Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls.

BACKGROUND: Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to estimate the prevalence and factors associated with liver fibrosis in PWH compared to population controls. METHODS: This was a cross-sectional cohort study comparing 342 PWH with 2190 population controls aged 50-70 years.Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were computed by logistic regression. RESULTS: The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM. In multivariate analysis, elevated LSM was associated with HIV (aOR, 1.84 [95% CI, 1.17-2.88]; P < .01); higher age (per decade: aOR, 3.34 [95% CI, 1.81-6.18]; P < .01); alanine aminotransferase (ALT) (per 10 IU/L: aOR, 1.25 [95% CI, 1.05-1.49]; P < .01); body mass index (BMI) (per 1 kg/m2: aOR, 1.17 [95% CI, 1.05-1.29]; P < .01), and previous exposure to didanosine (per year: aOR, 2.26 [95% CI, 1.01-5.06]; P = .04). CONCLUSIONS: The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM.

Hepatic Steatosis Associated With Exposure to Elvitegravir and Raltegravir.

Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with cumulative exposure to stavudine, elvitegravir, and raltegravir. Prospective trials are required to establish a causal association. Clinical Trials Registration. NCT02382822.

Prevalence and Risk Factors of Moderate-to-Severe Hepatic Steatosis in Human Immunodeficiency Virus Infection: The Copenhagen Co-morbidity Liver Study.

BACKGROUND: People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH. METHODS: The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression. RESULTS: The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P < .01). In multivariable analyses, HIV (aOR, 0.44; P < .01), female sex (aOR, 0.08; P = .03), physical activity level (aOR, 0.09; very active vs inactive; P < .01), and alcohol (aOR, 0.89 per unit/week; P = .02) were protective factors, whereas body mass index (BMI) (aOR, 1.58 per 1 kg/m2; P < .01), alanine transaminase (ALT) (aOR, 1.76 per 10 U/L; P < .01), and exposure to integrase inhibitors (aOR, 1.28 per year; P = .02) were associated with higher odds of M-HS. CONCLUSIONS: Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH.

Fraction of Exhaled Nitric Oxide Levels Are Elevated in People Living With Human Immunodeficiency Virus Compared to Uninfected Controls, Suggesting Increased Eosinophilic Airway Inflammation.

BACKGROUND: Increased risk of asthma and chronic obstructive pulmonary disease has been reported in people living with human immunodeficiency virus (PLWH). Fraction of exhaled nitric oxide (FeNO) is a marker of eosinophilic airway inflammation. We assessed FeNO levels in PLWH and matched uninfected controls and investigated whether human immunodeficiency virus (HIV) status is independently associated with elevated FeNO. METHODS: FeNO was quantified by NIOX Vero and pulmonary function was assessed by spirometry in 432 PLWH from the Copenhagen Comorbidity in HIV Infection Study and in 1618 age- and sex-matched uninfected controls from the Copenhagen General Population Study. Elevated FeNO was defined as ≥25 parts per billion. Associations between FeNO and HIV status were adjusted for known potential confounders. RESULTS: Mean age of PLWH was 50.7 (standard deviation [SD], 11.1) years and 97.4% received combination antiretroviral therapy. PLWH had higher FeNO than uninfected controls (median, 17.0 [interquartile range {IQR}, 11.0-26.0] vs 13.0 [IQR, 9.0-19.0]; P < .001). Also, PLWH had a higher prevalence of elevated FeNO than uninfected controls (27.5% vs 12.3%; P < .001). This association remained after adjusting for age, sex, height, smoking status, use of airway medication, blood eosinophils, and immunoglobulin E (adjusted OR [aOR], 3.56 [95% CI, 2.51-5.04]; P < .001). Elevated FeNO was associated with self-reported asthma (aOR, 2.65 [95% CI, 1.66-4.24]; P < .001) but not with airflow limitation (aOR, 1.07 [95% CI, .71-1.62]; P = .745). CONCLUSIONS: HIV status was independently associated with elevated FeNO, suggesting increased eosinophilic airway inflammation. The potential impact on chronic lung disease pathogenesis needs further investigation.

Poor Concordance Between Liver Stiffness and Noninvasive Fibrosis Scores in HIV Infection Without Viral Hepatitis.

People living with human immunodeficiency virus (PLWH) are at higher risk of liver fibrosis compared with the general population. As liver fibrosis is independently associated with poor long-term liver related outcomes and mortality,1 early detection is extremely important. Liver biopsy is considered gold standard for the diagnosis of liver fibrosis. However, this invasive procedure is only suitable for a selected group of patients because of the risk of serious complications. We aimed to estimate the concordance between vibration-controlled transient elastography (VCTE) and simple noninvasive liver fibrosis scores-Fibrosis-4 index (FIB4), aspartate aminotransferase-to-platelet ratio index (APRI), and nonalcoholic fatty liver disease fibrosis score (NFS)-in PLWH without viral hepatitis.

Increased Risk of Anemia, Neutropenia, and Thrombocytopenia in People With Human Immunodeficiency Virus and Well-Controlled Viral Replication.

BACKGROUND: Prior to the introduction of combination antiretroviral therapy (cART), cytopenias were common in people with human immunodeficiency virus (PWH), but it is unknown if well-controlled HIV infection is a risk factor for cytopenia. In this study we aimed to determine if HIV infection is an independent risk factor for anemia, neutropenia, lymphocytopenia, and thrombocytopenia. METHODS: PWH with undetectable viral replication and absence of chronic hepatitis infection (n = 796) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study and matched uninfected controls from the Copenhagen General Population Study (n = 2388). Hematology was analyzed in venous blood samples. Logistic regression analyses adjusted for age, sex, ethnicity, smoking status, alcohol, and high-sensitivity C-reactive protein were performed to determine possible associations between HIV and cytopenias. RESULTS: PWH had a higher prevalence of anemia (6.9% vs 3.4%, P < .001), neutropenia (1.3% vs 0.2%, P < .001), and thrombocytopenia (5.5% vs 2.7%, P < .001) compared with uninfected controls. HIV was independently associated with anemia-adjusted odds ratio (aOR) of 2.0 (95% confidence interval [CI], 1.4-3.0); neutropenia aOR, 6.3 (95% CI, 2.0-19.6); and thrombocytopenia aOR, 2.7 (95% CI, 1.8-4.2). No association was found between HIV and lymphocytopenia. CONCLUSIONS: Cytopenia is rare in people with well-controlled HIV, but HIV remains a risk factor for anemia, neutropenia, and thrombocytopenia and requires ongoing attention and monitoring.

Copenhagen comorbidity in HIV infection (COCOMO) study: a study protocol for a longitudinal, non-interventional assessment of non-AIDS comorbidity in HIV infection in Denmark.

BACKGROUND: Modern combination antiretroviral therapy (cART) has improved survival for people living with HIV (PLWHIV). Non-AIDS comorbidities have replaced opportunistic infections as leading causes of mortality and morbidity, and are becoming a key health concern as this population continues to age. The aim of this study is to estimate the prevalence and incidence of non-AIDS comorbidity among PLWHIV in Denmark in the cART era and to determine risk factors contributing to the pathogenesis. The study primarily targets cardiovascular, respiratory, and hepatic non-AIDS comorbidity. METHODS/DESIGN: The Copenhagen comorbidity in HIV-infection (COCOMO) study is an observational, longitudinal cohort study. The study was initiated in 2015 and recruitment is ongoing with the aim of including 1500 PLWHIV from the Copenhagen area. Follow-up examinations after 2 and 10 years are planned. Uninfected controls are derived from the Copenhagen General Population Study (CGPS), a cohort study including 100,000 uninfected participants from the same geographical region. Physiological and biological measures including blood pressure, ankle-brachial index, electrocardiogram, spirometry, exhaled nitric oxide, transient elastography of the liver, computed tomography (CT) angiography of the heart, unenhanced CT of the chest and upper abdomen, and a number of routine biochemical analysis are uniformly collected in participants from the COCOMO study and the CGPS. Plasma, serum, buffy coat, peripheral blood mononuclear cells (PBMC), urine, and stool samples are collected in a biobank for future studies. Data will be updated through periodical linking to national databases. DISCUSSION: As life expectancy for PLWHIV improves, it is essential to study long-term impact of HIV and cART. We anticipate that findings from this cohort study will increase knowledge on non-AIDS comorbidity in PLWHIV and identify targets for future interventional trials. Recognizing the demographic, clinical and pathophysiological characteristics of comorbidity in PLWHIV may help inform development of new guidelines and enable us to move forward to a more personalized HIV care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02382822 .

High incidence of subclinical peripheral artery disease in people with HIV.

OBJECTIVE: Atherosclerosis is common in people with HIV (PWH). Peripheral artery disease (PAD) is the peripheral manifestation of atherosclerosis, but little is known about the incidence of PAD in PWH. Our objective was to determine the PAD incidence in PWH and to investigate potential risk factors. DESIGN: Prospective longitudinal study on PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) study cohort. METHODS: We performed ankle-brachial index (ABI) measurements at study entry and at 2-year follow-up and included participants with normal ABI at study entry. We defined de novo PAD as ABI ≤0.9 at follow-up. Using Poisson regression adjusted for age, sex, and smoking, we investigated the role of traditional and HIV-related risk factors, including inflammatory markers. RESULTS: Of 844 PWH followed for a median duration of 2.3 years, 30 (3.6%) developed de novo PAD. All cases were subclinical. Diabetes (relative risk [RR] = 4.90 [95% confidence interval [CI]: 1.99-12.1]), current CD4 + cell count <350 cells/µl (2.66 [1.06-6.71]), longer duration of antiretroviral therapy (antiretroviral therapy [ART], 1.88 [1.06-3.33] per decade), and concentrations of high-sensitivity C-reactive protein (1.33 [1.08-1.63] per doubling) and interleukin-6 (1.38 [1.06-1.80] per doubling), were associated with de novo PAD. CONCLUSIONS: PWH had a high incidence of de novo subclinical PAD. Diabetes, low current CD4 + cell count, duration of ART, and inflammatory markers were associated with de novo PAD, indicating a possible role in PAD pathogenesis in PWH.

Identification of two different coagulation phenotypes in people living with HIV with undetectable viral replication.

Altered coagulation has been reported in people living with HIV (PLWH) with ongoing viral replication and may predispose to cardiovascular diseases. However, less is known about coagulation in PLWH with undetectable viral replication. In a cross-sectional observational study, we investigated whether HIV infection with undetectable viral replication is independently associated with activated partial thromboplastin time (APTT) and coagulation factor II-VII-X concentrations out of reference. Logistic regression analyses were used to assess the association of HIV infection with APTT and coagulation factor II-VII-X, after adjusting for age, sex, smoking status, alcohol consumption, BMI, diabetes and hsCRP. 936 PLWH with undetectable viral replication from the Copenhagen Co-morbidity in HIV infection study (COCOMO-study) and 2955 uninfected controls were included. Higher prevalence of short APTT was found in PLWH compared to controls (13.5% vs. 7.6%, P < 0.001). Furthermore, higher prevalence of low coagulation factor II-VII-X was found in PLWH than in controls (9.6% vs. 7.4%, P = 0.022). HIV was independently associated with short APTT (adjusted odds ratio (aOR) 2.3 (95% CI 1.7-2.9), P < 0.001) and low coagulation factor II-VII-X (aOR 1.4 (95% CI 1.0-1.9), P = 0.046). Few participants among PLWH and controls had both short APTT and low coagulation factor II-VII-X, 2.1% vs. 0.8%, respectively. We found evidence of both procoagulant (short APTT) and anticoagulant (low coagulation factor II-VII-X) alterations in PLWH with undetectable viral replication, and our findings suggest that two different coagulation phenotypes exist in participants with treated HIV infection.

Prevalence of anti-hepatitis E virus immunoglobulin G in HIV-infected individuals over three decades.

BACKGROUND: Hepatitis E virus (HEV) genotype 3 is endemic in Europe, and the infection is mostly subclinical or acute and self-limiting. However, persistent infection is described among HIV-infected individuals. The prevalence of antibodies against HEV (anti-HEV) among HIV-infected persons varies geographically and is unknown in Denmark. Rates of co-infection with HEV among HIV-infected individuals in Denmark over three decades, from the early 1980s to 2013, were investigated. METHODS: A total of 2506 HIV-infected persons were investigated from two cohorts followed at Hvidovre Hospital, Denmark. Blood samples were tested retrospectively for anti-HEV, including samples from 2216 persons who were enrolled in a prospective clinical cohort and followed between 1995 and 2013, as well as samples from 290 persons from a historical cohort followed between 1980 and 1994. For anti-HEV seroconverting individuals, serial samples were tested for HEV RNA. Factors associated with anti-HEV status were explored using multivariable logistic regression analysis. RESULTS: The overall HEV seroprevalence rates were stable during the 1980s, 1990s, and 2000-2013 (23.1%, 22.9%, and 23.7%, respectively). In all decades, rates of anti-HEV increased with older age, and anti-HEV seropositivity was associated with older generations, HIV risk group, and geographic origin. Persistent HEV infection was not detected in any of 57 individuals with anti-HEV seroconversion. CONCLUSIONS: HEV seroprevalence rates were stable in HIV-infected individuals from the early 1980s to 2013. Rates increased with age. No evidence of persistent HEV infection was detected. Infection with HEV is frequent, but persistent HEV infection is rare among HIV-infected individuals.

[Magnetic resonance imaging for the diagnosis of non-alcoholic fatty liver disease].

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease with an estimated overall prevalence of 25% in the global adult population. Liver biopsy is the gold standard for the diagnosis of NAFLD. However, the risk of complications and collection of only 1/50,000 of the total liver volume, limits this diagnostic method in an unselected population. Non-invasive diag-nostic methods are warranted, and magnetic resonance imaging of the liver for NAFLD has shown promising results.

Iodine excretion in school children in Copenhagen.

INTRODUCTION: Studies of dietary habits show a high iodine intake in children in Denmark. Iodine excretion in children has not previously been assessed. Iodine excretion in adults is below the recommended threshold, and it is therefore being discussed to increase the fortification level. The main objective of this study was to assess iodine excretion in children living in Copenhagen to establish whether a moderate increase in iodine fortification would lead to excess iodine intake in this group. METHODS: Children in first and fifth grade were recruited through schools in Copenhagen. In total, 244 children de-ivered a urine sample. Urine samples were analysed for iodine and creatinine, and the results were expressed as urinary iodine concentration (UIC) and as estimated 24-h iodine excretion. Iodine excretion in children was also compared with that of adults living in the same area, investigated in a prior study. RESULTS: The median UIC was within the recommended level; 145 (range: 116-201) µg/l for boys and 128 (range: 87-184) µg/l for girls, and was lower in fifth grade students than in first grade students. Estimated 24-h iodine excretion was higher in boys than in girls, but did not differ according to grade. The UIC was higher in children than in adults from the same area. CONCLUSIONS: The iodine excretion among schoolchildren in Copenhagen, an area with a relatively high iodine content in tap water, was within the recommended range as assessed by the UIC. An increased iodine fortification will not have negative consequences for this group. FUNDING: The Ministry of Food, Agriculture and Fisheries. TRIAL REGISTRATION: not relevant.

Iodine deficiency in pregnancy is prevalent in vulnerable groups in Denmark.

INTRODUCTION: Iodine is essential for the production of thyroid hormones. In pregnancy, physiological changes occur that can lead to iodine deficiency and impairment of fetal neurological development. We aimed to assess the iodine intake in pregnant women in Eastern Denmark, compare iodine levels in Eastern and Western Denmark and to identify potentially vulnerable groups. METHODS: This was a cross-sectional cohort study of pregnant Danish women (n = 240). Questionnaires and urine samples were collected at the Ultrasound Clinic, Hvidovre Hospital, Denmark, and urinary iodine concentrations (UIC) (µg/l) were measured. Predictors of iodine supplement use were examined by multivariate logistic regression models. RESULTS: The pregnant women from Eastern Denmark had a median age of 30 years and the median gestational week at which they were included in the study was week 19. The majority took iodine-containing supplements (86%). The median UIC was 118 (interquartile range (IQR): 79-196) µg/l in iodine supplement users and 82 (IQR: 41-122) µg/l in non-users (p < 0.001). Predictors of not using iodine supplement in Eastern and Western Denmark were short maternal education, non-Danish origin and pre-pregnancy obesity. CONCLUSIONS: The iodine status in Danish pregnant women was below WHO recommendations. Iodine supplement non-users are at a particular risk of iodine deficiency. Low maternal education, non-Danish origin and pre-pregnancy obesity are predictors of non-iodine supplement use. An increase in iodine fortification may be recommended to improve the iodine status in pregnant Danish women. FUNDING: none. TRIAL REGISTRATION: not relevant.