Predictors of liver disease progression in people living with HIV-HBV co-infection on antiretroviral therapy.

BACKGROUND: In people living with HIV-HBV, liver fibrosis progression can occur even with suppressive antiretroviral therapy (ART). We investigated the relationship between liver fibrosis and biomarkers of inflammation, apoptosis, and microbial translocation. METHODS: In this observational cohort study adults living with HIV-HBV already on effective ART were recruited in Australia and Thailand and followed for 3 years including 6 monthly clinical review and blood tests and annual transient elastography. Differences in clinical and laboratory predictors of liver fibrosis progression were tested followed by regression analysis adjusted for CD4+ T-cells at study entry. A linear mixed model was fitted to longitudinal data to explore changes over time. FINDINGS: 67 participants (85% male, median age 49 y) were followed for 175 person-years. Median duration of ART was 10 years (interquartile range (IQR) 8-16 years). We found 11/59 (19%) participants during 3-years follow-up (6/100 person-years) met the primary endpoint of liver disease progression, defined as increased Metavir stage from baseline to final scan. In regression analysis, progressors compared to non-progressors had higher levels of high mobility group box 1 protein (HGMB1), (median (IQR) 3.7 (2.6-5.0) and 2.4 ng/mL (1.5-3.4) respectively, adjusted relative risk 1.47, 95% CI [1.00, 2.17]) and lower nadir CD4+ T-cell percentage (median 4% (IQR 2-8) and 11% (4-15) respectively (relative risk 0.93, 95% CI [0.88, 0.98]). INTERPRETATION: Progression in liver fibrosis occurs in people with HIV-HBV on suppressive ART. Fibrosis progression was associated with higher HMGB1 and lower percentage nadir CD4+ T-cell count, highlighting the importance of early initiation of HBV-active ART. FUNDING: This work was supported by NHMRC project grant 1101836; NHMRC practitioner fellowship 1138581 and NHMRC program grant 1149990. The funder had no role in study design, data collection, data analysis, interpretation, writing of this manuscript or decision to submit for publication.

Drivers and barriers to COVID-19 vaccination in Australians with cancer.

PURPOSE: To understand the drivers and barriers for COVID-19 vaccination in people with cancer in Australia. METHODS: A cross-sectional, online survey, distributed nationally following the establishment of community vaccination programs, wider availability of COVID-19 vaccines and emergence of new variants. Consisting of 21 questions, the survey was designed to determine the behavioural and social drivers of vaccination, participant demographics, underlying disease and treatment, and vaccination status. It was open from the 10th of August 2021 to the 7th of September 2021, recruiting people who had a previous history of cancer (diagnosed or treated in the past 5 years). RESULTS: A total of 1506 responses were included in the final analysis. Overall, 87.8% reported a positive attitude toward vaccination and 83.1% had received at least one dose of a COVID-19 vaccine. Perceived risk of COVID-19 infection (for self and others) and engagement with a trusted health professional were key drivers for vaccination, while concerns about vaccine development, safety and side effects were barriers. Concerns about vaccination mostly stemmed from a place of misinformation, rather than a broader disregard of vaccines. Just over a third (497, 34.3%) of the respondents were concerned that the vaccine would impact their cancer treatment. CONCLUSION: Overall, participants had positive attitudes toward COVID-19 vaccination and thought it was safe. Findings supported the role of health professionals and cancer organisations as trusted information providers and calls for more, credible information to help people with cancer make informed decisions about the COVID-19 vaccine.

Robust SARS-CoV-2 T cell responses with common TCRαß motifs toward COVID-19 vaccines in patients with hematological malignancy impacting B cells.

Immunocompromised hematology patients are vulnerable to severe COVID-19 and respond poorly to vaccination. Relative deficits in immunity are, however, unclear, especially after 3 vaccine doses. We evaluated immune responses in hematology patients across three COVID-19 vaccination doses. Seropositivity was low after a first dose of BNT162b2 and ChAdOx1 (∼26%), increased to 59%-75% after a second dose, and increased to 85% after a third dose. While prototypical antibody-secreting cells (ASCs) and T follicular helper (Tfh) cell responses were elicited in healthy participants, hematology patients showed prolonged ASCs and skewed Tfh2/17 responses. Importantly, vaccine-induced expansions of spike-specific and peptide-HLA tetramer-specific CD4+/CD8+ T cells, together with their T cell receptor (TCR) repertoires, were robust in hematology patients, irrespective of B cell numbers, and comparable to healthy participants. Vaccinated patients with breakthrough infections developed higher antibody responses, while T cell responses were comparable to healthy groups. COVID-19 vaccination induces robust T cell immunity in hematology patients of varying diseases and treatments irrespective of B cell numbers and antibody response.

HIV DNA persists in hepatocytes in people with HIV-hepatitis B co-infection on antiretroviral therapy.

BACKGROUND: HIV can infect multiple cells in the liver including hepatocytes, Kupffer cells and infiltrating T cells, but whether HIV can persist in the liver in people with HIV (PWH) on suppressive antiretroviral therapy (ART) remains unknown. METHODS: In a prospective longitudinal cohort of PWH and hepatitis B virus (HBV) co-infection living in Bangkok, Thailand, we collected blood and liver biopsies from 18 participants prior to and following ART and quantified HIV and HBV persistence using quantitative (q)PCR and RNA/DNAscope. Antiretroviral (ARV) drug levels were quantified using mass spectroscopy. FINDINGS: In liver biopsies taken prior to ART, HIV DNA and HIV RNA were detected by qPCR in 53% (9/17) and 47% (8/17) of participants respectively. Following a median ART duration of 3.4 years, HIV DNA was detected in liver in 61% (11/18) of participants by either qPCR, DNAscope or both, but only at very low and non-quantifiable levels. Using immunohistochemistry, HIV DNA was observed in both hepatocytes and liver infiltrating CD4+ T cells on ART. HIV RNA was not detected in liver biopsies collected on ART, by either qPCR or RNAscope. All ARVs were clearly detected in liver tissue. INTERPRETATION: Persistence of HIV DNA in liver in PWH on ART represents an additional reservoir that warrants further investigation. FUNDING: National Health and Medical Research Council of Australia (Project Grant APP1101836, 1149990, and 1135851); This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024.

Pro-fibrogenic role of alarmin high mobility group box 1 in HIV-hepatitis B virus coinfection.

OBJECTIVE: Liver disease is accelerated in people with HIV (PWH) with hepatitis B virus (HBV) coinfection. We hypothesized that liver fibrosis in HIV-HBV is triggered by increased hepatocyte apoptosis, microbial translocation and/or HIV/HBV viral products. DESIGN: Sera from PWH with HBV coinfection versus from those with HBV only or putative mediators were used to examine the pathogenesis of liver disease in HIV-HBV. METHODS: We applied sera from PWH and HBV coinfection versus HBV alone, or putative mediators (including HMGB1), to primary human hepatic stellate cells (hHSC) and examined pro-fibrogenic changes at the single cell level using flow cytometry. High mobility group box 1 (HMGB1) levels in the applied sera were assessed according to donor fibrosis stage. RESULTS: Quantitative flow cytometric assessment of pro-fibrogenic and inflammatory changes at the single cell level revealed an enhanced capacity for sera from PWH with HBV coinfection to activate hHSC. This effect was recapitulated by lipopolysaccharide, HIV-gp120, hepatocyte conditioned-media and the alarmin HMGB1. Induction of hepatocyte cell death increased their pro-fibrogenic potential, an effect blocked by HMGB1 antagonist glycyrrhizic acid. Consistent with a role for this alarmin, HMGB1 levels were elevated in sera from PWH and hepatitis B coinfection compared to HBV alone and higher in those with HIV-HBV with liver fibrosis compared to those without. CONCLUSIONS: Sera from PWH and HBV coinfection have an enhanced capacity to activate primary hHSC. We identified an increase in circulating HMGB1 which, in addition to HIV-gp120 and translocated microbial products, drove pro-fibrogenic changes in hHSC, as mechanisms contributing to accelerated liver disease in HIV-HBV.

Circulating BAFF and CXCL10 levels predict response to pegylated interferon in patients with HBeAg-positive chronic hepatitis B.

BACKGROUND: B-cell activating factor (BAFF), an essential cytokine for B lymphocytes activation, has been implicated in the pathogenesis of chronic viral hepatitis. However, the role of BAFF in patients with chronic hepatitis B (CHB) undergoing antiviral therapy is unknown. METHODS: Patients with HBeAg-positive CHB treated with 48-week pegylated interferon (PEG-IFN; n = 42), who had stored plasma samples during treatment were recruited. Serial plasma levels of BAFF and C-X-C motif chemokine 10 (CXCL10) during therapy were measured. RESULTS: Combined response (CR), defined as HBeAg seroconversion with HBV DNA < 2,000 IU/mL plus HBsAg decline ≥ 1 log10 IU/mL at 24 weeks post-treatment, was achieved in 11 (26.2%) patients. BAFF levels were elevated during treatment but decreased to pre-treatment levels after PEG-IFN cessation in both responders and non-responders. Low baseline BAFF (< 770 pg/ml) and high CXCL10 (≥ 320 pg/ml) levels were independently associated with CR in multivariate analysis. Baseline CXCL10/BAFF ratio of ≥ 0.45 was predictive of CR with positive and negative predictive values of 61.5 and 89.7%, respectively. CONCLUSIONS: In summary, low baseline BAFF and high CXCL10 levels were associated with treatment response to PEGIFN. The combined measurement of these immune markers may help individualized decision-making in patients with HBeAg-positive CHB.

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

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.

Impact of a hospital-wide sepsis pathway on improved quality of care and clinical outcomes in surgical patients at a comprehensive cancer centre.

PURPOSE: Sepsis is a significant complication following cancer surgery. Although standardised care bundles improve sepsis outcomes in other populations, the benefits in cancer patients are unclear. The objectives of this study were to describe the epidemiology of sepsis in cancer patients post-surgery, and to evaluate the impact of a clinical sepsis pathway on management and clinical outcomes. METHODS: A standardised hospital-wide sepsis pathway was developed in 2013, and all cases of sepsis at the Peter MacCallum Cancer Centre in 2014 were retrospectively evaluated. Inclusion criteria were sepsis onset during the 100-day period following a surgical procedure for cancer diagnosis. Patients were identified using ICD-10-AM sepsis discharge codes, audit documentation and the hospital's antimicrobial approval system. Sepsis episodes were classified as managed on- or off-pathway. RESULTS: A total of 119 sepsis episodes were identified. Of these, 71 (59.7%) were managed on the sepsis pathway. Episodes managed on-pathway resulted more frequently in administration of appropriate antibiotics compared to those off-pathway (94.4% vs. 66.7%, p < 0.001), and had shorter time to first-dose antibiotics (median 85 vs. 315 min, p < 0.001). Pathway utilisation was associated with significant reductions in need for inotropes (7% vs. 13%, p = 0.023), ventilation (3% vs. 10%, p = 0.006) and length of hospitalisation (median 15 vs. 30 days, p = 0.008). The most frequent source of infection was organ-space surgical site infection (24.4% of instances). CONCLUSIONS: A dedicated hospital-wide sepsis pathway had significant impact on the quality of care and clinical outcomes of sepsis in cancer surgery patients. Cost-benefit analysis of sepsis pathways for cancer patients is required.

Messy eaters: Swabbing prey DNA from the exterior of inconspicuous predators when foraging cannot be observed.

Complex coevolutionary relationships among competitors, predators, and prey have shaped taxa diversity, life history strategies, and even the avian migratory patterns we see today. Consequently, accurate documentation of prey selection is often critical for understanding these ecological and evolutionary processes. Conventional diet study methods lack the ability to document the diet of inconspicuous or difficult-to-study predators, such as those with large home ranges and those that move vast distances over short amounts of time, leaving gaps in our knowledge of trophic interactions in many systems. Migratory raptors represent one such group of predators where detailed diet studies have been logistically challenging. To address knowledge gaps in the foraging ecology of migrant raptors and provide a broadly applicable tool for the study of enigmatic predators, we developed a minimally invasive method to collect dietary information by swabbing beaks and talons of raptors to collect trace prey DNA. Using previously published COI primers, we were able to isolate and reference gene sequences in an open-access barcode database to identify prey to species. This method creates a novel avenue to use trace molecular evidence to study prey selection of migrating raptors and will ultimately lead to a better understanding of raptor migration ecology. In addition, this technique has broad applicability and can be used with any wildlife species where even trace amounts of prey debris remain on the exterior of the predator after feeding.

Surgical Simulation: Markers of Proficiency.

OBJECTIVE: Surgical simulation has become an integral component of surgical training. Simulation proficiency determination has been traditionally based upon time to completion of various simulated tasks. We aimed to determine objective markers of proficiency in surgical simulation by comparing novel assessments with conventional evaluations of technical skill. DESIGN: Categorical general surgery residents completed 10 laparoscopic cholecystectomy modules using a high-fidelity simulator. We recorded and analyzed simulation task times, as well as number of hand movements, instrument path length, instrument acceleration, and participant affective engagement during each simulation. Comparisons were made to Objective Structured Assessment of Technical Skill (OSATS) and Accreditation Council for Graduate Medical Education Milestones, as well as previous laparoscopic experience, duration of laparoscopic cholecystectomies performed by participants, and postgraduate year. Comparisons were also made to Fundamentals of Laparoscopic Surgery task times. Spearman's rho was utilized for comparisons, significance set at >0.50. SETTING: University of Missouri, Columbia, Missouri, an academic tertiary care facility. PARTICIPANTS: Fourteen categorical general surgery residents (postgraduate year 1-5) were prospectively enrolled. RESULTS: One hundred forty simulations were included. The number of hand movements and instrument path lengths strongly correlated with simulation task times (ρ 0.62-0.87, p < 0.0001), FLS task completion times (ρ 0.50-0.53, p < 0.0001), and prior real-world laparoscopic cholecystectomy experience (ρ -0.51 to -0.53, p < 0.0001). No significant correlations were identified between any of the studied markers with Accreditation Council for Graduate Medical Education Milestones, Objective Structured Assessment of Technical Skill evaluations, total previous laparoscopic experience, or postgraduate year level. Neither instrument acceleration nor participant engagement showed significant correlation with any of the conventional markers of real-world or simulation skill proficiency. CONCLUSIONS: Simulation proficiency, measured by instrument and hand motion, is more representative of simulation skill than simulation task time, instrument acceleration, or participant engagement.

Case Difficulty, Postgraduate Year, and Resident Surgeon Stress: Effects on Operative Times.

OBJECTIVE: We aimed to evaluate resident operative times in relation to postgraduate year (PGY), case difficulty and resident stress while performing a single surgical procedure. DESIGN: We prospectively examined operative times for 268 laparoscopic cholecystectomies, and analyzed relationships between PGY, case difficulty, and resident surgeon stress utilizing electrodermal activity. Each case operative times were divided into 3 separate time periods. Case Start and End times were recorded, as well as the time between the start of the operation and the time until the cystic structures were divided (Division). Case difficulty was determined by multiple trained observers with a high inter-rater concordance. SETTING: University of Missouri, a tertiary academic medical institution. PARTICIPANTS: All categorical general surgery residents at our institution. RESULTS: For each operative time period examined during laparoscopic cholecystectomy, operative time increased, with each incremental increase in difficulty resulting in approximately 130% longer times. Minimal differences in operative times were seen between PGY levels, except during the easiest cases (Start-End times: 38.5 ± 10.4 minutes vs 34.2 ± 10.8 minutes vs 28.9 ± 10.9 minutes, p 0.002). Resident stress poorly correlated with operative times regardless of case difficulty (Pearson coefficient range 0.0-0.22). CONCLUSIONS: Operative times are longer with increasing case difficulty. PGY level and resident surgeon stress appear to have minimal to no correlation with operative times, regardless of case difficulty.

Surgical resident technical skill self-evaluation: increased precision with training progression.

BACKGROUND: Surgical resident ability to accurately evaluate one's own skill level is an important part of educational growth. We aimed to determine if differences exist between self and observer technical skill evaluation of surgical residents performing a single procedure. MATERIALS AND METHODS: We prospectively enrolled 14 categorical general surgery residents (six post-graduate year [PGY] 1-2, three PGY 3, and five PGY 4-5). Over a 6-month period, following each laparoscopic cholecystectomy, residents and seven faculty each completed the Objective Structured Assessment of Technical Skills (OSATS). Spearman's coefficient was calculated for three groups: senior (PGY 4-5), PGY3, and junior (PGY 1-2). Rho (ρ) values greater than 0.8 were considered well correlated. RESULTS: Of the 125 paired assessments (resident-faculty each evaluating the same case), 58 were completed for senior residents, 54 for PGY3 residents, and 13 for junior residents. Using the mean from all OSATS categories, trainee self-evaluations correlated well to faculty (senior ρ 0.97, PGY3 ρ 0.9, junior ρ 0.9). When specific OSATS categories were analyzed, junior residents exhibited poor correlation in categories of respect for tissue (ρ -0.5), instrument handling (ρ 0.71), operative flow (ρ 0.41), use of assistants (ρ 0.05), procedural knowledge (ρ 0.32), and overall comfort with the procedure (ρ 0.73). PGY3 residents lacked correlation in two OSATS categories, operative flow (ρ 0.7) and procedural knowledge (ρ 0.2). Senior resident self-evaluations exhibited strong correlations to observers in all areas. CONCLUSIONS: Surgical residents improve technical skill self-awareness with progressive training. Less-experienced trainees have a tendency to over-or-underestimate technical skill.

Repository corticotropin injection as adjunctive therapy in patients with rheumatoid arthritis who have failed previous therapies with at least three different modes of action.

OBJECTIVE: Many types of treatment are available for patients with rheumatoid arthritis (RA), however, some patients fail to achieve remission. This report aims to determine the safety and efficacy of using repository corticotropin injection (RCI) as an adjunctive therapy in patients with RA refractory to at least three therapeutics with different mechanisms of action. METHOD: In this open-label, interventional, single-group study, patients received 80 U RCI twice weekly via subcutaneous injection over 12 weeks. Changes in the Ritchie-Camp Articular Index and health assessment questionnaire scores were monitored for changes from baseline measures. RESULTS: Eight patients were enrolled and consisted of seven females and one male with an average age of 64.6 years and disease duration of 20.9 years. Use of RCI resulted in significant improvement in swollen and tender joint counts. The disease activity score 28 and the physician and patient visual analog scale scores were significantly reduced at treatment week 12. The reduction in health assessment questionnaire scores did not reach statistical significance after RCI treatment. Once RCI therapy was discontinued, all improvements in disease activity score 28, physician and patient visual analog scale, and tender and swollen joint counts achieved during treatment were lost by the week 16 follow-up visit. CONCLUSION: While larger clinical trials are necessary to further confirm the efficacy of RCI in patients with refractory RA, the response of patients with refractory RA in this study suggests that RCI can be an effective add-on therapy for patients who have exhausted several classes of treatments. Furthermore, this study suggests that RCI has an alternative mode of action, compared to other available antirheumatic drugs.

HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment.

: HIV infection has a significant impact on the natural history of chronic hepatitis B virus (HBV) infection, with increased levels of HBV DNA, accelerated progression of liver disease and increased liver-associated mortality compared with HBV monoinfection. Widespread uptake and early initiation of HBV-active antiretroviral therapy has substantially improved the natural history of HIV-HBV coinfection but the prevalence of liver disease remains elevated in this population. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease and seroconversion in HIV-HBV coinfection in the era of HBV-active antiretroviral therapy and the effects of HIV directly on liver disease. We also review novel therapeutics for the management of HBV with a particular emphasis on clinical strategies being developed for an HBV cure and an HIV cure and their impact on HIV-HBV coinfected individuals.

Objective Measurement of Clinical Competency in Surgical Education Using Electrodermal Activity.

OBJECTIVE: Within the realm of surgical education, there is a need for objective means to determine surgical competence and resident readiness to operate independently. We propose a novel, objective method of assessing resident confidence and clinical competence based on measurement of electrodermal activity (EDA) during live surgical procedures. We hypothesized that with progressive training, EDA responses to the stress of performing surgery would exhibit decline, elucidating an objective correlate of clinical competence. DESIGN: EDA was measured using galvanic skin response sensors worn by residents performing laparoscopic cholecystectomy on sequential live human patients over an 8-month period. Baseline, phasic (peak) and tonic EDA responses were measured as a fractional change from baseline. SETTING: University of Missouri, Columbia, Missouri, an academic tertiary care facility. PARTICIPANTS: Fourteen categorical general surgery residents and 5 faculty surgeons were voluntarily enrolled and participated through completion. RESULTS: Tonic fractional change (FCTONIC) was highest in PGY3 residents compared with postgraduate year (PGY) 1 and 2 residents (7.199 vs. 2.100, p = 0.004, 95% CI: 8.58-1.61 and PGY4 and 5 residents (7.199 vs. 2.079, p = 0.002, 95% CI: 8.38-0.29). Phasic fractional change in EDA (FCPHASIC) exhibited a progressive decline across resident training levels, with PGY1 and 2 residents having the highest response, and faculty displaying the lowest FCPHASIC responses. Statistical differences were seen between FCPHASIC faculty and PGY4 and 5 (3.596 vs. 6.180, p = 0.004, 95% CI: 0.80-4.36), PGY4 and 5, and PGY3 (6.180 vs. 15.998, p = 0.003, 95% CI: 3.33-16.3), as well as among all residents and faculty (13.057 vs. 3.596, p = 0.004, 95% CI: 15.8-3.1). CONCLUSION: Phasic EDA changes decrease with increasing clinical competence. For those participants with the lowest and highest levels of competence, tonic EDA changes are minimal. Tonic EDA changes follow an inverse-U shape with differing levels of clinical competence.

Lipopolysaccharide, immune activation, and liver abnormalities in HIV/hepatitis B virus (HBV)-coinfected individuals receiving HBV-active combination antiretroviral therapy.

We investigated the relationship between microbial translocation, immune activation, and liver disease in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection. Lipopolysaccharide (LPS), soluble CD14, CXCL10, and CCL-2 levels were elevated in patients with HIV/HBV coinfection. Levels of LPS, soluble CD14, and CCL-2 declined following receipt of HBV-active combination antiretroviral therapy (cART), but the CXCL10 level remained elevated. No markers were associated with liver disease severity on liver biopsy (n = 96), but CXCL10, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α, and interferon γ (IFN-γ) were all associated with elevated liver enzyme levels during receipt of HBV-active cART. Stimulation of hepatocyte cell lines in vitro with IFN-γ and LPS induced a profound synergistic increase in the production of CXCL10. LPS may contribute to liver disease via stimulating persistent production of CXCL10.

CXCL-10, interleukin-12 and interleukin-21 are not immunological predictors of HBeAg seroconversion in HIV-1-HBV coinfection following HBV-active antiretroviral therapy.

BACKGROUND: Interferon stimulated chemokine CXCL-10, interleukin (IL)-12 (p70) and IL-21 have been associated with HBsAg and HBeAg loss following treatment of HBV monoinfection. The aim of this study was to determine whether these factors were also associated with HBsAg and HBeAg loss in HIV-HBV-coinfected patients following HBV-active combination antiretroviral therapy (cART). METHODS: HIV-HBV-coinfected patients with HBeAg seroconversion (n=12; seroconverters [SC]) were compared to patients who did not seroconvert (n=13; non-seroconverters [NSC]). CXCL-10, IL-12 and IL-21 (Luminex Bead Array, Life Technologies, Grand Island, NY, USA) were measured in plasma prior to initiation of HBV-active cART (baseline), at the time of seroconversion (T0) and at the closest time point before (T-1) and after (T+1) seroconversion. RESULTS: Levels of CXCL-10 declined significantly in all patients following HBV-active cART (P<0.05 for both SC and NSC; Kruskall-Wallis, Dunn's post-test). There was no difference between SC and NSC in the level of CXCL-10, IL-12 and IL-21 at any time point. CONCLUSIONS: We found no evidence that CXCL-10, IL-12 or IL-21 were associated with HBeAg seroconversion following HBV-active cART. Other immunological determinants should be explored in this setting.

HIV and co-infections.

Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti-retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub-Saharan Africa where rates of opportunistic co-infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV-infected patients globally. These include co-infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co-infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co-infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co-infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.

Human immunodeficiency virus infection and the liver.

Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non-alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries.