Antiviral Therapy

Mechanisms underlying the heightened myocardial infarction risk among HIV-infected women (versus non-HIV-infected women) remain unclear. Our objectives were to assess epicardial adipose tissue (EAT) volume and its associations among asymptomatic women with and without HIV.

A total of 55 HIV-infected and 27 non-HIV-infected women without known cardiovascular disease who underwent cardiac CT and metabolic/immune phenotyping were included. EAT volume derived from CT was compared among women with and without HIV, and within-group EAT associations were assessed. Next, immune and atherosclerotic plaque parameters were compared among groups stratified by HIV serostatus and high/low EAT (defined in reference to median EAT for each serostatus group).

Asymptomatic HIV-infected women and age-matched non-HIV-infected women with comparable mean body mass index (28 ±1 versus 29 ±1 kg/m²) had similar median (IQR) volumes of EAT (54 [41–79] versus 65 [41–78] cm³; P>0.05); however, different within-group associations were noted. Markers of monocyte activation/arterial inflammation differed by HIV serostatus/EAT volume subgroup (CXCL10 [P=0.02], sCD163 [P=0.004], sCD14 [P=0.03], Lp-PLA₂ [P=0.04]; P for overall ANOVA) and were highest among HIV-infected women with excess EAT (versus HIV-infected women without excess EAT, non-HIV-infected women with excess EAT and non-HIV-infected women without excess EAT). The percentage of segments with non-calcified coronary plaque also differed by HIV serostatus/EAT volume subgroup and was highest among HIV-infected women with excess EAT.

Asymptomatic women with and without HIV have similar volumes of EAT, but drivers of EAT may differ between groups. HIV-infected women with excess EAT have highest-level immune activation and the highest percentage of non-calcified plaque. Future studies are needed to determine whether EAT contributes pathogenetically to HIV-associated cardiovascular disease in women.

There is evidence that HIV antiretroviral therapy adverse effects may be sex-dependent, but data examining these sex differences in muscle strength is scarce. Our aim was to compare dynamic and isokinetic parameters of muscle strength between HIV-infected men and women to HIV-uninfected subjects.

In this cross-sectional study, muscle strength was evaluated in 44 HIV-infected (20 men, 24 women) and 25 age-, race- and body mass index-matched HIV-uninfected subjects (11 men, 14 women). We assessed knee flexion and extension efforts in isokinetic dynamometer at angular velocities of 60° and 180°/s, and 1 repetition maximum test (1RM) for bench press, leg press and arm curl exercises, respectively. Lean body mass (LBM) was measured using bioelectrical impedance.

HIV-infected men had significantly less dynamic muscle strength for 1RM total (262.5 versus 357.2 kg), bench press (48.6 versus 60.3 kg), leg press (182.7 versus 261 kg) and arm curl (31.2 versus 36.5 kg) compared to HIV-uninfected men (P≤0.05); no differences were found among women. Men had lower values for peak torque in extension and flexion movements at 60°/s and 180°/s, while HIV-infected women presented higher peak torque in extension movement at 60°/s compared to controls. No differences were found in LBM. Moreover, isokinetic evaluation demonstrated that HIV-infected subjects showed greater acceleration and deceleration time in some variables, compared to controls, related to difficulty in activating motor units.

HIV infection is associated with impaired dynamic and isokinetic strength in men compared to HIV-uninfected controls, but not in women.

To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART.

SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2–3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used.

We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC.

We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

High genetic variability at the reverse transcriptase (RT) region of HBV could confer resistance to nucleoside/nucleotide analogues (NUCs). The aim of this study was to identify new RT amino acid (AA) substitutions related to NUC resistance.

HBV RT sequences of genotype C from 501 chronic hepatitis B (CHB) patients were analysed to identify potential RT substitutions related to NUC resistance. In vitro studies without and with NUCs were performed in a HepG2 cell line transfected by clones with RT harbouring wild-type or substituted AA(s) of interest.

Among 261 NUC-treated CHB patients, we found a high detection rate of rtM204I/V substitution (30.7% [80/261]). We identified a new substitution of rtH55R, and its detection rate had a significantly increasing trend from 3.8% (9/240) in the untreated group to 7.2% (13/181) or 33.8% (27/80) in the treated group with rtM204 or with rtM204I/V substitutions (P<0.0001). In vitro studies showed that rtH55R had a similar HBV DNA level compared to wild type. The rtH55R+rtM204I clone had a significantly better replication capacity than the rtM204I clone without NUCs (P<0.05). The replication capacity of the rtM204I clone was found to significantly decrease under lamivudine treatment, but this was not found in the rtH55R+rtM204I clone.

We identified a new HBV RT substitution of rtH55R in genotype-C-infected CHB patients. It is frequently found in combination with rtM204I/V substitution under NUC treatment. In vitro studies suggest that it might play some replication compensatory role in rtM204I mutants under lamivudine treatment.

The tendency for haemorrhagic stroke in patients with chronic HCV infection has emerged recently but the finding may be confounded by comorbidities. Proving the causality between HCV infection and haemorrhagic stroke is mandatory. Our study was designed to investigate the incidence of intracranial haemorrhage in HCV-infected patients with and without treatment.

In the 11-year and population-based retrospective study, we acquired data from the Taiwan National Health Insurance Research Database. The patients with major comorbidities were excluded and 97,198 HCV-infected patients were included for analysis. Treated and untreated cohorts were matched with propensity score to make the confounding factors in two groups comparable. Cox proportional hazard regression analysis was performed to evaluate the hazard ratio of haemorrhagic stroke in the cohorts. We applied survival analysis to compare the cumulative incidence of outcome events between the two cohorts.

After matching, the incidence density (ID) of haemorrhagic stroke in the untreated cohort is significantly higher than in the treated cohort (ID: 1.0 versus 0.6 events per 1,000 person-years; P=0.0014). The adjusted hazard ratio (aHR) of haemorrhagic stroke is significantly reduced in the treated group (P<0.05). Cumulative incidence of haemorrhagic stroke is significantly lower in the treated group than in the untreated group (P=0.013).

The study demonstrates that antiviral therapy significantly reduces the events of intracranial haemorrhage in HCV-infected patients and consolidates the novel concept that chronic HCV infection is a risk factor for haemorrhagic stroke.

Daclatasvir (DCV; non-structural [NS]5A inhibitor) plus asunaprevir (ASV; NS3 inhibitor) plus beclabuvir (BCV; non-nucleoside NS5B inhibitor) is an approved regimen for hepatitis C virus (HCV) genotype (GT)-1 treatment in Japan. A comprehensive analysis of pre-treatment and treatment-emergent HCV resistance to this regimen ± ribavirin (RBV) was performed.

Data were pooled from five Phase 2/3 studies of DCV+ASV+BCV±RBV given for 12 weeks to GT-1a- or GT-1b-infected patients. The prevalence and impact of pre-treatment resistance-associated substitutions (RAS) in NS5A, NS3, and NS5B on sustained virological response (SVR) was assessed, as were emergent RAS and their post-treatment persistence.

Baseline NS5A RAS (GT-1a: M28T, Q30H/L/R/S, L31M, Y93C/H; GT-1b: L31I/M, Y93C/H) were present in 5% (26/561) of GT-1a and 16% (85/537) of GT-1b sequences. SVR12 for GT-1b without RBV was 100% (82/82) with RAS and >99% (427/428) without RAS. For GT-1a, SVR12 without RAS was 97% (85/88) with RBV and 92% (410/447) without RBV; SVR12 with RAS was 100% (2/2) with RBV and 54% (13/24) without RBV. Baseline NS3 (at R155 or D168) and NS5B (at P495) RAS were rare (≤1%). Treatment-emergent NS5A RAS (mostly Q30E/H/K/R+Y93H/N) in GT-1a persisted 60 weeks post-treatment, while NS3 RAS (mostly R155K) and NS5B-P495L/S were no longer detected after 48 or 24 weeks, respectively.

DCV+ASV+BCV+RBV was highly efficacious in HCV GT-1 infection, including HCV GT-1b with NS5A RAS. The fitness of treatment-emergent RAS post-treatment was NS5A > NS3 > NS5B; NS3 and NS5B RAS were generally replaced by wild-type sequence within 48 weeks.

Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection.

A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL).

Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients.

The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry.

Nucleoside/nucleotide analogue (NA) therapy could be life-saving in chronic hepatitis B (CHB) with spontaneous severe acute exacerbation (SAE). We aimed to investigate the ultra-short virological responses to NA.

We conducted a randomized controlled trial in which CHB patients with spontaneous SAE were randomized to receive lamivudine (LVD) or entecavir (ETV) between July 2012 and April 2016 (ClinicalTrials.gov: NCT01627223). The serum HBV viral loads on day 1 (baseline), 3, 5, 8, 15, 22, 29, 85 and 180 after initiating NA therapy were checked and analysed.

In total, 17 patients (7 in LVD and 10 in ETV group) were recruited, and 3 patients (17.7%) died or received liver transplantation due to hepatic failure. The median (IQR) HBV DNA decline on days 3, 5, 8, 15, 22, 29, 85 and 180 were 1.38 (1.09–1.50), 2.36 (1.89–2.58), 3.19 (2.21–3.51), 3.76 (2.54–4.40), 3.43 (2.44–4.75), 4.00 (3.01–5.04), 5.00 (3.61–6.21) and 6.50 (4.12–7.20) log IU/ml, respectively. The baseline characteristics were basically similar between the two groups, and the dynamic changes in HBV DNA were not significantly different between the two groups. Further analysis of the patients with high HBV viral load (>6 log IU/ml) revealed that a similar baseline HBV DNA level in the two groups (LVD versus ETV: median 8.0 [7.5–8.8] versus 7.7 [6.6–8.4] log IU/ml; P=0.45), and the dynamic changes of HBV DNA were very similar.

CHB with spontaneous SAE responded similarly to treatment using either LVD or ETV, with both drugs inducing a rapid decline of HBV viral load.

Roughly 15 million people worldwide have hepatitis delta, the most severe form of chronic viral hepatitis that often leads to cirrhosis and liver cancer. Injection drug users (IDUs) are the largest HDV reservoir. Their resurgence in North America and Europe may represent a new opportunity for HDV to spread more widely.

We examined all consecutive active IDUs seen for the first time and enrolled in detoxification programmes at two clinics in Spain during two periods (1993–1996 and 2011–2014, respectively). Serum markers of HIV, HBV and HDV infection were tested.

A total of 209 IDUs were examined in the first period. Mean age was 27-years-old. All had markers of past or current HBV infection. The rate of HIV-antibody (Ab), hepatitis B surface antigen (HBsAg) and HDV-Ab was as follows: 122 (58.4%), 73 (34.9%) and 62 (29.7%), respectively. Serum HDV-Ab was recognized in 53.4% of HBsAg+ and 16.9% of HBsAg- patients (P<0.001). Positivity for HDV-Ab was associated with HIV regardless HBsAg status. In the second period we tested 47 active IDUs. Anti-HDV was found in only two (4.2%), both immigrants from HDV endemic countries and with HBsAg+.

Acute HBV–HDV coinfections and self-limited HDV infections were frequent in the 1990s among IDUs in Spain, especially in HIV+ individuals. In contrast, circulation of HDV has dramatically declined among active IDUs in Spain and is currently very rare, being concentrated in foreign immigrants. It may refect the benefit of universal HBV vaccination as well as the success of needle exchange programmes in Spain.

Despite being used by more than 18 million people our understanding of the extent of the effects of antiretrovirals on the human body and other organisms remains incomplete. In addition, the direct effect of antiretrovirals on the gut microbiota of HIV-infected individuals has been largely overlooked in microbiome studies concerned with HIV-infected individuals.

Here we tested 25 antiretrovirals on Bacillus subtilis and Escherichia coli using a broth microdilution assay to assess whether these drugs have an antibacterial effect.

We found that several widely used antiretroviral drugs have in vitro antibacterial activity against both gram-positive and gram-negative commensal bacteria. Efavirenz inhibited the growth of B. subtilis with a minimum inhibitory concentration (MIC) of 16 μg/ml (in all three replicates), while 2‘,3‘-dideoxyinosine and zidovudine inhibited the growth of E. coli with an MIC of 16–32 μg/ml and 0.016–0.125 μg/ml (respectively).

Given the large and increasing number of individuals on antiretrovirals, and the lifelong nature of HIV treatment, this proof-of-concept report could have several potential implications, including an impact of antiretrovirals on bacterial coinfections, as well as potentials for drug discovery and repositioning.