Achieving consistency in measures of HIV-1 viral suppression across countries:derivation of an adjustment based on international antiretroviral treatment cohort data

INTRODUCTION: The third of the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets is to achieve a 90% rate of viral suppression (HIV viral load <1000 HIV-1 RNA copies/ml) in patients on antiretroviral treatment (ART) by 2020. However, some countries use different thresholds when reporting viral suppression, and there is thus a need for an adjustment to standardize estimates to the <1000 threshold. We aim to propose such an adjustment, to support consistent monitoring of progress towards the "third 90" target. METHODS: We considered three possible distributions for viral loads in ART patients: Weibull, Pareto and reverse Weibull (imposing an upper limit but no lower limit on the log scale). The models were fitted to data on viral load distributions in ART patients in the International epidemiology Databases to Evaluate AIDS (IeDEA) collaboration (representing seven global regions) and the ART Cohort Collaboration (representing Europe), using separate random effects models for adults and children. The models were validated using data from the World Health Organization (WHO) HIV drug resistance report and the Brazilian national ART programme. RESULTS: Models were calibrated using 921,157 adult and 37,431 paediatric viral load measurements, over 2010-2019. The Pareto and reverse Weibull models provided the best fits to the data, but for all models, the "shape" parameters for the viral load distributions differed significantly between regions. The Weibull model performed best in the validation against the WHO drug resistance survey data, while the Pareto model produced uncertainty ranges that were too narrow, relative to the validation data. Based on these analyses, we recommend using the reverse Weibull model. For example, if a country reports an 80% rate of viral suppression at <200 copies/ml, this model estimates the proportion virally suppressed at <1000 copies/ml is 88.3% (0.80(0.56) ), with uncertainty range 85.5-90.6% (0.80(0.70) -0.80(0.44) ). CONCLUSIONS: Estimates of viral suppression can change substantially depending on the threshold used in defining viral suppression. It is, therefore, important that viral suppression rates are standardized to the same threshold for the purpose of assessing progress towards UNAIDS targets. We have proposed a simple adjustment that allows this, and this has been incorporated into UNAIDS modelling software

Understanding the treatment benefit of hyperimmune anti-influenza intravenous immunoglobulin (Flu-IVIG) for severe human influenza

Background: Antibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT 006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalized with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A. Methods: To probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalized with influenza A or B viruses (IAV or IBV) were analyzed for antibody isotype/subclass and Fcγ receptor (FcγR) binding by ELISA, bead-based multiplex, and NK cell activation assays. Results: Influenza-specific FcγR-binding antibodies were elevated in Flu-IVIG–infused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcγR binding were associated with more favorable outcomes. Flu-IVIG therapy also improved the odds of a more favorable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcγR-binding antibody was associated with less favorable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favorable outcome in participants with low levels of anti-IAV Fc-functional antibody. Conclusion: These detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies

Advancing HIV Treatment and Health Outcomes: Insights from Comprehensive Cohort Studies on Viral Suppression, Treatment Response, Immune Recovery, Metabolic and Long-Term Complications among People Living with HIV

This thesis presents a comprehensive investigation into various aspects of HIV treatment and health outcomes, providing insights on key factors that influence viral suppression, treatment response, immune recovery, metabolic factors, and long-term complications. The thesis includes studies encompassing diverse populations across different geographic regions, providing valuable insights into the global landscape of HIV care and studies that focus on HIV epidemic in the Asia-Pacific region. Viral suppression is estimated in children and adolescents, and adults on antiretroviral therapy (ART), incorporating adjustments for missing viral load measurements. Only 59% of children and adolescents and 65% of adults living with HIV had virological suppression at 3 years after ART. Notably, these proportions vary significantly across regions. These robust estimates enhance the understanding of treatment effectiveness in achieving viral suppression across diverse global contexts. Another investigation focuses on HIV treatment outcomes among individuals who acquired the virus through injecting drug use in the Asia-Pacific region. CD4 recovery and viral suppression improved over time after ART, despite the association of advanced HIV disease at ART initiation and sub-optimal adherence with the outcomes. The results illustrate unique challenges faced by this population and offer insights for tailored interventions and support systems. The impact of first-line integrase strand transfer inhibitors (INSTI) on CD4/CD8 ratio recovery is also explored. Compared to other ART regimens, those on INSTI experience higher CD4/CD8 ratio recovery and normalization rates, providing important insights for optimizing therapeutic strategies. Furthermore, the interplay between body mass index, immune recovery, virological failure, weight gain and cardiovascular disease (CVD) risk is investigated. Lastly, the incident liver cirrhosis, its associated factors, and CVD risks are studied. Individuals with liver cirrhosis are also found to have higher CVD risk scores, indicating the broader health implications of liver diseases in people with HIV. In conclusion, this thesis offers a comprehensive exploration of HIV treatment and health outcomes, spanning viral suppression, treatment response, immune recovery, metabolic factors, and long-term complications. The knowledge gained could inform strategies for optimizing HIV care globally and enhance the long-term well-being of people living with HIV

Efficacy and improvement of lipid profile after switching to rilpivirine in resource limited setting: real life clinical practice

Abstract Background Long-term success of cART is possible if the regimen is convenient and less-toxic. This study assessed the efficacy and safety of switching from a first-line NNRTI or boosted PI-based regimens to RPV-based regimens among virologically suppressed participants in resource-limited setting (RLS). Methods This is a prospective cohort study. Participants with plasma HIV-RNA < 50 copies/mL receiving cART were switched from a PI- or NNRTI-based, to a RPV-based regimen between January 2011 and April 2018. The primary endpoint was the proportion of patients with plasma HIV-1 RNA level < 50 copies/mL after 12 months of RPV. The secondary endpoint was the virological response at 24 months and safety endpoint (change in lipid profiles and kidney function from baseline to 12 months). Results A total of 320 participants were enrolled into the study. The rationale for switching to RPV was based on toxicity of the current regimen (57%) or desire to simplify cART (41%). Totally, 177 (55%) and 143 (45%) participants were on NNRTI and boosted PI, respectively, prior to switching to RPV. After 12 months, 298 (93%) participants maintained virological suppression. There were significant improvements in the lipid parameters: TC (− 21 (IQR − 47 to 1) mg/dL; p < 0.001), LDL (− 14 (IQR − 37 to 11) mg/dL; p < 0.001) and TG (− 22 (IQR − 74 to 10) mg/dL; p < 0.001). Also, there was a small but statistically significant decrease in eGFR (− 4.3 (IQR − 12 to 1.1) mL/min per 1.73m2; p < 0.001). Conclusions In RLS where integrase inhibitors are not affordable, RPV-based regimens are a good alternative option for PLHIV who cannot tolerate first-line NNRTI or boosted PI regimen, without prior NNRTI/PI resistance. Trial registration HIV-NAT 006 cohort, clinical trial number: NCT0041198

Assessing the impacts of short-course multidrug-resistant tuberculosis treatment in the Southeast Asia Region using a mathematical modeling approach.

This study aimed to predict the impacts of shorter duration treatment regimens for multidrug-resistant tuberculosis (MDR-TB) on both MDR-TB percentage among new cases and overall MDR-TB cases in the WHO Southeast Asia Region. A deterministic compartmental model was constructed to describe both the transmission of TB and the MDR-TB situation in the Southeast Asia region. The population-level impacts of short-course treatment regimens were compared with the impacts of conventional regimens. Multi-way analysis was used to evaluate the impact by varying programmatic factors (eligibility for short-course MDR-TB treatment, treatment initiation, and drug susceptibility test (DST) coverage). The model predicted that overall TB incidence will be reduced from 246 (95% credible intervals (CrI), 221-275) per 100,000 population in 2020 to 239 (95% CrI, 215-267) per 100,000 population in 2035, with a modest reduction of 2.8% (95% CrI, 2.7%-2.9%). Despite the slight reduction in overall TB infections, the model predicted that the MDR-TB percentage among newly notified TB infections will remain steady, with 2.4% (95% CrI, 2.1-2.9) in 2020 and 2.5% (95% CrI, 2.3-3.1) in 2035, using conventional MDR-TB treatment. With the introduction of short-course regimens to treat MDR-TB, the development of resistance can be slowed by 38.6% (95% confidence intervals (CI), 35.9-41.3) reduction in MDR-TB case number, and 37.6% (95% CI, 34.9-40.3) reduction in MDR-TB percentage among new TB infections over the 30-year period compared with the baseline using the standard treatment regimen. The multi-way analysis showed eligibility for short-course treatment and treatment initiation greatly influenced the impacts of short-course treatment regimens on reductions in MDR-TB cases and percentage resistance among new infections. Policies which promote the expansion of short-course regimens and early MDR-TB treatment initiation should be considered along with other interventions to tackle antimicrobial resistance in the region

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

ObjectivesMucosal-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.MethodsA 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.ResultsHCV-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%, PConclusionsThese 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

CD4/CD8 ratio normalization rates and low ratio as prognostic marker for non-AIDS defining events among long-term virologically suppressed people living with HIV

Abstract Background Immune restoration is often incomplete after ART in HIV patients, both quantitatively and qualitatively. We studied the incidence and probability of CD4/CD8 normalization in an adult Thai HIV cohort and explored the predictive value of the ratio for developing of non-AIDS defining events (NAEs). Methods We analyzed data from HIV-infected Thai adults between 1996 and 2017 in the HIV-NAT 006 prospective long-term cohort in Bangkok, Thailand. Normalization was defined as CD4/CD8 ratio ≥ 1 on two consecutive visits, and normalization probability was calculated using the Kaplan–Meier method. NAEs were a composite endpoint including cardiovascular or cerebrovascular diseases, chronic kidney diseases, non-AIDS defining malignancies and death. Multivariate Cox regression was used to evaluate demographic, disease and treatment characteristics associated with CD4/CD8 ratio normalization and NAEs. Results A total of 800 ART-naïve patients with baseline CD4/CD8 ratio of  0.45 were independently associated with higher risk of progression to NAEs in the multivariate analysis. Conclusions Our findings showed that complete immune recovery is uncommon in an Asian setting and earlier ART initiation at higher CD4 counts may have increased the ratio sooner. The findings demonstrate the use of CD4/CD8 ratio as a prognostic marker for clinical progression of NAEs. Trial registration HIV-NAT 006 cohort, clinical trial number: NCT0041198

Study of fault zone and basin structure of 2019 Mw5.5 Ye-U earthquake sequence beneath Central Myanmar Basin

Accurate and precise location of earthquake sequence is critical to better understand seismotectonics, such as better delineation fault geometry and understanding of the rupture of the earthquakes. However, nearfield seismic observations are usually rare for such study. Here we study a unique dense nodal array data acquired by the deployment after the 31/08/2019 Mw5.5 crustal earthquake that is located ~50km to the west of Sagaing fault near Mandalay beneath ShweBo Central Myanmar Basin (CMB). The network, composed of 20 nodal stations with station spacing of ~5km, was deployed ~ 2 weeks after the mainshock and continuously recording for ~ 40 days. High quality waveforms containing clear P and S phase arrivals, and an interesting P-to-S phase converted at the basement of CMB were recorded for aftershocks. We applied a machine learning based automatic phase detection software (Earthquake-Transformer) to the dataset and detected 1143 events that were recorded by at least 3 stations. Double difference relocation of these aftershocks reveals a near E-W trending fault with a dimension of ~10km along strike and located between 7 to 12 km in depth. The strike of aftershock lineation is highly consistent with the focal mechanism derived from regional waveform inversion, indicating a left lateral strike-slip fault beneath CMB. Mainshock epicenter refined by a path calibration technique is located to the western edge of the seismicity, suggesting an eastward rupture directivity of the mainshock. Taking advantage of the P-basin-S converted phase at the basement of CMB, we constrained the thickness of the basin to be 5 ± 0.7 km. Strong strength of the P-basin-S phase requires sharp velocity change between the basin and bedrock. It is possible that the earthquake sequence is a result of small block rotation that has been taking place beneath the CMB due to the convergence of India plate. Another possible explanation is a conjugate fault system associated with 2012 Mw 6.8 Thabeikkyin earthquake sequence which ruptured close to Sagaing fault

Association of Phenotypic Aging Marker with comorbidities, frailty and inflammatory markers in people living with HIV

Abstract Background Aging characteristics in people living with HIV (PLWH) are heterogeneous, and the identification of risk factors associated with aging-related comorbidities such as neurocognitive impairment (NCI) and frailty is important. We evaluated predictors of novel aging markers, phenotypic age (PhenoAge) and phenotypic age acceleration (PAA) and their association with comorbidities, frailty, and NCI. Methods In a cohort of PLWH and age- and sex-matched HIV-negative controls, we calculated PhenoAge using chronological age and 9 biomarkers from complete blood counts, inflammatory, metabolic-, liver- and kidney-related parameters. PAA was calculated as the difference between chronological age and PhenoAge. Multivariate logistic regression models were used to identify the factors associated with higher (>median) PAA. Area under the receiver operating characteristics curve (AUROC) was used to assess model discrimination for frailty. Results Among 333 PLWH and 102 HIV-negative controls (38% female), the median phenotypic age (49.4 vs. 48.5 years, p = 0.54) and PAA (− 6.7 vs. -7.5, p = 0.24) was slightly higher and PAA slightly less in PLWH although this did not reach statistical significance. In multivariate analysis, male sex (adjusted odds ratio = 1.68 [95%CI = 1.03–2.73]), current smoking (2.74 [1.30–5.79]), diabetes mellitus (2.97 [1.48–5.99]), hypertension (1.67 [1.02–2.72]), frailty (3.82 [1.33–10.93]), and higher IL-6 levels (1.09 [1.04–1.15]), but not HIV status and NCI, were independently associated with higher PAA. PhenoAge marker discriminated frailty better than chronological age alone (AUROC: 0.75 [0.66–0.85] vs. 0.65 [0.55–0.77], p = 0.04). In the analysis restricted to PLWH, PhenoAge alone predicted frailty better than chronological age alone (AUROC: 0.7412 vs. 0.6499, P = 0.09) and VACS index (AUROC: 0.7412 vs. 0.6811, P = 0.34) despite not statistically significant. Conclusions While PLWH did not appear to have accelerated aging in our cohort, the phenotypic aging marker was significantly associated with systemic inflammation, frailty, and cardiovascular disease risk factors. This simple aging marker could be useful to identify high-risk PLWH within a similar chronological age group