Lapsing Quickly into Fatalism: Bell on Backward Causation.

This is a dialogue between Huw Price and Travis Norsen, loosely inspired by a letter that Price received from J. S. Bell in 1988. The main topic of discussion is Bell's views about retrocausal approaches to quantum theory and their relevance to contemporary issues.

Can Hepatitis C Virus (HCV) Direct-Acting Antiviral Treatment as Prevention Reverse the HCV Epidemic Among Men Who Have Sex With Men in the United Kingdom? Epidemiological and Modeling Insights.

BACKGROUND: We report on the hepatitis C virus (HCV) epidemic among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) in the United Kingdom and model its trajectory with or without scaled-up HCV direct-acting antivirals (DAAs). METHODS: A dynamic HCV transmission model among HIV-diagnosed MSM in the United Kingdom was calibrated to HCV prevalence (antibody [Ab] or RNA positive), incidence, and treatment from 2004 to 2011 among HIV-diagnosed MSM in the UK Collaborative HIV Cohort (UK CHIC). The epidemic was projected with current or scaled-up HCV treatment, with or without a 20% behavioral risk reduction. RESULTS: HCV prevalence among HIV-positive MSM in UK CHIC increased from 7.3% in 2004 to 9.9% in 2011, whereas primary incidence was flat (1.02-1.38 per 100 person-years). Over the next decade, modeling suggests 94% of infections are attributable to high-risk individuals, comprising 7% of the population. Without treatment, HCV chronic prevalence could have been 38% higher in 2015 (11.9% vs 8.6%). With current treatment and sustained virological response rates (status quo), chronic prevalence is likely to increase to 11% by 2025, but stabilize with DAA introduction in 2015. With DAA scale-up to 80% within 1 year of diagnosis (regardless of disease stage), and 20% per year thereafter, chronic prevalence could decline by 71% (to 3.2%) compared to status quo in 2025. With additional behavioral interventions, chronic prevalence could decline further to <2.5% by 2025. CONCLUSIONS: Epidemiological data and modeling suggest a continuing HCV epidemic among HIV-diagnosed MSM in the United Kingdom driven by high-risk individuals, despite high treatment rates. Substantial reductions in HCV transmission could be achieved through scale-up of DAAs and moderately effective behavioral interventions.

Biomarkers of inflammation and coagulation are associated with mortality and hepatitis flares in persons coinfected with HIV and hepatitis viruses.

BACKGROUND: Hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection with human immunodeficiency virus (HIV) has a greater risk of mortality than either HCV or HBV infection alone and is frequently associated with hepatitis flares after antiretroviral therapy (ART) initiation. METHODS: We performed a retrospective cohort study of 287 HIV-positive persons coinfected with HBV and/or HCV (70 had HBV coinfection only, 207 had HCV coninfection only, and 10 had HBV and HCV coinfections) who had pre-ART plasma samples evaluated for biomarkers associated with death (within 4 years) and/or hepatitis flare (within 4 months) after ART initiation. A predictive biomarker risk score was calculated. RESULTS: Forty-eight deaths and 50 hepatitis flares occurred. Nonsurvivors were older, had more prior AIDS-defining events, and had higher pre-ART triglycerides and aspartate transaminase levels. Detectable hyaluronic acid and higher d-dimer, interleukin 6, interleukin 8, and soluble CD14 levels were associated with death in univariate models and with a composite biomarker risk score. The risk of hepatitis flares was higher with HBV coinfection only (24.3%) and with HBV and HCV coinfection (50%) than with HCV coinfection only (13.5%). Higher levels of alanine transaminase and interleukin 10 were also associated with hepatitis flares. CONCLUSIONS: Among HIV-positive patients coinfected with HBV and/or HCV who are initiating ART, biomarkers of inflammation and coagulation are associated with an increased risk of death, whereas HBV coinfection and higher pre-ART interleukin 10 levels are associated with hepatitis flares.

Big bang, low bar-risk assessment in the public arena.

One of the basic principles of risk management is that we should always keep an eye on ways that things could go badly wrong, even if they seem unlikely. The more disastrous a potential failure, the more improbable it needs to be, before we can safely ignore it. This principle may seem obvious, but it is easily overlooked in public discourse about risk, even by well-qualified commentators who should certainly know better. The present piece is prompted by neglect of the principle in recent discussions about the potential existential risks of artificial intelligence. The failing is not peculiar to this case, but recent debates in this area provide some particularly stark examples of how easily the principle can be overlooked.

New Insights on Long-Term Hepatitis B Virus Responses in HIV-Hepatitis B virus Co-infected Patients: Implications for Antiretroviral Management in Hepatitis B virus-Endemic Settings.

BACKGROUND: WHO treatment guidelines recommend tenofovir plus lamivudine or emtricitabine as the nucleoside reverse transcriptase inhibitor backbone in first-line regimens for HIV-infected adults. Lamivudine alone is not recommended, because of the risk of hepatitis B virus (HBV) resistance. We studied HBV responses in a large cohort of co-infected patients in a resource-limited setting. SETTING: Clinical centers in Uganda and Zimbabwe. METHODS: DART was a randomized trial of monitoring practices in HIV-infected adults starting antiretroviral therapy. Baseline samples were tested retrospectively for HBV serological markers and HBV DNA. Longitudinal HBV DNA testing at 48 weeks and the last available sample before HBV-relevant modification of antiretroviral therapy was performed on patients with detectable HBV DNA at baseline. RESULTS: Two hundred twenty-four hepatitis B surface antigen-positive patients were followed for up to 4.8 years. Of the drugs with anti-HBV activity, 166 were prescribed lamivudine-tenofovir and 58 lamivudine alone. Ninety-eight percent (96/98) patients with baseline HBV DNA <6 log10 IU/mL achieved viral suppression at 48 weeks (HBV DNA <48 IU/mL), regardless of regimen, compared with 50%(26/52) for HBV DNA >6 log10 IU/mL. Of the 83 patients suppressed at 48 weeks and with follow-up data, only 7(8%) experienced viral rebound (range 200-3460 IU/mL). Of the 20 patients not suppressed at 48 weeks and with follow-up data, HBV DNA levels generally declined with lamivudine-tenofovir, but increased with lamivudine alone. Alanine transaminase flares were not observed in any patient who experienced viral rebound. CONCLUSIONS: The suppressive effect of lamivudine alone was highly durable (up to 5 years) in HIV-HBV co-infected patients with baseline HBV DNA <6 log10 IU/mL. It may be feasible to develop stratified approaches using lamivudine as the only drug with anti-HBV activity.

Prevalence of hepatitis B and hepatitis C in a UK genitourinary medicine clinic.

National guidelines state that hepatitis B and C testing should be targeted to those with risk factors. However, there is little data to support this recommendation. There is also limited data of viral hepatitis prevalence in attendees at genitourinary medicine clinics. We report the prevalence of hepatitis B infection in an unselected genitourinary medicine population, and hepatitis C directed by risk assessment including all men who have sex with men. Routinely collected clinic data from statutory returns was combined with laboratory test result data. Clinical notes of those testing positive were reviewed to determine risk factors and HIV status. HBsAg was positive in 13 (0.2%) of 6020 patients and hepatitis C Ab/Ag in 12 (1.0%) of 1153. All patients who tested positive for viral hepatitis infection had risk factors that would have prompted testing under national guidelines. Five of the 12 with positive hepatitis C Ab/Ag (0.4% of those tested) tested positive for hepatitis C RNA, indicating current infection. The prevalence of hepatitis B and C were in line with previously published data. Our results do provide support for the basis of targeted testing for viral hepatitis, as stipulated in national guidelines, in that all patients testing positive had risk factors.

Hepatitis B serological markers and plasma DNA concentrations.

OBJECTIVES: To examine hepatitis B (HBV) serological markers and plasma DNA concentrations in a large group of untreated HBV/HIV-coinfected individuals in two sub-Saharan settings. DESIGN: Baseline analysis of a randomized controlled trial. METHODS: DART was a large trial of treatment monitoring practices in HIV-infected adults with advanced disease starting antiretroviral therapy at centres in Kampala or Entebbe, Uganda (n = 2317) and Harare, Zimbabwe (n = 999). HBV serological markers [antibody to HBV core antigen, HBV surface antigen (HBsAg), antibody to HBV surface antigen, HBV 'e' antigen (HBeAg), and antibody to hepatitis B 'e' antigen] and plasma HBV DNA viral load were measured retrospectively on stored baseline samples. Logistic regression was used to examine associations with baseline demographic and clinical factors. RESULTS: The rate of HBsAg positivity was significantly higher in Zimbabwe than Uganda (12.2 vs. 7.7%, adjusted odds ratio = 1.54, P < 0.001) despite a similar prevalence of antibody to HBV core antigen (56.3 vs. 52.4%) in the two settings. Overall, HBsAg positivity was associated with male sex (adjusted odds ratio = 1.54, P < 0.001) but not with age, WHO disease stage, or CD4 cell count. HBeAg was detected among 37% of HBsAg-positive patients, with higher rates among those with advanced WHO stage (P = 0.02). Also in HBsAg-positive patients, HBV DNA was undetectable in 21%, detectable but below the level of quantification in 14%, and quantifiable in 65%. A total of 96% of HBeAg-positive and 70% of HBeAg-negative patients had detectable HBV DNA; 92 and 28% of patients, respectively, had HBV DNA viral load more than 2000 IU/ml. CONCLUSION: High rates of HBV coinfection were observed, highlighting the importance of ensuring that coinfected patients receive an antiretroviral regimen, whether first-line or not, that is active against both viruses.

Biochemical markers for post-operative fatigue after major surgery.

OBJECTIVE: To establish a link between tryptophan (a precursor for 5-hydroxytryptamine (5-HT) or serotonin, involved in sleep and fatigue) and post-operative fatigue after major surgery. BACKGROUND: There is a link between tryptophan (the precursor for the neurotransmitter 5-hydroxytryptamine), and its competitive binding with non-esterified fatty acids (NEFA) to albumin in the blood. An increase in the plasma concentration of free tryptophan can lead to an increased rate of synthesis of 5-HT in the brain. Free tryptophan competes with the branched chain amino acids (BCAA) for the same port of entry across the blood-brain barrier. It is suggested that the plasma concentration of these amino acids could be a marker of post-operative fatigue. In a previous study undertaken in this laboratory on patients undergoing two different types of major surgery, similar post-operative increases were observed in the plasma concentration of free tryptophan and the plasma concentration ratio of free tryptophan to branched chain amino acids. However, the study was retrospective and no measure of fatigue had been made. METHODS: In the present study, this deficiency has been addressed by administering a modified Profile of Mood States questionnaire to patients undergoing reconstructive or colorectal surgery. In addition, blood samples were measured for plasma free tryptophan, albumin, NEFA and branched chain amino acids before and on 2 days after surgery. RESULTS: There was a significant correlation between fatigue scores and plasma free tryptophan (P<0.000), and the plasma concentration ratio of free tryptophan/BCAA (P<0.016) after surgery in all the patients studied (n=34). This correlation was more marked in the colorectal-surgery patients, in whom surgery was more severe. In the three categories of patients receiving elective reconstructive surgery (n=24), those having breast reductions (n=6) had a lower plasma concentration of NEFA and appeared to recover from fatigue more quickly than those with pre-tibial lacerations or malignant melanoma. CONCLUSIONS: These data provide further evidence of a possible biochemical mechanism for central fatigue which involves a precursor of 5-HT. The provision of branched chain amino acids may help to combat the surge in free tryptophan that occurs during stress such as major surgery.

Systematic review and meta-analysis of L1-VLP-based human papillomavirus vaccine efficacy against anogenital pre-cancer in women with evidence of prior HPV exposure.

BACKGROUND: It is unclear whether L1-VLP-based human papillomavirus (HPV) vaccines are efficacious in reducing the likelihood of anogenital pre-cancer in women with evidence of prior vaccine-type HPV exposure. This study aims to determine whether the combined results of the vaccine trials published to date provide evidence of efficacy compared with control (hepatitis A vaccine/placebo). METHODS: A systematic review and meta-analysis was conducted. Randomized-controlled trials (RCTs) were identified from MEDLINE, Embase, Web of Science, PubMed, Cochrane Central Register of Controlled Trials and references of identified studies. The bivalent vaccine containing HPV-16 and 18 VLPs from GlaxoSmithKline Biologicals (Rixenstart, Belgium), the quadrivalent vaccine containing HPV-6, 11, 16, and 18 VLPs from Merck & Co., Inc., (Whitehouse Station, NJ USA), and the HPV-16 monovalent vaccine from Merck Research Laboratories (West Point, PA USA) were evaluated. FINDINGS: Three RCT reports and two post-trial cohort studies were eligible, comprising data from 13,482 women who were included in the vaccine studies but had evidence of HPV infection at study entry. Data on efficacy was synthesized using the Mantel-Haenszel weighted fixed-effect approach, or where there was heterogeneity between studies, the DerSimonian and Laird weighted random-effect approach. The mean odds ratio (OR) and 95% confidence interval (CI) for the association between Cervarix, Gardasil and HPV-16 monovalent vaccine and HPV-associated cervical intraepithelial neoplasia grade 3 or worse was 0·90 (95% CI: 0·56, 1·44). For the association between Gardasil and HPV-associated vulval/vaginal intraepithelial neoplasia grades 2-3, the overall OR and 95% CI was 2.25 (95% CI: 0·78, 6.50). Sample size and follow-up were limited. CONCLUSIONS: There was no evidence that HPV vaccines are effective in preventing vaccine-type HPV associated pre-cancer in women with evidence of prior HPV exposure. Small effects of vaccination however cannot be excluded and a longer-term benefit in preventing re-infection remains possible.

Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic review and meta-analysis.

BACKGROUND: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. METHODS: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. RESULTS: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. INTERPRETATION: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone.

Hepatitis B virus infection in HIV-positive individuals in the UK collaborative HIV cohort (UK CHIC) study.

BACKGROUND: Hepatitis B virus (HBV) infection is an increasingly important cause of morbidity and mortality in HIV-infected adults. This study aimed to determine the prevalence and incidence of HBV in the UK CHIC Study, a multicentre observational cohort. METHODS AND FINDINGS: 12 HIV treatment centres were included. Of 37,331 patients, 27,450 had at least one test (HBsAg, anti-HBs or anti-HBc) result post-1996 available. 16,043 were white, 8,130 black and 3,277 other ethnicity. Route of exposure was homosexual sex 15,223 males, heterosexual sex 3,258 males and 5,384 females, injecting drug use 862 and other 2,723. The main outcome measures used were the cumulative prevalence and the incidence of HBV coinfection. HBV susceptible patients were followed up until HBsAg and/or anti-HBc seroconversion incident infection, evidence of vaccination or last visit. Poisson regression was used to determine associated factors. 25,973 had at least one HBsAg test result. Participants with HBsAg results were typically MSM (57%) and white (59%) (similar to the cohort as a whole). The cumulative prevalence of detectable HBsAg was 6.9% (6.6 to 7.2%). Among the 3,379 initially HBV-susceptible patients, the incidence of HBV infection was 1.7 (1.5 to 1.9)/100 person-years. Factors associated with incident infection were older age and IDU. The main limitation of the study was that 30% of participants did not have any HBsAg results available. However baseline characteristics of those with results did not differ from those of the whole cohort. Efforts are on-going to improve data collection. CONCLUSIONS: The prevalence of HBV in UK CHIC is in line with estimates from other studies and low by international standards. Incident infection continued to occur even after entry to the cohort, emphasising the need to ensure early vaccination.

Positive and negative drug selection pressures on the N348I connection domain mutation: new insights from in vivo data.

BACKGROUND: There is conflicting evidence on specific reverse transcriptase inhibitors to which the N348I mutation in the connection domain of HIV type-1 reverse transcriptase confers resistance. Here, we examined associations between the emergence of N348I and antiretroviral history in a large clinical database. METHODS: We analysed 5,353 resistance tests (that were sequenced beyond codon 348) among 2,266 antiretroviral-experienced patients. Associations between N348I and individual antiretroviral drug exposure were estimated using a matched case-control approach. Cases were defined as the first resistance test where N348I was detected; for each case, the 10 closest (in calendar time) N348N tests were selected as controls. Odds ratios (ORs) adjusted for effects of all other drugs were estimated by conditional logistic regression. RESULTS: N348I was detected in 198 (8.7%) cases. Drugs that were statistically significantly positively associated with N348I were efavirenz (OR 1.55, 95% confidence interval [CI] 1.08-2.23; P=0.017) and nevirapine (OR 2.06, 95% CI 1.49-2.85; P<0.001). Tenofovir disoproxil fumarate (TDF) was significantly negatively associated (OR 0.27, 95% CI 0.15-0.48; P<0.001) with N348I. Similar findings were observed when the analysis was repeated to include only those tests within 2 years of the resistance test. Effects for zidovudine and stavudine were evident only in an additional analysis, which considered exposure to both drugs jointly within 2 years prior to the resistance test: exposure to zidovudine alone (OR 4.61, 95% CI 1.83-11.61; P<0.001) and exposure to stavudine alone (OR 3.39, 95% CI 1.32-8.71; P=0.011). CONCLUSIONS: This is the first clinical evidence to suggest that efavirenz might select for N348I in addition to nevirapine, that stavudine might select for N348I in addition to zidovudine and that TDF might protect against the mutation.