The involvement of HBV DNA integration in promoting hepatocarcinogenesis and the extent to which the intrahepatic HBV reservoir modulates liver disease progression remains poorly understood. We ...examined the intrahepatic HBV reservoir, the occurrence of HBV DNA integration and its impact on the hepatocyte transcriptome in hepatitis B 'e' antigen (HBeAg)-negative chronic hepatitis B (CHB).
Liver tissue from 84 HBeAg-negative patients with CHB with low (n=12), moderate (n=25) and high (n=47) serum HBV DNA was analysed. Covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) were evaluated by quantitative PCR, whole exome and transcriptome sequencing was performed by Illumina, and the burden of HBV DNA integrations was evaluated by digital droplet PCR.
Patients with low and moderate serum HBV DNA displayed comparable intrahepatic cccDNA and pgRNA, significantly lower than in patients with high HBV DNA, while hepatitis B core-related antigen correlated strongly with the intrahepatic HBV reservoir, reflecting cccDNA quantity. Whole exome integration was detected in a significant number of patients (55.6%, 14.3% and 25% in high, moderate and low viraemic patients, respectively), at a frequency ranging from 0.5 to 157 integrations/1000 hepatocytes. Hepatitis B surface antigen >5000 IU/mL predicted integration within the exome and these integrations localised in genes involved in hepatocarcinogenesis, regulation of lipid/drug metabolism and antiviral/inflammatory responses. Transcript levels of specific genes, including the proto-oncogene hRAS, were higher in patients with HBV DNA integration, supporting an underlying oncogenic risk in patients with low-level to moderate-level viraemia.
HBV DNA integration occurs across all HBeAg-negative patients with CHB, including those with a limited HBV reservoir; localising in genes involved in carcinogenesis and altering the hepatocyte transcriptome.
Objectives
We evaluated the virological response and resistance profile in combined antiretroviral therapy (cART)‐experienced HIV‐1‐infected patients starting a dual therapy with dolutegravir (DTG) ...and boosted darunavir (bDRV) for the first time.
Methods
Survival analyses were used to evaluate virological success (VS) and virological rebound (VR) in viraemic and virologically suppressed patients, respectively. Major resistance mutations (MRMs) and genotypic susceptibility score (GSS) were evaluated at baseline and after switch.
Results
Overall, 130 patients 62 (47.7%) viraemic; 68 (52.3%) virologically suppressed were retrospectively analysed. At the moment of switch, 81.5% accumulated one or more MRM protease inhibitor (PI), 35.7%; nucleoside(t)ide reverse transcriptase inhibitor (NRTI), 77.5%; non‐NRTI, 69.0%; integrase inhibitor (INI), 10.1%), but 77.7% harboured strains fully susceptible to DTG + bDRV. In viraemic patients, the overall probability of VS by 12 months of treatment was 91.7%. In virologically suppressed patients, the overall probability of VR was 10.5% by 24 months after therapy start. Patients with previous time under virological suppression ≤ 6 months showed a higher VR probability compared with others (37.5% vs. 6.7%, P < 0.002). Among 13 non‐responding patients for whom a genotypic resistance test result at failure was available, only two (15.4%) accumulated further resistance in integrase (Y143C/H/R; S147G and N155H) and protease (V32I, L33F, I54L).
Conclusions
In highly treatment‐experienced patients, the use of dual therapy based on DTG + bDRV appears to be a very good regimen for switch therapy, with a high rate of virological control in both viraemic and virologically suppressed patients. Among non‐responding patients, the selection of further resistance is a rare event.
Background & aims
We investigated the HCV‐RNA amount, variability and prevalence of resistance‐associated substitutions (RASs), in plasma, hepatic tumoral and non‐tumoral tissue samples in patients ...undergoing liver‐transplant/hepatic‐resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis.
Methods
Eighteen HCV‐infected patients undergoing LT/HR, 94.0% naïve to direct‐acting antivirals (DAAs), were analysed. HCV‐RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non‐tumoral tissues were analysed using Sanger and Ultra‐deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic‐variability and phylogenetic analysis were evaluated.
Results
At the time of LT/HR, HCV‐RNA was quantifiable in all compartments of DAA‐naïve patients and was generally lower in tumoral than in non‐tumoral tissues (median IQR = 4.0 1.2‐4.3 vs 4.33.1‐4.9 LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV‐RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non‐tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected‐patients, and by UDPS in other two patients. HCV‐compartmentalization resulted to be associated with HBcAb‐positivity (P = 0.013). UDPS showed approximately higher genetic‐variability in NS3/NS5A sequences in all compartments. Phylogenetic‐analysis showed defined and intermixed HCV‐clusters among/within all compartments, and were strongly evident in the only non‐cirrhotic patient, with plasma and non‐tumoral sequences generally more closely related.
Conclusions
Hepatic compartments showed differences in HCV‐RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV‐strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.
Background
With the success of antiretroviral therapy (ART), children born with HIV are more likely to reach adolescence. However, frequent non‐adherence to ART in adolescents living with HIV (ALHIV) ...leads to viral replication. Notably, a viraemic infection might lead to archived drug resistance mutations (ADRMs). Hence, within the context of the COVID‐19 pandemic, we aimed to compare the patterns of ADRMs in viraemic and non‐viraemic vertically infected ALHIV and to assess their immunity to and diagnosis of SARS‐CoV‐2.
Methods
A comparative study was conducted among COVID‐19‐unvaccinated ALHIV receiving ART in Yaoundé‐Cameroon over the period October 2021 to March 2022. Plasma HIV‐RNA was measured using Abbott® m2000rt; HIV‐1 genotyping was performed on buffy‐coat (HIV‐1 DNA) and ADRMs were interpreted using HIVdb.v9.0.1. Patterns of HIV‐1 ADRMs were compared between viraemic (≥ 1.60 log10HIV‐1 RNA copies/ml) and non‐viraemic (< 1.60 log10copies/ml) individuals. SARS‐CoV‐2 antibodies were assessed on whole blood using Abbott Panbio COVID‐19 immunoglobulin G/M (IgG/IgM) rapid test and COVID‐19 polymerase chain reaction test was performed using nasopharyngeal swab samples.
Results
Of the 60 ALHIV aged 17 (16–19) years, 51.6% female, median ART duration was 14 (12–16) years; 31/55 (56.3%) were exposed to nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based first‐line ART (of whom 19/31 transitioned to dolutegravir‐based ART in 2020) and 24/55 (43.6%) were on second‐line ART. Forty‐two out of 60 (70.0%) ALHIV were non‐viraemic; 43/60 (71.6%) were successfully sequenced. Overall the ADRM rate was 62.7% (27/43), with 69.2% (9/13) viraemic and 60.0% (18/30) non‐viraemic (p = 0.56). NNRTI‐ADRMs were significantly higher among viraemic ALHIV (69.2% vs. 46.7%, p = 0.030). Regarding immunity, those with CD4 nadir < 350 cells/μl had significantly higher rates of ADRMs adjusted odds ratio (aOR) = 3.20 (1.36–95.53), p = 0.03. In relation to COVID‐19 immunity, overall SARS‐CoV‐2 IgG seropositivity was 28.3% (17/60), whereas 0% (0/60) were seropositive to IgM; in particular, those with CD4 count nadir ≥ 350 cells/μl had higher odds of SARS‐CoV‐2 IgG seropositivity OR =7.85 (2.03–30.28), p < 0.01. No significant association was found between SARS‐CoV‐2 IgG seropositivity and HIV‐RNA (non‐viraemic, 33.3%; viraemic, 16.7%; p = 0.18). SARS‐CoV‐2 RNA prevalence was 4.5% (2/44). The two positive participants were with low‐levels of viral load (Ct > 30) and seropositive to IgG.
Conclusion
In the context of virological success, the majority of ALHIV harbour ADRMs, essentially driven by NNRTI mutations and low CD4 nadir. During the current pandemic, about one‐third of ALHIV were previously exposed to SARS‐CoV‐2. However, some children might have been exposed and uninfected and others might have been infected but showed no serological response at sampling. These findings support the use of NNRTI‐sparing regimens and the implementation of COVID‐19 barrier measures targeting ALHIV during such a pandemic.
In vitro, gp120 of both X4 and R5 HIV-1 strains activates human hepatic stellate cells, but if it can promote liver fibrosis in vivo is unknown. We aimed to evaluate if patients carrying X4 or R5 ...strains have a different liver fibrosis (LF) progression over time.
A total of 1,137 HIV-infected patients in ICONA cohort (21% females, 7% HCV co-infected) with an available determination of HIV-1 co-receptor tropism (CRT), a Fibrosis-4 Index for Liver Fibrosis (FIB-4) <3.25 and at least one-year follow-up were included. CRT was assessed by gp120 sequencing on plasma RNA and geno2pheno algorithm (10% false positive rate) or by Trofile. LF was assessed by means of FIB-4. LF progression was defined as an absolute score increase or a transition to higher fibrosis stratum and/or occurrence of liver-related clinical events.
A total of 249 (22%) patients carried X4 strains, which were associated with older age, lower CD4 count, lower nadir CD4, and intravenous drug use. Overall, X4 and R5 patients had similar baseline FIB-4 scores and similar mean FIB-4 slope after a median follow-up of 35 months. There was no difference between X4 and R5 for time to LF progression (p = 0.925). Estimated risk of LF at 24 months (95% CI) after baseline in X4 and R5 was 10.6% (8.3-12.9) and 9.9% (5.9-14.0), respectively. Age, HCV co-infection, diabetes, HIV-duration, HIV-RNA>100.000 cp/mL, antiretroviral therapy exposure were associated with LF progression at multivariate analysis.
A slight LF progression over time was observed in HIV-infected patients. No difference was demonstrated for X4 and R5 HIV-1 strains in accelerating LF evolution.
The study was undertaken in order to provide a snapshot from real clinical practice of virological presentation and outcome of patients developing immunosuppression‐driven HBV reactivation. Seventy ...patients with HBV reactivation were included (66.2% treated with rituximab, 10% with corticosteroids and 23.8% with other immunosuppressive drugs). Following HBV reactivation, patients received anti‐HBV treatment for a median (IQR) follow‐up of 31(13‐47) months. At baseline‐screening, 72.9% of patients were HBsAg‐negative and 27.1% HBsAg‐positive. About 71.4% had a diagnosis of biochemical reactivation median (IQR) HBV DNA and ALT: 6.9 (5.4‐7.8) log IU/mL and 359 (102‐775) U/L. Moreover, 10% of patients died from hepatic failure. Antiviral prophylaxis was documented in 57.9% and 15.7% of HBsAg‐positive and HBsAg‐negative patients at baseline‐screening (median IQR prophylaxis duration: 2415‐33 and 2517‐36 months, respectively). Notably, HBV reactivation occurred 2‐24 months after completing the recommended course of anti‐HBV prophylaxis in 35.3% of patients. By analysing treatment outcome, the cumulative probability of ALT normalization and of virological suppression was 97% and 69%, respectively. Nevertheless, in patients negative to HBsAg at baseline‐screening, only 27% returned to HBsAg‐negative status during prolonged follow‐up, suggesting the establishment of chronic infection. In conclusion, most patients received a diagnosis of HBV reactivation accompanied by high ALT and 10% died for hepatic failure, supporting the importance of strict monitoring for an early HBV reactivation diagnosis. Furthermore, HBV reactivation correlates with high risk of HBV chronicity in patients negative for HBsAg at baseline‐screening, converting a silent into a chronic infection, requiring long‐term antiviral treatment. Finally, a relevant proportion of patients experienced HBV reactivation after completing the recommended course of anti‐HBV prophylaxis, suggesting the need to reconsider proper duration of prophylaxis particularly in profound immunosuppression.
Background & Aims
The proportion of HCV‐infected patients over age 65 years in Western countries is increasing. This growth and the advent of new antiviral therapy bring into the question the ...real‐world efficacy and safety of the combination of sofosbuvir (SOF) and simeprevir (SMV) plus a flat dose of 800 mg/d ribavirin (RBV) in elderly patients with cirrhosis compared to younger patients.
Methods
Retrospective observational multicentre real‐life investigation study of SOF/SMV/RBV for a duration of 12 weeks in HCV genotype 1‐infected patients with cirrhosis.
Results
Of the 270 patients enrolled in this study, with compensated cirrhosis, 133 (49.2%) were ≥65 years of age. Sustained virological response at 12 weeks (SVR12) was achieved by 94.2% (129/137) of those aged <65 years and 97.7% (130/133) of those ≥65 years. Diabetes was the most common comorbidity in patients ≥65 years compared to younger patients (26.3% vs 12.4% P<.003). The most common adverse event (AE) in elderly patients was a grade 2 anaemia (35.3% vs 19.9% P<.004).
Conclusions
Sofosbuvir/simeprevir plus a daily flat dose of RBV 800 mg for 12 weeks was highly effective and safe in genotype 1 elderly patients with compensated cirrhosis.
To evaluate incidence rates of and predictors for any antiretroviral (ART) drug discontinuation by HCV infection status in a large Italian cohort of HIV infected patients. All patients enrolled in ...ICONA who started combination antiretroviral therapy (cART) containing abacavir or tenofovir or emtricitabine or lamivudine plus efavirenz or rilpivirine or atazanavir/r or darunavir/r (DRV/r) or lopinavir/r or dolutegravir or elvitegravir or raltegravir were included. Multivariate Poisson regression models were used to determine factors independently associated with single ART drug discontinuation. Inverse probability weighting method to control for potential informative censoring was applied. Data from 10,637 patients were analyzed and 1,030 (9.7%) were HCV-Ab positive. Overall, there were 15,464 ART discontinuations due to any reason in 82,415.9 person-years of follow-up (PYFU) for an incidence rate (IR) of 18.8 (95% confidence interval 95%CI 18.5–19.1) per 100 PYFU. No difference in IR of ART discontinuation due to any reason between HCV-infected and -uninfected patients was found. In a multivariable Poisson regression model, HCV-infected participants were at higher risk of darunavir/r discontinuation due to any reason (adjusted incidence rate ratio = 1.5, 95%CI 1.01–2.22,
p value = 0.045
) independently of demographics, HIV-related, ART and life-style factors. Among DRV/r treated patients, we found that HCV-viremic patients had twice the risk of ART discontinuation due to any reason than HCV-aviremic patients. In conclusion, HIV/HCV coinfected patients had a marginal risk increase of DRV/r discontinuation due to any reason compared with those without coinfection.
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