positive individuals. Cardiovascular risk factors, including the predictor of subclinical atherosclerosis, carotid intima-media thickness (cIMT), are reported to be associated with NCI. Data on NCI and its association with cIMT among HIV positive are limited, especially in Asian populations. We aimed to determine the prevalence of NCI and its association with cIMT among HIV-positive and HIV-negative aging Thai individuals. Cognitive performance was evaluated by the Thai version of Montreal Cognitive Assessment (MoCA) with a cutoff of <25/30 for diagnosis of NCI. Depression was evaluated by PHQ-9 Patient Depression Questionnaire, with scores ≥5 indicating depression. cIMT measurement was performed by experienced neurologists, and abnormal cIMT was defined as cIMT ≥0.9 mm or presence of carotid plaques. Among 340 well suppressed and aging HIV-positive and 102 HIV-negative matched participants, the median age (interquartile range) was 55 (52-59) years and 61.5% were males. For HIV positive group, the median duration on antiretroviral therapy was 18.3 years with median CD4 of 615.5 cells/mm, and 97.4% had current plasma HIV RNA <50 copies/mL. The most common antiretroviral agents used were tenofovir disoproxil fumarate (76.8%), lamivudine (70.3%), efavirenz (26.7%), and emtricitabine (23.8%). HIV-positive and HIV-negative participants performed comparably between each domain and had comparable prevalence of NCI (59.4% vs. 61.7%,  = .69). However, the HIV-positive group had a high prevalence of depression (24.71% vs. 13.73%,  = .019). HIV-positive status [adjusted odd ratio (aOR) 0.91; 95% confidence interval (CI) 0.57-1.47,  = .71] and cIMT (aOR 1.17; 95% CI 0.77-1.79,  = .47) were not significantly associated with NCI. Given the high prevalence of NCI and depression among aging HIV-positive individuals, routine screening for NCI and depression should be integrated into the HIV care services.
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http://dx.doi.org/10.1089/AID.2019.0139DOI Listing
September 2020

Autoimmune hepatitis in human immunodeficiency virus-infected patients: A case series and review of the literature.

World J Gastroenterol 2019 Sep;25(35):5388-5402

Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330,

Background: Abnormal liver chemistry is a common problem in human immunodeficiency virus (HIV)-infected patients. Common causes of abnormal liver enzymes in this population include viral hepatitis B/C or opportunistic infection, drug toxicity, and neoplasm. Autoimmune hepatitis is a rare cause of hepatitis in HIV-infected individuals; however, this condition has been increasingly reported over the past few years.

Case Summary: We present 13 HIV-infected patients (5 males and 8 females) who developed autoimmune hepatitis (AIH) after their immune status was restored, i.e. all patients had stable viral suppression with undetectable HIV viral loads, and median CD4+ counts of 557 cells/× 10 L. Eleven patients presented with chronic persistent elevation of aminotransferase enzyme levels. One patient presented with acute hepatitis and the other patient presented with jaundice. The median levels of aspartate aminotransferase and alanine aminotransferase enzymes were 178 and 177 U/mL, respectively. Elevation of immunoglobulin G levels was present in 11 (85%) patients. Antinuclear antibody and anti-smooth muscle antibody were positive in 11 (85%) and 5 (38%) patients. Liver biopsy was performed in all patients. They had histopathological findings compatible with AIH. The patients were started on prednisolone for remission induction, with good response. After improvement of the liver chemistry, the dose of prednisolone was tapered, and azathioprine was added as life-long maintenance therapy. At the last follow-up visit, all were doing well, without HIV viral rebound or infectious complications.

Conclusion: This report underscores the emergence of autoimmune hepatitis in the context of HIV infection.
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http://dx.doi.org/10.3748/wjg.v25.i35.5388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761245PMC
September 2019

Effect of Oral Oseltamivir on Virological Outcomes in Low-risk Adults With Influenza: A Randomized Clinical Trial.

Clin Infect Dis 2020 05;70(11):2317-2324

Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding.

Methods: From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3.

Results: Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection.

Conclusions: Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms.

Clinical Trials Registration: NCT01314911.
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http://dx.doi.org/10.1093/cid/ciz634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245154PMC
May 2020

Low CD4 Cell Counts Are Associated with Carotid Plaque and Intima-Media Thickness in Virologically Suppressed HIV-Infected Asians Older Than 50 Years.

AIDS Res Hum Retroviruses 2019 Nov/Dec;35(11-12):1160-1169. Epub 2019 Oct 29.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Center, Bangkok, Thailand.

Information about the prevalence, and risk factors for subclinical atherosclerosis in an Asian HIV-infected population is limited. Carotid intima-media thickness (cIMT) is one predictor for the risk of cardiovascular disease (CVDs) and mortality. We evaluated the prevalence and risk factors related to carotid atherosclerosis among well-suppressed HIV-infected adults receiving long-term ART from Thailand. This was a cross-sectional study of HIV-infected adults >50 years of age and free from CVDs from Thailand during 1 March 2016 and 30 May 2017. Ultrasonography of the carotid was performed and read by cIMT experienced neurologists who were blinded from the patient care. Subclinical atherosclerosis was defined by carotid plaque or cIMT of the common carotid artery (CCA) >0.9 mm. Totally 316 HIV-infected adults (61% males) were included. Median age was 54.4 years and 15.8% were diabetic, 40.2% had hypertension, and 12.7% were current smokers. The median duration of ART was 16.3 years and 32% were currently on boosted protease inhibitor. The mean overall cIMT of the common carotid arteries were 0.63 (IQR 0.55-0.72) mm. Men had higher cIMT than women, 0.64 (IQR 0.56-0.76) vs. 0.60 (IQR 0.53-0.70),  = .03. Overall, 3.8% had cIMT >0.9 mm and 24.4% had carotid plaque. From the multivariate logistic regression analysis, age per 1 year increase [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.003-1.12;  = .04] and nadir CD4 < 200 cells/mm (OR 1.8; 95%CI 1.02-3.18,  = .04) were significantly associated with subclinical atherosclerosis. High-sensitivity C-reactive protein was not associated with subclinical atherosclerosis. In this well-suppressed HIV-infected Aging Asian cohort with relatively low prevalence of current smokers, 26.9% of them had subclinical atherosclerosis. Advanced age and low nadir CD4 cell count were significantly associated with subclinical atherosclerosis. Given that approximately a quarter of the patients had carotid plaques, longitudinal studies to evaluate the development of future overt coronary artery disease and stroke are warranted.
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http://dx.doi.org/10.1089/AID.2019.0126DOI Listing
September 2020