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Metabolic associated fatty liver disease (MAFLD) is a chronic liver disease with the highest incidence in the world, which affects 1/4-1/3 of the world population and has a serious effect on people's health. As is a multi-systemic disease, MAFLD is closely related to the occurrence and prognosis of many diseases. Studies have shown that MAFLD is associated with viral infectious diseases, and their interaction affects the prognosis of the disease. This paper reviews the research progress in this field in recent years.Copyright © The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
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Introduction: BICSTaR (GS-EU-380-4472/GS-CA-380-4574/GS-IL-380- 5335) is an ongoing, multinational, observational cohort study evaluating real-world effectiveness and safety of B/F/TAF in ART naïve (TN) and ARTexperienced (TE) PLWH. Materials and Methods: This 12M pooled analysis included PLWH starting B/F/TAF in clinical practice from June 2018 to September 2020 (latterly during the COVID-19 pandemic) in Europe/Israel/Canada. Outcomes included virological effectiveness (HIV-1 RNA <50 copies/ml [missing=excluded]), persistence, drug-related adverse events (DRAEs), and laboratory parameters. Results: One-thousand one hundred thirty-five PLWH were included (Table 1). The TE group had older median age than TN. Of TE participants, 65%/20%/16% switched from INSTI/NNRTI/PI-based regimens (36% TDF/46% TAF/13% ABC);12% had prior virologic failure. Baseline resistance was documented in 124/535 participants (NRTI/NNRTI/PI/ INSTI=6%/6%/3%/0.2%). Prevalence of comorbidities (47%/72% TN/TE) and concomitant medication usage was high. At 12M, 97% (149/154) of TN and 96% (771/800) of TE participants had HIV-1 RNA <50 copies/ml, and persistence on B/F/TAF was high [91% (1032/1135)]. In a multivariable analysis, TE participants with neuropsychiatric disorder ongoing at baseline had lower odds for viral suppression (odds ratio=0.45, 95% CI: 0.21-0.96). There was no emergence of resistance to the components of B/F/TAF. DRAEs occurred in 13% (148/1135) of participants;gastrointestinal and neuropsychiatric DRAEs were the most common (3% each). Discontinuations due to DRAEs were low (TN 4%;TE 6%). Serious DRAEs were rare (0.2%;2 TE participants with depression). Lipidchanges are shown (Figure 1). Conclusion: B/F/TAF was associated with high levels of effectiveness and persistence after 12M in this large real-world cohort of TN and TE PLWH with a high comorbidity burden. Effectiveness was demonstrated across key subgroups (females, older participants, late presenters). Importantly, there were no new or unexpected safety findings. Collectively, these real-world data continue to support the use of B/F/TAF in clinical practice.
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Background: Knowing the true incidence of HIV-1 infections (recent infections) among people newly diagnosed is pivotal to monitoring the course of the epidemic. We have developed a Primer ID Next Gen Sequencing (PID-NGS) assay to identify recent infection by measuring within-host viral diversity over multiple regions of the HIV-1 genome. We implemented a state-wide project to identify recent infections and transmitted drug resistance mutations (DRMs) in diagnostic samples in near real time. Methods: Serum samples from individuals with newly HIV-1 diagnoses (diagnostic sample collected within 30 days of diagnosis) were sequenced. PID-NGS libraries were constructed covering the coding regions for protease, a portion of reverse transcriptase, integrase, and the env gene. The use of the PID-NGS strategy allows for significant error correction and also a definition of the sampling depth of the viral population. Recent infection was defined as within 9-month of infection. DRMs were summarized at detection sensitivities of 30%, 10% and 1% based on viral population sampling depth. Results: From Jan 2018 to Jun 2021, we successfully sequenced partial genomes from 743 individuals with new diagnoses. Year 2020 had the lowest number of new diagnoses (Fig 1a, red bar). Overall, 39.2% of samples were inferred to have represented infection within the previous 9 months. Percent of recent infection varied significantly over the years, increasing from 29.6% in late 2018 to 50.9% in early 2020, but decreasing significantly to 32.7% in 2021 (Fig 1a, blue lines). Individuals younger than 30 y/o were more likely to be identified with recent infection (p<0.01). NNRTI DRMs, especially K103N, were the most abundant DRMs. Fig 1b shows the trend of DRMs over the four years. We observed a trend of decrease in the overall NNRTI DRMs and an increase in the NRTI DRMs in the population. Further analysis suggests that the increase in NRTI DRMs were from TAMs and their revertants, while clinically important NRTI DRMs (K65R and M184) were low (<1%). Conclusion: We have demonstrated a state-wide, all-in-one platform to monitor HIV-1 recency and DRMs in new diagnoses. The number of new diagnoses decreased significantly in 2020 in concert with the COVID-19 pandemic which suggests a decrease in overall HIV testing. The decline in the percentage of recent infections in early 2021 signals a return to broader HIV-1 testing and diagnosis. The increase of other NRTI DRMs suggests ongoing evolution at these sites within the viral population.
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Background: Lenacapavir (LEN), a potent first-in-class inhibitor of HIV-1 capsid function, is in development for treatment and prevention of HIV-1 infection. CAPELLA is an ongoing, Phase II/III study in heavily treatment-experienced (HTE) people with HIV-1 (PWH) with multidrug-resistance and ongoing viremia (≥ 400 copies/mL) evaluating LEN in combination with an optimized background regimen (OBR). Methods: In the randomized cohort (Cohort 1), participants were assigned (2:1) to add oral LEN or placebo to their failing regimen (600 mg on Day 1[D] and 2 and 300 mg on D8). At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg every 6 months;those on placebo started the 2-week oral lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, OBR at D15. In the non-randomized cohort (Cohort 2), participants started OBR concurrent with LEN (oral lead-in → SC). We report the secondary endpoint of W52 efficacy by FDA-snapshot algorithm in the randomized cohort and additional available efficacy and safety from both cohorts. Results: 72 participants were enrolled: 36 in each cohort. Overall, 25% were female, 38% Black, median age 52 years, 19% had VL > 100k c/mL, 64% had CD4 <200 cells/μ L, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, InSTI), and 17% did not have any fully active agents in the OBR. In Cohorts 1 and 2 at W26, 81% (29/36) and 81% (29/36) achieved VL<50 c/mL. At W52, in Cohort 1, 83% (30/36) had VL< 50 c/mL;most in Cohort 2 have not reached W52 yet. At W52, CD4 count increased by a median 83 cells/μ L (Q1 to Q3: 21 to 142, n=41). Eight participants had emergent LEN resistance (4 in Cohort 1 and 4 in Cohort 2);other than 1 who died at W11 (previously reported), all 7 either had evidence of poor adherence to the OBR (n=4) or did not have any fully active agents in the OBR (n=3).No participant experienced a study drug-related serious adverse event. One participant discontinued LEN at W52 due to an AE of Grade 1 injection site nodule. LEN-related injection site reactions (ISRs) occurred in 63% (45/72) and were mostly mild or moderate (43/45). The most common non-ISR AEs were nausea and diarrhea (13% each) and COVID-19 (11%). Conclusion: Subcutaneous LEN in combination with OBR led to high rates of virologic suppression and immunologic recovery in HTE PWH at one year and was well tolerated. These results support the ongoing evaluation of LEN for treatment of multi-drug resistant HIV-1 infection.
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Background: In 2018, Uganda began programmatically switching individuals with HIV-1 RNA <1,000 copies/mL on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART to a fixed-dose regimen of tenofovir/lamivudine/dolutegravir (TLD). Our objective was to estimate the population effectiveness of the TLD transition in public-sector clinics in Uganda. Methods: We conducted a prospective cohort study that enrolled adults ≥18 years who were switched from NNRTI-based first-line ART to TLD at public-sector clinics in Uganda. We observed participants at 3 study visits over 1 year. We obtained blood specimens at each visit and conducted HIV-1 RNA viral load (VL) testing using Cepheid Xpert assays. We fit multivariable logistic regression models to assess predictors of our composite outcome of interest of viral suppression (<50 copies/mL) with retention in care 1 year after switch to TLD. Results: We enrolled 500 participants with a median age of 47 years (IQR 40-53);41% were women. The most common regimen prior to switch was lamivudine/tenofovir/efavirenz (44%), and median duration on ART prior to switch was 8.8 years (IQR 5.7-12.2). Over 95% (n=475/499) were virally suppressed (<50 copies/mL) at the time of switch to TLD. The final visit for all participants occurred a median of 54 weeks (IQR 49-67) after enrollment, with some participants affected by delays due to COVID-19 mitigation measures. One participant self-elected to disenroll. Only 3% (n=13/499) of participants discontinued TLD due to side effects or clinician discretion. We observed 1% mortality (n=6/499), 2% (n=10/499) lost to follow-up, and 5% (n=23/499) with HIV-1 RNA ≥50 copies/mL at 1 year, with a median VL of 252 copies/mL (IQR 81-78,200 copies/mL). Overall, 92% (n=459/499) were virally suppressed and in care at 1 year. An HIV-1 RNA ≥50 copies/mL at the time of switch to TLD, male gender, and any self-reported ART adherence <90% were all significant negative predictors of the composite outcome of retention in care with a suppressed VL (Table). Conclusion: Rates of viral suppression with retention in care >90% after 1 year on TLD, as well as a 2% TLD discontinuation rate, affirm World Health Organization guidelines for the regional transition to TLD. Nonetheless, an 8% failure rate in HIV-endemic countries corresponds to a large population of individuals. Long-term surveillance of this population, strategies to combat imperfect adherence, and continued attention to treatment options after failure on TLD may be needed.
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Background: Single-tablet tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) has been rapidly adopted as 1st-line ART for patients initiating treatment and switching from virally-suppressive NNRTI-based 1st regimens in PEPFAR programs. There are limited data, however, on effectiveness and emergence of resistance to TLD in programmatic settings where plasma HIV-1 RNA and drug resistance testing are not used widely. Methods: A prospective observational study is being performed at 13 ACTG sites in six countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe) coincident with TLD rollout to assess efficacy and emergence of HIV drug resistance following TLD for 1st, 2nd or 3rd-line ART. This report focuses on the 2 Groups that completed enrollment and 6 months of follow-up: Group 1b (Gp1b) participants on NNRTI-based ART for at least 6 months with HIV-1 RNA ≤1000 cps/mL before switch to TLD;and Group 4 (Gp4) ART-naïve participants initiating 1st-line TLD. The primary objective was to estimate the proportions of participants on TLD with HIV-1 RNA ≤1000 cps/mL and with new DTG resistance mutations at 6 months. Results:\From 10/2019-10/2020, we enrolled 600 participants who started TLD: 421 in Gp1b (median age 41years;80% female) and 179 in Gp4 (median age 35years;42% female). In Gp1b, median time on ART was 6.6y (IQR 3.3-10.3);88% were taking EFV with 3TC+TDF or FTC+TDF. In Gp4, median baseline HIV-1 RNA was 4.4 log10 cps/mL (IQR 3.5-5.1). Six participants in Gp1b (1.4%) and 6 in Gp4 (3.4%) discontinued TLD by 6 months, due to withdrawal or loss to follow-up (6 participants), adverse events considered related to TLD (4), and death (2;both Gp4;1 from TB, 1 unknown cause). Among participants followed on TLD to 6 months, 90% in Gp1b (373/415) and 86% in Gp4 (149/173) had a 6-month HIV-1 RNA result (missing values mainly due to COVID-related virtual visits). HIV-1 RNA ≤1000, <200 and <50 cps/mL was achieved in 99%, 98.4%, and 96% of participants in Gp1b and in 90%, 87.2%, and in 84.6% of Gp4, respectively (Table). A new mutation possibly selected by DTG was observed in 1 participant in Gp1b (T97AT) and none in Gp4. Conclusion: TLD was well tolerated and achieved excellent viral suppression in ART-naïve participants and in participants who switched from virally-suppressive 1st-line ART. An emerging InSTI mutation of uncertain significance was seen in only one participant. These data support early tolerability and efficacy of TLD transition in the public sector.