Monocyte phenotype and extracellular vesicles in HIV-1, HIV-2, and HIV-1/2 dual infection.

OBJECTIVE: AIDS-defining illness develops at higher CD4 + T-cell counts in individuals infected with HIV-2 compared with HIV-1-infected, which suggests that the two types of HIV may have different effects on other compartments of the immune system. We here investigate monocyte phenotype, activation and macrophage-derived extracellular vesicles in individuals with different HIV types. DESIGN: Cross-sectional. METHODS: ART-naive HIV-1 ( n  = 83), HIV-2 ( n  = 63), and HIV-1/2 dually positive ( n  = 27) participants were recruited in Bissau, Guinea-Bissau, together with HIV-negative controls ( n  = 26). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for monocyte phenotype and activation, and plasma was analyzed for extracellular vesicle forms of CD163 and CD206. RESULTS: Compared with HIV-negative controls, all groups of HIV-positive participants had a skewed monocyte phenotype with a higher proportion of intermediate monocytes, increased CD163 expression and elevated serum levels of the inflammatory biomarkers soluble (s)CD163 and sCD206. HIV-2-positive participants had lower CD163 monocyte expression than HIV-1-positive participants, regardless of HIV RNA or CD4 + cell count. Levels of sCD206 extracellular vesicles were increased in all HIV groups, and higher in HIV-1 compared with HIV-2-positive participants. CONCLUSION: The monocyte phenotype of HIV-2-positive participants deviated less from healthy controls than did HIV-1 participants. HIV-2-positive participants also had a lower concentration of extracellular CD206 vesicles compared with HIV-1-positive participants. This does not explain the difference in AIDS development.

Kidney transplantation from an HIV-positive deceased donor to an HIV-positive recipient.

Preliminary data on HIV-positive donor to HIV-positive recipient kidney transplantation suggest promising patient outcomes without adverse events. This is an important step in expanding the donor pool and opportunity for transplantation in HIV-positive patients.We herein report the first case of HIV-positive donor to HIV-positive recipient kidney transplantation in Denmark. Our patient has demonstrated a successful post-transplant course with excellent 1-year graft function, no rejection episodes, good virological control with undetectable HIV RNA, no signs of HIV-associated nephropathy, and no superinfections or opportunistic infections.This case corroborates findings from previous studies showing that kidney transplantation from carefully selected HIV-infected donors to carefully selected HIV-infected recipients seems to be a safe and effective treatment option, and supports the opportunity to expand the organ donor pool for this group of patients with end-stage renal disease.

Incidence of Hepatocellular Carcinoma and Decompensated Liver Cirrhosis and Prognostic Accuracy of the PAGE-B HCC Risk Score in a Low Endemic Hepatitis B Virus Infected Population.

Purpose: We aimed to determine incidence of hepatocellular carcinoma (HCC) and decompensated liver cirrhosis in persons with chronic hepatitis B virus (HBV) infection in Denmark stratified by disease phase, liver cirrhosis, and treatment status at baseline. Additionally, we aimed to assess the prognostic value of the PAGE-B HCC risk score in a mainly non-cirrhotic population. Patients and Methods: In this register-based cohort study, we included all individuals over the age of 18, with chronic HBV infection first registered between 2002 and 2016 in at least one of three nationwide registers. The study population was followed until HCC, decompensated liver cirrhosis, death, emigration, or December 31, 2017, which ever came first. Results: Among 6016 individuals included in the study, 10 individuals with and 23 without baseline liver cirrhosis developed HCC during a median follow up of 7.3 years (range 0.0-15.5). This corresponded to five-year cumulative incidences of 7.1% (95% confidence interval (CI) 2.0-12.3) and 0.2% (95% CI 0.1-0.4) in persons with and without baseline liver cirrhosis. The five-year cumulative incidence of decompensated liver cirrhosis was 0.7% (95% CI 0.5-1.0). Among 2038 evaluated for liver events stratified by disease phase, incidence of HCC was low in all who were non-cirrhotic and untreated for HBV at baseline. PAGE-B score was evaluated in 1529 persons. The 5-year cumulative incidence of HCC was 0, 0.8 (95% CI 0.5-1.8), and 8.7 (95% CI 1.0-16.4) in persons scoring <10, 10-17 and >17, respectively (c-statistic 0.91 (95% CI 0.84-0.98)). Conclusion: We found low incidence of HCC and decompensated liver cirrhosis in persons with chronic HBV infection in Denmark. Moreover, the PAGE-B score showed good accuracy for five-year risk of developing HCC in the population with chronic HBV infection in Denmark.

Ischemic Heart Disease in Chronic Hepatitis B: A Danish Nationwide Cohort Study.

Objective: Data on the risk of ischemic heart disease (IHD) in patients with chronic hepatitis B virus (CHB) are conflicting. Our objective was to address the rate of IHD in patients with CHB compared with individuals without CHB (control-persons) from the general population. Study Design and Setting: We conducted a cohort study of prospectively obtained data from Danish nationwide registries. We produced cumulative incidence curves and calculated the unadjusted incidence rate ratio (IRR) of IHD in persons with and without CHB. The adjusted association between having CHB and developing IHD was examined using a cause-specific Cox regression model. Results: In total, 6472 persons with CHB and 62,251 age- and sex-matched individuals from the general population were followed for 48,840 and 567,456 person-years, respectively, during which 103 (1,59%) with CHB and 1058 (1,70%) control-persons developed IHD. The crude IRR was 1.13 (95% CI: 0.91-1.39). CHB did not have a statistically significant effect on the rate of IHD after adjusting for several confounding factors (adjusted hazard ratio: 0.96, 95% CI: 0.76-1.21). Conclusion: In this nationwide cohort study, we did not find any difference between rate of IHD in persons with CHB in comparison with the general population.

Mortality and cause of death in persons with chronic hepatitis B virus infection versus healthy persons from the general population in Denmark.

The study aimed to determine adjusted all-cause mortality and cause of death in persons with chronic hepatitis B virus (HBV) infection compared with age- and sex-matched persons from the general population. We used nationwide registers to identify persons aged ≥18 years with chronic HBV infection in 2002-2017 in Denmark and included 10 age- and sex-matched controls for each. Follow-up was from 6 months after diagnosis until death, emigration, or 31 December 2017. Mortality rate ratios (MRRs) adjusted for age, sex, employment, origin and comorbidity were calculated using Poisson regression. Unadjusted cause-specific mortality rate ratios with 95% confidence intervals were calculated assuming a Poisson distribution. A total of 6988 persons with chronic HBV infection and 69,847 controls were included. During a median follow-up of 7.7 years (range 0.0-15.5), 315 (5%) persons with-and 1525 (2%) without-chronic HBV infection died. The adjusted all-cause MRR was 1.5 (95% CI 1.2-2.0). Persons with chronic HBV infection had increased mortality due to liver disease including hepatocellular carcinoma (MRR 12.3 [8.6-17.7]), external causes (MRR 3.3 [2.5-4.7]), endocrine disease (MRR 3.2 [1.8-5.4]), genitourinary disease (MRR 3.2 [1.2-7.6]) and neoplasms (except hepatocellular carcinoma; MRR 1.6 [1.2-2.0]). In conclusion, this study showed an increased all-cause mortality in persons with chronic HBV infection in comparison with age- and sex-matched persons without chronic HBV infection which remained after adjustment for several confounding factors. Excess mortality was mainly associated with liver disease, but also external factors, endocrine disease, genitourinary disease and neoplasms (excluding hepatocellular carcinoma).

Altered balance between collagen formation and degradation after successful direct-acting antiviral therapy of chronic hepatitis C.

The effect of direct-acting antiviral (DAA) therapy on extracellular matrix (ECM) turnover, a prominent feature of chronic hepatitis C (CHC), is unknown. ECM protein degradation and formation generate fragments reflecting the tissue turnover balance when quantified in the blood. PRO-C3 and PRO-C4 reflect type III and IV collagen formation; C3M and C4M are degradation markers of type III and IV. We aimed to assess the markers' dynamics with DAA therapy in CHC patients. Plasma PRO-C3, PRO-C4, C3M and C4M were assessed before, during and up till one year after 12-24 weeks of DAA therapy in 77 CHC patients with advanced fibrosis (n = 14) or cirrhosis (n = 63). Liver stiffness was evaluated using transient elastography. PRO-C3, C3M and C4M levels decreased significantly (P < .00001) while PRO-C4 was unchanged (P = .20) during the study period. There was a steep decrease in the PRO-C3/C3M ratio during DAA therapy and follow-up (P < .02). The PRO-C4/C4M ratio was unchanged (P > .27). The dynamics of the collagen markers behaved similarly between patients with advanced fibrosis and cirrhosis. However, the cirrhosis patients had >20% higher levels of C3M, PRO-C4 and C4M at all time points (P < .05). The collagen markers correlated with liver stiffness at baseline and follow-up.Markers of type III and IV collagen formation and degradation decreased during and after successful DAA therapy in CHC patients with advanced liver disease, and associated with disease severity. These results indicate an altered balance between collagen formation and degradation after viral clearance suggesting favourable effects on liver fibrosis.

Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome.

Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis.

Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319: G151-G156, 2020. First published June 29, 2020; doi:10.1152/ajpgi.00128.2020.-Effects of direct-acting antiviral (DAA) treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediately after DAA therapy and relate the findings to hepatic inflammation and structural changes. In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in 9 CHC patients with cirrhosis and 10 healthy volunteers. Hepatic inflammation was evaluated by alanine aminotransferase (ALT) and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG). Before treatment, the FHNC in the patients was half of the controls [16.4 L/h (8.2-24.5) vs. 33.4 (29.2-37.6), P = 0.0004]; after successful DAA treatment, it normalized [28.4 (15.9-40.9), P = 0.008 vs. baseline]. DAA treatment normalized ALT (P < 0.0001) and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (P < 0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (P < 0.01). Liver stiffness fell by 30% (P < 0.05) but remained over the cirrhosis threshold. HVPG was not affected (P = 0.59). DAA treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early onset part of the expected clinical DAA treatment benefit.NEW & NOTEWORTHY Antiviral treatment of chronic hepatitis C restores the liver's reduced capacity to produce urea along with an improvement in liver inflammation without immediate effects on structural liver changes. The effect is suggested to be an important early onset part of the expected clinical treatment benefit.

[Elimination of hepatitis C virus in Denmark].

In Denmark, about 50% of patients with chronic hepatitis C virus (HCV) infection are undiagnosed. Since 2014, therapy containing direct-acting antivirals (DAA) has proven efficient and is available to all patients, who have a chronic HCV infection and a Danish personal identification number. The World Health Organization has a goal of elimination of viral hepatitis in 2030. Elimination of HCV in Denmark should focus on reducing HCV transmission, incidence and prevalence, combined with treatment with DAA of all infected patients. Micro-elimination strategies may play a major role, but a national strategy is lacking.

Hepatitis B and C in the adult population of Bissau, Guinea-Bissau: a cross-sectional survey.

OBJECTIVE: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are prevalent in West Africa. To address the WHO 2030 goals of a 90% reduction in incidence and a 65% reduction in mortality for both infections, we assessed the prevalence of HBV and HCV from surveys in the general population. METHODS: Participants in this cross-sectional survey were included from randomly selected houses in a demographic surveillance site in Bissau, Guinea-Bissau. Participants were interviewed and had a blood sample drawn for viral analyses (HBsAg, anti-HBs, anti-HBc, anti-HCV and HCV RNA). Risk factors of HBV and HCV infection were determined by binomial regression adjusted for sex and age. RESULTS: A total of 2715 participants were included in this study. The overall HBsAg prevalence was 18.7% (95% CI: 17.3-20.2%). HBsAg was associated with male sex (adjusted risk ratio (aRR): 1.64), and prevalence decreased with age >34 years. HBV exposure was found in 91.9% of participants. Although 72.6% of individuals without sexual debut had been exposed to HBV, ever engaging in a sexual relationship was associated with higher risk of HBV exposure (aRR 1.18). The anti-HCV prevalence was 0.5% (95% CI: 0.3-0.9%), and 78.6% of those had detectable HCV RNA. Risk factors for anti-HCV sero-positivity were age above 55 (aRR 10.60), a history of blood transfusion (aRR 5.07) and being in a polygamous marriage (aRR 3.52). CONCLUSION: In Guinea-Bissau initiatives to implement treatment and widespread testing are needed to reach the WHO 2030 goals.

OBJECTIF: Le virus de l'hépatite B (VHB) et le virus de l'hépatite C (VHC) sont répandus en Afrique de l'Ouest. Pour atteindre les objectifs de 2030 de l'OMS d'une réduction de 90% de l'incidence et de 65% de la mortalité pour les deux infections, nous avons évalué la prévalence du VHB et du VHC à partir d'enquêtes dans la population générale. MÉTHODES: Les participants inclus dans cette enquête transversale provenaient de foyers sélectionnés au hasard dans un site de surveillance démographique à Bissau, en Guinée-Bissau. Les participants ont été interrogés et ont subi un prélèvement d'échantillon de sang pour des analyses virales (HBsAg, anti-HBs, anti-HBc, anti-HCV et ARN du HCV). Les facteurs de risque d'infection par le VHB et le VHC ont été déterminés par la régression binomiale ajustée en fonction du sexe et de l'âge. RÉSULTATS: 2.715 participants ont été inclus dans cette étude. La prévalence globale de l'HBsAg était de 18,7% (IC95%: 17,3-20,2%). L'HBsAg était associé au sexe masculin (rapport de risque ajusté (aRR): 1,64), et la prévalence diminuait avec l'âge >34 ans. Une exposition au VHB a été observée chez 91,9% des participants. Bien que 72,6% des personnes sans début d'activité sexuelle aient été exposées au VHB, le fait de s'engager dans des relations sexuelles était associé à un risque plus élevé d'exposition au VHB (aRR: 1,18). La prévalence d'anti-VHC était de 0,5% (IC95%: 0,3-0,9%) et 78,6% d'entre eux avaient de l'ARN du VHC détectable. Les facteurs de risque de séropositivité anti-VHC étaient l'âge de plus de 55 ans (aRR: 10,60), les antécédents de transfusion sanguine (aRR: 5,07) et le fait d'être dans un mariage polygame (aRR: 3,52). CONCLUSION: En Guinée-Bissau, des initiatives pour mettre en œuvre un traitement et des tests généralisés sont nécessaires pour atteindre les objectifs de l'OMS 2030.

Time-dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct-acting antiviral therapy of chronic hepatitis C.

Sofosbuvir-based direct-acting antiviral (DAA) therapy generally cures chronic hepatitis C (CHC) infections, however, the effects on the underlying liver disease and the potential rate of recovery are unclear. We aimed to investigate the effects of DAA therapy on liver inflammation, fibrosis, metabolic function and cognitive function and the time course in CHC patients with advanced liver disease. Seventy-one CHC patients with advanced liver disease were studied before, during and one year after successful sofosbuvir-based DAA therapy. Liver inflammation was assessed by plasma sCD163 and sMR levels (ELISA), fibrosis by liver stiffness (transient elastography), function by galactose elimination capacity (GEC) and cognitive performance by continuous reaction time (CRT). During DAA therapy, we observed a rapid sCD163 decline from baseline to end of treatment (6.9 vs 3.8 mg/L, P < .0001), whereas the change in sMR was more subtle (0.37 vs 0.30 mg/L, P < .0001). Liver stiffness decreased by 20% at end of treatment (17.8 vs 14.3 kPa, P < .0001), together suggesting rapid resolution of liver inflammation. One year after treatment, liver stiffness decreased by an additional 15% (P < .0001), suggestive of fibrosis regression. The GEC improved at follow-up (all: 1.74 vs 1.98 mmol/min), mainly at 12 weeks post-treatment, both in patients with cirrhosis (n = 56) and those with advanced liver fibrosis (n = 15) (P < .001). The CRT improved at one-year follow-up (1.86 vs 2.09, P = .04). In conclusion, successful DAA therapy of CHC proves beneficial in advanced liver disease, with an initial rapid resolution of liver inflammation and a subsequent gradual but steady improvement in liver fibrosis, metabolic liver function and reaction time.

Acceptance and Feasibility of Partner Notification to HIV Infected Individuals in Guinea-Bissau.

As partner notification (PN) has shown effective in increasing the number of partners of HIV infected patients being tested we aimed to evaluate the feasibility of implementing PN in the West-African country Guinea-Bissau. Patients enrolled were offered the choice of three different PN methods. Acceptance, successful referrals and HIV status of partners were evaluated. Of 697 patients offered PN, 495 (71.0%) accepted and listed 547 partners. At end of follow-up 118 (21.5%) partners had been tested of which 44 (37.3%) were HIV infected. HIV infected partners had a higher median CD4 count at diagnosis compared with index patients; 401 cells/mm3 versus 240 cells/mm3, p < 0.001. The results indicate that implementation of PN is feasible, effective in identifying HIV infected partners and enables initiation of earlier treatment, yet there are major barriers to bringing partners in for testing which should be addressed in order to exploit the full potential of PN.

"Development in well-being and social function among Danish hemophilia patients with HIV: a three-wave panel study spanning 24 years".

BACKGROUND: Between 1975 and 1985 a total of 91 Danish patients with moderate and severe hemophilia (PWH) was infected with HIV constituting a major scandal in the Danish health care system. This study describes the burden of HIV infection among Danish PWH by evaluating changes from 1988 to 2012 in well-being, social function, experiencing stigma and openness about disease among Danish HIV+ PWH. METHODS: Three anonymous surveys were conducted in 1988, 2001 and 2012 targeting all Danish patients with moderate to severe hemophilia. Survey responses were received from 53, 21 and 18 HIV+ PWH respectively. A matched comparison sample of HIV- PWH was identified for each survey-year, using propensity score matching. Differences for each survey-year and trends over time were analyzed using ordinal logistic regression. RESULTS: In 1988, HIV+ PWH had more psychosomatic symptoms than HIV- PWH, but in 2001 life satisfaction was higher among HIV+ PWH than among HIV- PWH. Tests of differences in trend over time showed larger improvements in life satisfaction among HIV+ PWH than HIV- PWH, while HIV- PWH showed an increase in educational level compared to HIV+ PWH. Analysis restricted to HIV+ PWH showed an increase in perceived stigmatization. CONCLUSIONS: Differences between Danish HIV+ and HIV- PWH regarding well-being and psychosomatic symptoms seem to have evened out between 1988 and 2012. However, results suggest that HIV+ PWH still experience stigmatization and lower levels of education.

Discriminatory rapid tests cause HIV-type misclassification-evaluation of three rapid tests using clinical samples from Guinea-Bissau.

BACKGROUND: Discrimination among HIV types is important because HIV-2 is naturally resistant to some of the first-line drugs used in the treatment of HIV-1. We evaluated three assays for HIV-type discriminatory capacity: SD Bioline HIV 1/2 3.0 (Bioline), First Response HIV 1-2-0 Card Test (First Response) and Genie III HIV-1/HIV-2 (Genie III). METHODS: Based on results from the Bioline assay, samples from 239 HIV-infected patients from the Bissau HIV cohort in Guinea-Bissau were retrospectively selected for evaluation. Genie III and First Response were scored by three independent readers and compared with a reference test (INNO-LIA HIV I/II Score) confirmed by HIV RNA as well as DNA detection. RESULTS: The best performing test was Genie III, with an average agreement with the reference test of 93.4%, followed by First Response (86.1%) and Bioline (72.4%). First Response and Bioline were scored with a false high number of HIV-1/2 dual infections. For both First Response and Genie III, there were discrepancies among independent readers, and some tests were scored as HIV non-reactive. CONCLUSIONS: Using these rapid tests with a suboptimal performance will presumably result in a high rate of false HIV-1/2 dual diagnoses, depriving patients of alternative treatment options in cases of treatment failure.

T-cell and B-cell perturbations are similar in ART-naive HIV-1 and HIV-1/2 dually infected patients.

BACKGROUND: HIV-2 may slow progression of a subsequently acquired HIV-1 infection through cross-neutralizing antibodies and polyfunctional CD8 T cells. We hypothesized that HIV-1/2 dually infected patients compared with HIV-1-infected patients had more preserved immune maturation subsets and less immune activation of T and B cells. METHODS: ART-naive patients with HIV-1 (n = 83) or HIV-1/2 dual (n = 27) infections were included in this cross-sectional study at an HIV clinic in Guinea-Bissau. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry according to T-cell maturation and activation, regulatory T-cell fraction, and B-cell maturation and activation. RESULTS: HIV-1/2 dually infected patients had lower levels of HIV-1 RNA compared with patients with HIV-1 infection, but the levels of total HIV RNA (HIV-1 and HIV-2) were similar in the two patient groups. T-cell maturation, and proportions of regulatory T cells (FoxP3+) were also similar in the two groups. HIV-1/2 dually infected patients had higher proportions of CD4 and CD8 T cells positive for the activation marker CD38, but there was no difference in other T-cell activation markers (CD28, CTLA-4, PD-1). HIV-1/2 dually infected patients also had higher proportions of IgM-only B cells and plasmablasts. CONCLUSION: HIV-1/2 was not associated with less immune perturbations than for HIV-1 infection.

T-cell and B-cell perturbations identify distinct differences in HIV-2 compared with HIV-1-induced immunodeficiency.

BACKGROUND: For unknown reasons, HIV-2 is less pathogenic than HIV-1, and HIV-2-induced immunodeficiency may be different from that caused by HIV-1. Previous immunological studies have hinted at possible shifts in both T-cell and B-cell subsets, which we aimed to characterize further. METHODS: From an HIV clinic in Guinea-Bissau, 63 HIV-2, 83 HIV-1, and 26 HIV-negative participants were included. All HIV-infected participants were ART-naive. The following cell subsets were analysed by flow cytometry; T cells (maturation and activation), regulatory T cells, and B cells (maturation and activation). RESULTS: After standardizing for sex, age, and CD4 T-cell count HIV-2 had 0.938 log10 copies/ml lower HIV RNA levels than the HIV-1-infected patients. Whereas T-cell maturation and regulatory T-cell profiles were similar between patients, HIV-2-infected patients had higher proportions of CD8CD28 and lower proportions of CD8PD-1+ T cells than HIV-1-infected patients. This finding was independent of HIV RNA levels. HIV-2 was also associated with a more preserved proportion of naive B cells. CONCLUSION: HIV-2 is characterized by lower viral load, and lower T-cell activation, which may account for the slower disease progression.

The Prevalence of Human Immunodeficiency Virus Coinfection Among Patients Newly Diagnosed With Chronic Hepatitis B or C in Denmark: A Nationwide Cohort Study.

BACKGROUND: Early identification of patients with chronic viral hepatitis coinfected with human immunodeficiency virus (HIV) is essential for optimal care. The objectives of this study were to estimate the prevalence of HIV coinfection among patients newly diagnosed with chronic viral hepatitis, HIV testing prevalence, and identify factors associated with coinfection. METHODS: Patients with chronic viral hepatitis newly enrolled in The Danish Database for Hepatitis B and C between 2002 and 2015 were identified. The HIV coinfection prevalence was calculated, and risk factors associated with HIV coinfection were estimated by logistic regression. RESULTS: In total, 8490 patients were included: 3091 had chronic hepatitis B (CHB), 5305 had chronic hepatitis C (CHC), and 94 had CHB and CHC. The prevalence of HIV coinfection was 4.4% (95% confidence interval [CI], 4.0-4.9) and was higher among CHC and CHB-CHC patients than CHB patients with a prevalence of 5.3% (95% CI, 4.7-5.9), 6.4% (95% CI, 2.4-13.4), and 2.9 (95% CI, 2.3-3.5), respectively (P < .0001). The HIV testing prevalence increased from 65% to 88% between 2002 and 2014 concurrently with a decrease in the HIV coinfection prevalence from 7.8% (95% CI, 5.5-10.7) to 1.6% (95% CI, 0.7-3.2). Age 35-50 years, male sex, and sexual route of viral hepatitis transmission were associated with HIV coinfection with odds ratios of 4.42 (95% CI, 1.40-13.94), 2.21 (95% CI, 1.74-2.81), and 8.81 (95% CI, 6.30-12.33), respectively. CONCLUSIONS: The prevalence of HIV coinfection among patients with newly diagnosed chronic viral hepatitis decreased concurrently with an increase in HIV testing prevalence.

Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules.

Common CCR5-∆32 and HLA alleles only explain a minority of the HIV long-term non-progressor (LTNP) and elite controller (EC) phenotypes. To identify rare genetic variants contributing to the slow disease progression phenotypes, we performed whole exome sequencing (WES) on seven LTNPs and four ECs. HLA and CCR5 allele status, total HIV DNA reservoir size, as well as variant-related functional differences between the ECs, LTNPs, and eleven age- and gender-matched HIV-infected non-controllers on antiretroviral therapy (NCARTs) were investigated. Several rare variants were identified in genes involved in innate immune sensing, CD4-dependent infectivity, HIV trafficking, and HIV transcription mainly within the LTNP group. ECs and LTNPs had a significantly lower HIV reservoir compared to NCARTs. Furthermore, three LTNPs with variants affecting HIV nuclear import showed integrated HIV DNA levels below detection limit after in vitro infection. HIV slow progressors with variants in the TLR and NOD2 pathways showed reduced pro-inflammatory responses compared to matched controls. Low-range plasma levels of fibronectin was observed in a LTNP harboring two FN1 variants. Taken together, this study identified rare variants in LTNPs as well as in one EC, which may contribute to understanding of HIV pathogenesis and these slow progressor phenotypes, especially in individuals without protecting CCR5-∆32 and HLA alleles.

Protease Inhibitors or NNRTIs as First-Line HIV-1 Treatment in West Africa (PIONA): A Randomized Controlled Trial.

BACKGROUND: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are recommended as part of first-line treatment for HIV-1 in Africa. However, NNRTI-based regimens are more prone to resistance development than protease inhibitors (PIs) in a context in which drug interruptions are frequent. The aim of this study was to compare the efficacy and tolerability of NNRTIs with PIs in HIV-1-infected patients in Guinea-Bissau. METHODS: This open-label randomized, 2-arm superiority trial compared the use of 2 NRTIs plus either one NNRTI (efavirenz or nevirapine) or one PI (lopinavir/ritonavir) in treatment-naive HIV-1-infected adults in the Bissau HIV Cohort (ClinicalTrials.gov, NCT0019235). The primary endpoint was HIV-1 RNA <400 copies per milliliter after 12 months of treatment. RESULTS: Between May 5, 2011, and April 26, 2013, 400 patients were included in the study. In an intention-to-treat analysis, the proportions of patients with viral suppression were similar in the NNRTI [65/197 (33.0%)] and PI [68/203 (33.5%)] arms (P = 0.92). No PI resistance was detected, but high-level NNRTI resistance was seen in 17/30 (56.7%) of NNRTI vs. 3/26 (11.5%) of PI-treated patients, P < 0.01. After 1 year of follow-up, 65 patients died (16.3%) and 93 were lost to follow-up (23.3%). There was no difference in mortality (hazard ratio 0.84, 95% confidence interval: 0.51 to 1.36) or frequency of clinical adverse events between treatment arms [NNRTI: 73/197 (37.1%); and PI: 69/203 (34.0%); P = 0.52]. CONCLUSIONS: In patients at an HIV clinic in Guinea-Bissau, treatment with PIs led to less development of resistance compared with NNRTIs but was not superior in terms of viral suppression, CD4 cell increment, mortality, or severe adverse events.

Rapid and persistent decline in soluble CD163 with successful direct-acting antiviral therapy and associations with chronic hepatitis C histology.

BACKGROUND AND AIM: Soluble CD 163 (sCD163) is released from activated liver macrophages in chronic viral hepatitis C (HCV) and serum levels reflect liver disease severity. The impact of direct-acting antiviral (DAA)-therapy on sCD163-levels and the ability of sCD163 to predict the presence of liver fibrosis remain unclear. In a combined observational and prospective study, we aimed to investigate changes in sCD163 with DAA-treatment, to investigate associations between sCD163 and histopathological activity and fibrosis and to validate the sCD163-based fibrosis score in HCV-patients. METHODS: We examined three groups of patients: an Australian (n = 28) treated with pegylated-interferon and a first-generation DAA, a Danish (n = 38) treated with sofosbuvir-based DAA-regimens and a Japanese (n = 562) assessed for activity and fibrosis (Metavir scoring system) in liver biopsies. Serum sCD163-levels were quantified by ELISA. RESULTS: Thirteen (46%) of the Australian patients achieved sustained virological response (SVR) and only these patients had significant decreases in sCD163-levels (2.7 (95%CI:1.9-3.6) vs. 4.1(2.9-5.7) mg L - 1, p = .008). In the Danish group, 37 (97%) patients achieved SVR at 12-weeks post-treatment with 32% reduction in sCD163-levels (5.0 (4.3-5.8) vs. 7.4 (6.3-8.7), p < .001). The decline was rapid and persisted 12 months after treatment cessation (p < .007). sCD163 levels increased in parallel with inflammatory activity and fibrosis (p < .001). The sCD163-based fibrosis score outperformed established fibrosis scores for significant fibrosis (areas under the receiver operating characteristics curves (AUROCs): 0.79 (0.75-0.83) vs. aspartate aminotransferase to platelet ratio index (APRI) 0.73 (0.69-0.77), Fibrosis-4 (FIB-4) 0.74 (0.70-0.78), p < .001). CONCLUSION: sCD163-levels decline rapidly with successful DAA therapy and are associated with histological inflammatory activity and fibrosis, confirming a key role for macrophages in HCV inflammation and fibrosis and supporting sCD163 as a biomarker of treatment response.