Progressive multifocal leukoencephalopathy in systemic lupus erythematosus treated with pembrolizumab.

This case report discusses a patient with systemic lupus erythematosus (SLE) treated with low-dose azathioprine who developed progressive multifocal leukoencephalopathy (PML). PML is a rare, severe, demyelinating disease linked to John Cunningham polyomavirus (JCV) reactivation.Treated with pembrolizumab, an immune checkpoint inhibitor, the patient initially improved. However, after the fourth dose, her condition rapidly worsened resulting in treatment discontinuation and death. Similar cases highlight the complex interplay of factors in PML development in SLE patients, including immunosuppression and genetic factors. The use of pembrolizumab in PML and SLE necessitates careful consideration of potential complications.

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.

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).

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.

Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation.

OBJECTIVES: We describe factors associated with and barriers to initiation of Direct Acting Antiviral (DAA) treatment in patients with chronic hepatitis C, who fulfill national fibrosis treatment guidelines in Denmark. MATERIALS AND METHODS: In this nationwide cohort study, we included patients with chronic hepatitis C from The Danish Database for Hepatitis B and C (DANHEP) who fulfilled fibrosis treatment criteria. Factors associated with treatment initiation and treatment failure were determined by logistic regression analyses. Medical records were reviewed from patients who fulfilled fibrosis treatment criteria, but did not initiate DAA treatment to determine the cause. RESULTS: In 344 (49%) of 700 patients, who fulfilled treatment criteria, factors associated with DAA treatment initiation were transmission by other routes than injecting drug use odds ratio (OR) 2.13 (CI: 1.38-3.28), previous treatment failure OR 2.58 (CI: 1.84-3.61) and ALT above upper limit of normal OR 1.60 (CI: 1.18-2.17). The most frequent reasons for not starting treatment among 356 (51%) patients were non-adherence to medical appointments (n = 107/30%) and ongoing substance use (n = 61/17%). Treatment failure with viral relapse occurred in 19 (5.5%) patients, who were more likely to have failed previous treatment OR 4.53 (CI: 1.59-12.91). CONCLUSIONS: In this nationwide cohort study, we found non-adherence to medical appointments and active substance use to be major obstacles for DAA treatment initiation. Our findings highlight the need for interventions that can overcome these barriers and increase the number of patients who can initiate and benefit from curative DAA treatment.

Soluble Macrophage Mannose Receptor (sCD206/sMR) as a Biomarker in Human Immunodeficiency Virus Infection.

Macrophages play important roles during human immunodeficiency virus (HIV) infection, reflected by changes in macrophage-activation biomarker soluble CD163 (sCD163). Here, we present data on the novel macrophage-activation biomarker soluble mannose receptor/CD206 (sCD206) in HIV infection. We investigated sCD206 blood levels at baseline and follow-up with/without antiretroviral therapy (ART), in 212 patients with HIV type 1 (HIV-1), HIV type 2 (HIV-2), or dual infection. At baseline, there was no difference in sCD206 level between HIV types, and sCD206 was unchanged at follow-up without ART. However, in contrast to sCD163, sCD206 levels decreased significantly for both HIV-1 and HIV-2, but not for HIV-1/2 patients, during ART. Further investigations are needed to establish sCD206 as a biomarker in HIV infection.

Increased mortality among HIV infected patients with cryptococcal antigenemia in Guinea-Bissau.

Cryptococcal antigenemia may precede development of cryptococcal meningitis and death among patients with advanced HIV infection. Among 200 retrospectively and randomly selected ART-naïve patients with CD4 counts < 100 cells/µl from Guinea-Bissau, 20 (10%) had a positive cryptococcal antigen test. Self-reported headache and fever were predictors of a positive test, while cryptococcal antigenemia was a strong predictor of death within the first year of follow-up, MRR 2.22 (95% CI: 1.15-4.30). Screening for cryptococcal antigenemia should be implemented for patients with advanced HIV in Guinea-Bissau. Pre-emptive anti-fungal therapy should be initiated prior to ART-initiation if the screening is positive.

Sofosbuvir based treatment of chronic hepatitis C genotype 3 infections-A Scandinavian real-life study.

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) genotype 3 infection with advanced liver disease has emerged as the most challenging to treat. We retrospectively assessed the treatment outcome of sofosbuvir (SOF) based regimes for treatment of HCV genotype 3 infections in a real life setting in Scandinavia. METHODS: Consecutive patients with chronic HCV genotype 3 infection were enrolled at 16 treatment centers in Denmark, Sweden, Norway and Finland. Patients who had received a SOF containing regimen were included. The fibrosis stage was evaluated by liver biopsy or transient liver elastography. The following treatments were given according availability and local guidelines: 1) SOF + ribavirin (RBV) for 24 weeks, 2) SOF + daclatasvir (DCV) +/-RBV for 12-24 weeks, 3) SOF + pegylated interferon alpha (peg-IFN-α) + RBV for 12 weeks or 4) SOF/ledipasvir (LDV) + RBV for 12-16 weeks. The primary endpoint was sustained virological response (SVR) assessed at week 12 (SVR12) after end of treatment. RESULTS: We included 316 patients with a mean age of 55 years (range 24-79), 70% men, 49% treatment experienced, 58% with compensated cirrhosis and 12% with decompensated cirrhosis.In the modified intention to treat (mITT) population SVR12 was achieved in 284/311 (91%) patients. Among 26 treatment failures, five had non-response, 3 breakthrough and 18 relapse. Five patients were not included in the mITT population. Three patients died from reasons unrelated to treatment and two were lost to follow-up. The SVR12 rate was similar for all treatment regimens, but lower in men (p = 0.042), and in patients with decompensated liver disease (p = 0.004). CONCLUSION: We found that sofosbuvir based treatment in a real-life setting could offer SVR rates exceeding 90% in patients with HCV genotype 3 infection and advanced liver disease.

Mortality Rates in Patients With Chronic Hepatitis C and Cirrhosis Compared With the General Population: A Danish Cohort Study.

BACKGROUND: Knowledge about mortality rates (MRs) in patients with chronic hepatitis C (CHC) with cirrhosis is limited. This study aimed to estimate all-cause MRs among patients with CHC with or without cirrhosis in Denmark compared with the general population. METHODS: Patients registered in the Danish Database for Hepatitis B and C with CHC and a liver fibrosis assessment were eligible for inclusion. Liver fibrosis was assessed by means of liver biopsy, transient elastography, and clinical cirrhosis. Up to 20 sex- and age-matched individuals per patient were identified in the general population. Data were extracted from nationwide registries. RESULTS: A total of 3410 patients with CHC (1014 with cirrhosis), and 67 315 matched individuals were included. Adjusted MR ratios (MRRs) between patients with or without cirrhosis and their comparison cohorts were 5.64 (95% confidence interval [CI], 4.76-6.67) and 1.94 (1.55-2.42), respectively. Cirrhosis among patients was associated with an MRR of 4.03 (95% CI, 3.43-4.72). A cure for CHC was associated with an MRR of 0.64 (95% CI, 0.40-1.01) among cirrhotic patients and 2.33 (1.47-3.67) compared with the general population. CONCLUSIONS: MRs were high among patients with CHC with or without cirrhosis compared with the general population. Curing CHC was associated with a reduction in MR among cirrhotic patients, but the MR remained higher than the general population.

Cohort Profile: The Bissau HIV Cohort-a cohort of HIV-1, HIV-2 and co-infected patients.

The West African country Guinea-Bissau is home to the world's highest prevalence of HIV-2, and its HIV-1 prevalence is rising. Other chronic viral infections like human T-lymphotropic virus type 1 (HTLV-1) and hepatitis B virus are common as well. The Bissau HIV Cohort was started in 2007 to gain new insights into the overall effect of introducing antiretroviral treatment in a treatment-naïve population with concomitant infection with three retroviruses (HIV-1, HIV-2 and HTLV-1) and tuberculosis. The cohort includes patients from the HIV clinic at Hospital Nacional Simão Mendes, the main hospital in Bissau, the capital of the country. From July 2007 to June 2013, 3762 HIV-infected patients (69% HIV-1, 18% HIV-2, 11% HIV-1/2 and 2% HIV type unknown) were included in the world's largest single-centre HIV-2 cohort. Demographic and clinical data are collected at baseline and every 6 months, together with CD4 cell count and routine biochemistry analyses. Plasma and cells are stored in a biobank in Denmark. The Bissau HIV Cohort is administered by the Bissau HIV Cohort study group. Potential collaborators are invited to contact the chair of the cohort study group, Christian Wejse, e-mail: [wejse@dadlnet.dk].

Neutralizing antibodies in patients with chronic hepatitis C, genotype 1, against a panel of genotype 1 culture viruses: lack of correlation to treatment outcome.

The correlation of neutralizing antibodies to treatment outcome in patients with chronic hepatitis C virus (HCV) infection has not been established. The aim of this study was to determine whether neutralizing antibodies could be used as an outcome predictor in patients with chronic HCV, genotype 1, infection treated with pegylated interferon-α and ribavirin. Thirty-nine patients with chronic hepatitis C, genotype 1a or 1b, with either sustained virologic response (n = 23) or non-sustained virologic response (n = 16) were enrolled. Samples taken prior to treatment were tested for their ability to neutralize 6 different HCV genotype 1 cell culture recombinants (1a: H77/JFH1, TN/JFH1, DH6/JFH1; 1b: J4/JFH1, DH1/JFH1, DH5/JFH1). The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer). We observed no genotype or subtype specific differences in NAb50-titers between patients with chronic HCV infection with and without sustained virologic response when tested against any of the included culture viruses. However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100-6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50-400) against all other included isolates. Subsequent studies demonstrated that the efficient neutralization of DH6/JFH1 could be linked to engineered adaptive mutations in the envelope-2 protein. In analysis of envelope 1 and 2 sequences of HCV, recovered from a subset of patients, we observed no apparent link between relatedness of patient sequences with culture viruses used and the corresponding neutralization results. In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection. High neutralization susceptibility of DH6/JFH1 could be correlated with adaptive envelope mutations previously highlighted as important for neutralization. Our study emphasizes the importance of using multiple culture viruses for neutralization studies and contributes to the current knowledge about neutralizing epitopes, important for future therapeutic- and vaccine-studies.

Negative HCV-RNA 2 weeks after initiation of treatment predicts sustained virological response to pegylated interferon alfa-2a and ribavirin in patients with chronic hepatitis C.

OBJECTIVE: The aim of this study was to examine the early viral kinetics as predictor for sustained virological response (SVR) during hepatitis C treatment. MATERIALS AND METHODS: We included patients with biopsy-proven chronic hepatitis C and ALT above the upper limit of normal, who received a standard treatment of pegylated interferon alfa-2a and ribavirin. The HCV-RNA concentration (limit of detection 20 IU/mL) was determined at days 0, 1, 2, 3, 4, 7, 14, 21 and monthly thereafter. RESULTS: Among 46 patients who completed the trial, 30 (65%) had SVR. Low baseline viral load, IL28B genotype CC and absence of cirrhosis were statistically associated with SVR. In multivariate analysis only absence of cirrhosis and HCV-RNA negativity at day 14 were independent predictors for SVR. Eight patients who became HCV-RNA negative on day 14 as well as 13 of 14 patients (93%) with HCV-RNA levels of <1000 IU/mL at day 7 obtained a SVR. Among 8 of 18 (44%) genotype 1 and 4 patients with more than a one log drop in HCV-RNA titer at day 7, 75% achieved SVR. CONCLUSIONS: We observed a correlation between low HCV-RNA titers in week 2 and SVR during pegylated interferon/ribavirin-based treatment. This may help identify a group of patients for whom SVR may be obtained without the addition of directly acting antivirals, and thereby save the patients for unnecessary side effects and the health care system for additional costs.

Treatment for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection - Danish national guidelines 2011.

The Danish Society of Infectious Diseases and Danish Society of Gastroenterology and Hepatology set up a committee in 2007 to produce national guidelines for treatment of viral hepatitis B and C. The 2011 version of the guidelines have been endorsed by the scientific societies and are presented below. Annual updates will be available at the websites of the societies. As this present English version has been written six months after the Danish 2011 version, it contains minor changes that will be integrated in the Danish 2012 version, available at the end this year. EPIDEMIOLOGY: Viral hepatitis is not common in Denmark. The prevalence has not been determined by national surveys, but it is estimated that 10,000-15,000 patients are chronically infected with hepatitis B and 15,000-20,000 with chronic hepatitis C. The majority of patients with HBV infection in Denmark are emigrants from high endemic countries, probably infected at birth or early childhood in their country of origin, while the majority of patients with HCV infection have been infected by drug use. For both groups it is estimated that only half of the patients have been diagnosed, of whom only 20% attends specialized care for their chronic viral hepatitis. CLINICAL CARE: According to the Danish National Board of Health, patients with chronic viral hepatitis should be followed with regular intervals, at clinics specialized in either infectious diseases or gastroenterology/hepatology. The primary aim is to identify patients with significant liver disease to initiate treatment in order to prevent development of cirrhosis and death. This is primarily done by liver biopsy, but screening for fibrosis with non-invasive methods such as elastography may be sufficient in some patients. Patients with established cirrhosis should enter screening programs for complications such as esophageal varices and hepatocellular carcinoma.

Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial.

INTRODUCTION: Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy. METHODS: In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms. RESULTS: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients. CONCLUSION: Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed. TRIAL REGISTRATION: Clinicaltrials.gov NCT00647244.

Molecular and epidemiological profiles of hepatitis C virus genotype 4 in Denmark.

The prevalence of hepatitis C virus (HCV) genotype 4 has increased throughout Europe. This is an epidemiological study of patients infected chronically with HCV genotype 4 in Denmark. The HCV strains analyzed originated from patient samples collected between 1999 and 2007 as part of the national Danish hepatitis B and C network, DANHEP. Sequence analyses were based on the envelope 1 region of HCV. Results from a total of 72 patients indicated a high degree of genetic heterogeneity. Fifty-six patients (78%) were infected with one of the three dominating subtypes: 4d, 4a, or 4r. The remaining 16 patients (22%) were infected with subtypes 4h, 4k, 4l, 4n, 4o, or 4Unclassified. Three epidemiological profiles were identified: (1) patients infected with HCV by intravenous drug use were infected solely with subtype 4d. They were all of European origin, and 15 of the 16 patients were ethnic Danes. No single transmission event could be confirmed, but the pairwise nucleotide identity within the patients of Danish origin was relatively high (∼95%), suggesting a recent introduction into Denmark. (2) The 21 patients infected with subtype 4a all came from Northern Africa, Egypt, Pakistan, or the Middle East. (3) Patients from Southern Africa dominated among patients infected with subtype 4r (10 of 12 patients). This study demonstrates that HCV genotype 4d has been introduced in and spread among Danish intravenous drug users. The remaining subtypes show restricted distribution, infecting almost exclusively patients from geographical areas with a relatively high prevalence of HCV genotype 4 infections.

High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment.

Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

Pre-screening HIV-1 reverse transcriptase resistance mutations in subtype B patients using a novel multiplex primer extension assay.

Antiretroviral therapy is standard treatment for HIV-infected patients. Such therapy has decreased mortality and morbidity, but treatment success is often jeopardized by the emergence of viral drug resistance. Moreover, in recent years there has been a reported rise in the incidence of transmitted drug resistance, highlighting the importance of pre-treatment resistance screening. In this report, we describe the development and utility of a sensitive multiplex approach for detecting mutations conferring drug resistance to HIV-1 reverse transcriptase inhibitors. This protocol, termed HIV-SNaPshot, utilizes a multiplex primer extension assay with capillary electrophoresis reporting altered nucleotides at nine important drug resistance mutation positions. Mutations were successfully detected to levels of 5% in viral quasispecies populations. Furthermore, although developed and optimised for HIV-1 subtype B, drug resistance mutations could also be detected in most non-B subtypes. Comparison of the HIV-SNaPshot with the commercial Viroseq genotyping system in 10 patients gave similar results, but importantly, additional resistance mutations were identified in several patients by the HIV-SNaPshot assay. Thus, the HIV-SNaPshot is a method capable to support standard genotyping for the determination of minority HIV-1 resistance mutations, with equivalent and perhaps greater sensitivity than Viroseq.

Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study.

BACKGROUND: Human immunodeficiency virus (HIV) infection predisposes to progressive multifocal leukoencephalopathy (PML). Here, we describe the incidence, presentation, and prognosis of PML in HIV-1-infected patients during the period before highly active antiretroviral therapy (HAART) (1995-1996) and during the early HAART (1997-1999) and late HAART (2000-2006) periods. METHODS: Patients from a nationwide population-based cohort of adult HIV-1-infected individuals were included. We calculated incidence rates of PML and median survival times after diagnosis. We also described neurological symptoms at presentation and follow-up. RESULTS: Among 4,649 patients, we identified 47 patients with PML. The incidence rates were 3.3, 1.8, and 1.3 cases per 1000 person-years at risk in 1995-1996, 1997-1999, and 2000-2006, respectively. The risk of PML was significantly associated with low CD4(+) cell count, and 47% of cases were diagnosed by means of brain biopsy or polymerase chain reaction analysis for JC virus. The predominant neurological symptoms at presentation were coordination disturbance, cognitive defects, and limb paresis. Thirty-five patients died; the median survival time was 0.4 years (95% confidence interval [CI], 0.0-0.7) in 1995-1996 and 1.8 years (95% CI, 0.6-3.0) in both 1997-1999 and 2000-2006. CD4(+) cell count >50 cells/microL at diagnosis of PML was significantly associated with reduced mortality. CONCLUSIONS: The incidence of PML in HIV-infected patients decreased after the introduction of HAART. Survival after PML remains poor. In the management of PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

Liver biopsy performance and histological findings among patients with chronic viral hepatitis: a Danish database study.

We investigated the variance of liver biopsy frequency and histological findings among patients with chronic viral hepatitis attending 10 medical centres in Denmark. Patients who tested positive for HBsAg or HCV- RNA were retrieved from a national clinical database (DANHEP) and demographic data, laboratory analyses and liver biopsy results were collected. A total of 1586 patients were identified of whom 69.7% had hepatitis C, 28.9% hepatitis B, and 1.5% were coinfected. In total, 771 (48.6%) had a biopsy performed (range 33.3-78.7%). According to the Metavir classification, 29.3% had septal fibrosis (> or =F2) and 13.9% had cirrhosis (F4). The frequency of cirrhosis varied from 8.3 to 18.6% among centres, and was independently associated with age, male gender, elevated alanine-aminotransferase (ALT) and non-Danish origin. Among 141 patients with hepatitis C and known duration of infection, cirrhosis had developed in 23% after 20 y of infection. Age above 40 y was a better predictor of cirrhosis than elevated ALT. National database comparison may identify factors of importance for improved management of patients with chronic viral hepatitis.

Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression.

BACKGROUND: The nef gene from HIV-1 has been shown to be an important pathogenic factor when considering development of AIDS. Detection of nef variants with an effect on immune modulation is important to understand HIV-1 pathogenesis and has possible impact on treatment strategies. METHODS: The nef gene of HIV-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. RESULTS: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS.