Single nucleotide polymorphism (SNP) rs3751143 in P2RX7 is associated with therapy failure in chronic Q fever while rs7125062 in MMP1 is associated with fewer complications.

OBJECTIVES: Chronic Q fever is a persistent infection with the intracellular bacterium Coxiella burnetii. Development of chronic Q fever is associated with single nucleotide polymorphisms (SNPs) in genes encoding for pattern recognition receptors, for phagolysosomal pathway components and for matrix metalloproteinases (MMPs). We evaluated the association of SNPs in these innate-immunity and MMP genes with clinical outcomes. METHODS: SNPs were selected from previous association studies and analysed in a cohort of patients with chronic Q fever. The primary outcome was all-cause mortality; secondary outcomes were therapy failure and chronic Q fever-related complications. Subdistribution hazard ratios (SHR) were calculated. RESULTS: Nineteen SNPs were analysed in 134 patients with proven and 29 with probable chronic Q fever. In multivariable analysis, none of the selected SNPs was associated with all-cause mortality. However, SNP rs3751143 located in P2RX7 appeared to be associated with therapy failure (SHR 2.42; 95% confidence interval, 1.16-5.05; p 0.02), which is in line with other reports, showing that a loss of function of the P2X7 receptor leads to inefficient killing of intracellular organisms. In addition, SNP rs7125062 located in MMP1, involved in the cleavage of extracellular matrix, was associated with fewer chronic Q fever-related complications such as acute aneurysms (SHR 0.49; 95% confidence interval, 0.29-0.83; p 0.008). CONCLUSIONS: A polymorphism in P2RX7, known to lead to loss of function of the receptor and inefficient killing of intracellular organisms, and a polymorphism in MMP1 were respectively associated with more therapy failures and fewer complications such as acute aneurysms in patients with chronic Q fever.

Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial.

OBJECTIVES: To investigate whether antibiotic treatment of 6 days' duration is non-inferior to treatment for 12 days in patients hospitalized for cellulitis. METHODS: This multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial enrolled adult patients hospitalized for severe cellulitis who were treated with intravenous flucloxacillin. At day 6 participants with symptom improvement who were afebrile were randomized between an additional 6 days of oral flucloxacillin or placebo in a 1:1 ratio, stratified for diabetes and hospital. The primary outcome was cure by day 14, without relapse by day 28. Secondary outcomes included a modified cure assessment and relapse rate by day 90. RESULTS: Between August 2014 and June 2017, 151 of 248 included participants were randomized. The intention-to-treat population consisted of 76 and 73 participants allocated to 12 and 6 days of antibiotic therapy, respectively (mean age 62 years, 67% males, 24% diabetics); 38/76 (50.0%) and 36/73 (49.3%) were cured in the 12- and 6-day groups respectively (ARR 0.7 percentage points, 95%CI: -15.0 to 16.3). Cure rates were 56/76 (73.7%) and 49/73 (67.1%) with the modified cure assessment (ARR 6.6, 95%CI: -8.0 to 20.8). After initial cure without relapse, day 90 relapse rates were higher in the 6-day group (6% versus 24%, p < 0.05). CONCLUSIONS: Given the wide confidence intervals, we can neither confirm nor refute our hypothesis that 6 days of therapy is non-inferior to 12 days of therapy. However, a 6-day course resulted in significantly more frequent relapses by day 90. These findings require confirmation in future studies.

Efficacy and safety of long-term maraviroc use in a heterogeneous group of HIV-infected patients: A retrospective cohort study.

Since the registration of maraviroc (MVC) as an antiretroviral agent in 2008, only studies with a follow-up time of <5 years have been published. Therefore, little is known about its long-term safety and efficacy in clinical practice. In this cohort study, data on long-term follow-up of MVC treatment in routine practice were analysed. A retrospective cohort study was conducted at University Medical Centre Utrecht with a follow-up period up to almost 10 years. The efficacy and tolerability of MVC-containing antiretroviral therapy (ART) was analysed in human immunodeficiency virus type 1 (HIV-1)-infected patients. The cohort consisted of 111 HIV patients who were treated for a median of 11.0 years (IQR 4.0-15.0 years) and with a median of 4 (IQR 2-6) previous ART regimens. The median time of MVC use was 49 months (IQR 21-82 months). Mean CD4+ T-cell counts continued to increase up to 9 years following initiation of MVC. Patients with a detectable viral load (≥50 copies/mL HIV-RNA) at the start of MVC-containing ART reached high proportions of viral suppression. Only three patients (2.7%) experienced treatment failure despite optimal therapy. Nine patients (8.1%) discontinued MVC owing to intolerance of their ART regimen. Severe laboratory abnormalities were deemed to be unrelated to MVC use. During the 487 person-years of follow-up, 18 patients (16.2%) died. MVC use in this heavily pre-treated cohort was generally well tolerated during long-term follow-up. Furthermore, use of MVC resulted in a good immunological and virological response in clinical practice.

Chronic Q fever-related complications and mortality: data from a nationwide cohort.

OBJECTIVES: Chronic infection with Coxiella burnetii (chronic Q fever) can cause life-threatening conditions such as endocarditis, infected vascular prostheses, and infected arterial aneurysms. We aimed to assess prognosis of chronic Q fever patients in terms of complications and mortality. METHODS: A large cohort of chronic Q fever patients was assessed to describe complications, overall mortality and chronic Q fever-related mortality. Chronic Q fever-related mortality was expressed as a case fatality rate (number of chronic Q fever-related deaths/number of chronic Q fever patients). RESULTS: Complications occurred in 166 of 439 (38%) chronic Q fever patients: in 61% of proven (153/249), 15% of probable (11/74), and 2% of possible chronic Q fever patients (2/116). Most frequently observed complications were acute aneurysms (14%), heart failure (13%), and non-cardiac abscesses (10%). Overall mortality was 38% (94/249) for proven chronic Q fever patients (median follow-up 3.6 years) and 22% (16/74) for probable chronic Q fever patients (median follow-up 4.7 years). The case fatality rate was 25% for proven (63/249) chronic Q fever patients and 4% for probable (3/74) chronic Q fever patients. Overall survival was significantly lower in patients with complications, compared to those without complications (p <0.001). CONCLUSIONS: In chronic Q fever patients, complications occur frequently and contribute to the mortality rate. Patients with proven chronic Q fever have the highest risk of complications and chronic Q fever-related mortality. Prognosis for patients with possible chronic Q fever is favourable in terms of complications and mortality.

Strategies for achieving viral hepatitis C micro-elimination in the Netherlands.

The Netherlands is striving to achieve national elimination of the hepatitis C virus (HCV) as one of the first countries worldwide. The favorable HCV epidemiology with both low prevalence and incidence, together with access to care and treatment, present excellent conditions to further build on towards this objective. The Dutch national plan on viral hepatitis, introduced in 2016, defines targets in the HCV healthcare cascade and provides a structural framework for the development of elimination activities. Since many different stakeholders are involved in HCV care in the Netherlands, focus has been placed on micro-elimination initiatives as a pragmatic and efficient approach. These numerous micro-eliminations projects have brought the Netherlands closer to HCV elimination. In the near future, efforts specifically have to be made in order to optimize case-finding strategies and to successfully accomplish the nationwide implementation of the registration and monitoring system of viral hepatitis mono-infections, before this final goal can be reached. The upcoming years will then elucidate if the Dutch' hands on approach has resulted in sufficient progress against HCV and if the Netherlands will lead the way towards nationwide HCV elimination.

Syndromic sample-to-result PCR testing for respiratory infections in adult patients.

BACKGROUND: Syndromic sample-to-result (SS2R) poly merase chain reaction (PCR) can rapidly identify causative pathogens of respiratory tract infections (RTI). We evaluated diagnostic accuracy and applicability of one of the current SS2R diagnostics, the FilmArray® Respiratory Viral Panel. METHODS: We performed a prospective study among adults presenting with symptoms of RTI at the Emergency Department of the University Medical Centre Utrecht (the Netherlands) during the 2016-2017 viral respiratory season. Clinical data were collected. We compared SS2R results on nasopharyngeal swabs to conventional real time PCR, calculated turnaround times (TAT) and explored implementation barriers using questionnaires. RESULTS: 62 Patients were included (64.5 yr [interquartile range (IQR) 44.3-75.0]). SS2R sensitivity was 82.9% [95% confidence interval (CI) 67.9-92.9] and specificity was 95.2% [95% CI 76.2-99.9] for detection of all present viruses (n = 60). Kappa agreement (0.73 [95% CI 0.56-0.90]) was good (p = 0.000). Median SS2R TAT was 2:06 hours [IQR 1:45-3:17] compared to 32:00 hours [IQR 26:50-40:42] of conventional PCR (n = 49, p = 0.000). Ease-of-use and fast TAT were unanimously reported as benefits, and low test capacity with a single SS2R system as drawback. CONCLUSION: SS2R testing for respiratory viruses offers a rapid and reliable diagnostic method which has great potential for more efficient and targeted management in adult patients with RTI.

The effect of measuring serum doxycycline concentrations on clinical outcomes during treatment of chronic Q fever.

Background: First choice treatment for chronic Q fever is doxycycline plus hydroxychloroquine. Serum doxycycline concentration (SDC) >5 µg/mL has been associated with a favourable serological response, but the effect on clinical outcomes is unknown. Objectives: To assess the effect of measuring SDC during treatment of chronic Q fever on clinical outcomes. Methods: We performed a retrospective cohort study, to assess the effect of measuring SDC on clinical outcomes in patients treated with doxycycline and hydroxychloroquine for chronic Q fever. Primary outcome was the first disease-related event (new complication or chronic Q fever-related mortality); secondary outcomes were all-cause mortality and PCR-positivity. Multivariable analysis was performed with a Cox proportional hazards model, with shared-frailty terms for different hospitals included. Results: We included 201 patients (mean age 68 years, 83% male): in 167 patients (83%) SDC was measured, 34 patients (17%) were treated without SDC measurement. First SDC was >5 µg/mL in 106 patients (63%), all with 200 mg doxycycline daily. In patients with SDC measured, dosage was adjusted in 41% (n = 68), concerning an increase in 64 patients. Mean SDC was 4.1 µg/mL before dosage increase, and 5.9 µg/mL afterwards. SDC measurement was associated with a lower risk for disease-related events (HR 0.51, 95% CI 0.26-0.97, P = 0.04), but not with all-cause mortality or PCR-positivity. Conclusions: SDC measurement decreases the risk for disease-related events, potentially through more optimal dosing or improved compliance. We recommend measurement of SDC and striving for SDC >5 µg/mL and <10 µg/mL during treatment of chronic Q fever.

The Montreal Cognitive Assessment-Basic (MoCA-B) is not a reliable screening tool for cognitive decline in HIV patients receiving combination antiretroviral therapy in rural South Africa.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) are frequently occurring comorbidities in HIV-positive patients, diagnosed by means of a neuropsychological assessment (NPA). Due to the magnitude of the HIV-positive population in Sub-Saharan Africa, easy-to-use cognitive screening tools are essential. METHODS: This was a cross-sectional clinical trial involving 44 HIV-positive patients (on stable cART) and 73 HIV-negative controls completing an NPA, the International HIV Dementia Scale (IHDS), and a culturally appropriate cognitive screening tool, the Montreal Cognitive Assessment-Basic (MoCA-B). HAND were diagnosed by calculating Z-scores using internationally published normative data on NPA, as well as by using data from the HIV-negative group to validate the MoCA-B. RESULTS: One hundred and seventeen patients were included (25% male, median age 35 years, median 11 years of education). A moderate correlation was found between the MoCA-B and NPA total Z-score (Pearson's r=0.36, p=0.02). Area under the curve (AUC) values for MoCA-B and IHDS were 0.59 and 0.70, respectively. The prevalence of HAND in HIV-positive patients was 66% when calculating Z-scores using published normative data versus 48% when using the data from the present HIV-negative cohort. CONCLUSION: The MoCA-B appeared not to be a valid screening tool for HAND in this setting. The prevalence of HAND in this setting is high, but appeared overestimated when using published norms.

Osteoporosis and osteopenia are not associated with T-cell activation in older cART-treated HIV-infected patients.

BACKGROUND: A higher risk of developing osteopenia/ osteoporosis has been seen in HIV-infected patients. We compared HIV-infected patients, all treated with combination antiretroviral therapy (cART), with a low bone mineral density (BMD) (T-score < -1) to those with a normal BMD (T-score > -1), examining the relation with T-cell activation and bone turnover markers (c-terminal telopeptide (CTX) and procollagen type 1 amino-terminal propeptide (P1NP)). METHODS: In this single visit pilot study, bone turnover markers, T-cell activation (CD38 + HLA - DR +) and senescence (CD57+) of T cells were measured in patients who had previously undergone dual energy X-ray absorptiometry scanning. RESULTS: All study participants (n = 16) were male, on cART, with a median age of 61 years (IQR 56-66). Nine patients had osteopenia/osteoporosis. When comparing the patients with osteopenia/osteoporosis with those with a normal BMD, no differences in activation and senescence were found. A relation was seen between higher bone formation (P1NP) and patients who were on cART for longer. The median length of cART use was 5.5 years (IQR 4.5-7.8), with all patients on nucleoside reverse transcriptase inhibitors, 88% on tenofovir, 63% on non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 38% on protease inhibitors. Osteopenia/osteoporosis was seen in 100% of the patients on protease inhibitors versus 30% of those on NNRTIs. CONCLUSION: This study did not find an association between activated T cells and BMD, thus did not explain the higher prevalence of osteopenia/osteoporosis in HIV-infected patients. Interestingly, this small pilot showed that cART might influence BMD, with a possible negative effect for protease inhibitors and a possible protective effect for NNRTIs. These results warrant further investigation.

Review of functional MRI in HIV: effects of aging and medication.

HIV-associated neurocognitive disorder (HAND) is a frequently occurring comorbidity of HIV infection. Evidence suggests this condition starts subclinical before a progression to a symptomatic stage. Blood oxygenated level dependent (BOLD) fMRI has shown to be a sensitive tool to detect abnormal brain function in an early stage and might therefore be useful to evaluate the effect of HIV infection on brain function. An extensive literature search was performed in June 2015. Eligibility criteria for included studies were as follows: (1) conducting with HIV-positive patients, (2) using BOLD fMRI, and (3) including a HIV-negative control group. A total of 19 studies were included in the review including 931 participants. Differences in activation between HIV-positive and -negative participants were found when testing multiple domains, i.e., attention, (working) memory, and especially executive functioning. Overall, HIV-positive patients showed hyperactivation in task-related brain regions despite equal performances as controls. Task performance was degraded only for the most complex tasks. A few studies investigated the effect of aging on fMRI, and most of them found no interaction with HIV infection. Only three studies evaluated the effect of combination antiretroviral therapy (cART) on functional data suggesting an increase in activation with the use of cART. fMRI is a sensitive instrument to detect subtle cognitive changes in HIV patients. Open questions remain regarding the effects of cART on fMRI and the effects of aging on fMRI.

Performance of hepatitis C virus (HCV) direct-acting antivirals in clinical trials and daily practice.

In recent years a revolution in hepatitis C virus drug development has taken place from troublesome regimens with pegylated interferon-alfa for 24 to 48 weeks with limited success to all-oral single tablet regimens taken for 12 weeks with very high chances of success. These promising results are not available to everybody. Depending on, for example, geographical factors with limited availability of new compounds, virus factors like hepatitis C virus genotype and host factors like presence of cirrhosis, these favorable outcomes can be compromised. This review discusses the recent clinical trials (from phase 3 registration through real-world application), highlighting the different available regimens and their success rates.

Cardiovascular risk prediction in HIV-infected patients: comparing the Framingham, atherosclerotic cardiovascular disease risk score (ASCVD), Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk prediction models.

OBJECTIVES: The aim of the study was to compare the predictions of five popular cardiovascular disease (CVD) risk prediction models, namely the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, the Framingham Heart Study (FHS) coronary heart disease (FHS-CHD) and general CVD (FHS-CVD) models, the American Heart Association (AHA) atherosclerotic cardiovascular disease risk score (ASCVD) model and the Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) model. METHODS: A cross-sectional design was used to compare the cumulative CVD risk predictions of the models. Furthermore, the predictions of the general CVD models were compared with those of the HIV-specific D:A:D model using three categories (< 10%, 10-20% and > 20%) to categorize the risk and to determine the degree to which patients were categorized similarly or in a higher/lower category. RESULTS: A total of 997 HIV-infected patients were included in the study: 81% were male and they had a median age of 46 [interquartile range (IQR) 40-52] years, a known duration of HIV infection of 6.8 (IQR 3.7-10.9) years, and a median time on ART of 6.4 (IQR 3.0-11.5) years. The D:A:D, ASCVD and SCORE-NL models gave a lower cumulative CVD risk, compared with that of the FHS-CVD and FHS-CHD models. Comparing the general CVD models with the D:A:D model, the FHS-CVD and FHS-CHD models only classified 65% and 79% of patients, respectively, in the same category as did the D:A:D model. However, for the ASCVD and SCORE-NL models, this percentage was 89% and 87%, respectively. Furthermore, FHS-CVD and FHS-CHD attributed a higher CVD risk to 33% and 16% of patients, respectively, while this percentage was < 6% for ASCVD and SCORE-NL. CONCLUSIONS: When using FHS-CVD and FHS-CHD, a higher overall CVD risk was attributed to the HIV-infected patients than when using the D:A:D, ASCVD and SCORE-NL models. This could have consequences regarding overtreatment, drug-related adverse events and drug-drug interactions.

Clinical outcome of maraviroc-containing therapy in heavily pre-treated HIV-1-infected patients.

Available data on the use of maraviroc (MVC) in clinical settings are limited. In this cohort study, the clinical outcomes of HIV-1-infected patients treated with MVC were analysed and the predictive values of different tropism assays were compared. Baseline viral tropism was assessed and compared by phenotypic (Trofile and MT-2) and genotypic assays. Virological and immunological responses were evaluated. In total, 62 predominantly extensively pre-treated patients started MVC [median GSS 2.0 (IQR 2.0-2.5)]. Tropism assays were performed on baseline samples of 58 patients (93.5%). Thirty-two samples (80.0%) were classified as R5 by Trofile, 41 (80.4%) by genotypic tropism test (GTT) and 17 (81.0%) by MT-2. At least two types of tropism assay were performed on samples from 39 patients, whereas in 15 patients all three assays were performed (concordance 84.8-94.1%). Plasma HIV-RNA was <50 copies/mL in 82.1%, 85.0% and 68.8% of patients after 12, 24 and 36 months, respectively; median CD4 cell increase was 199 (IQR 108-283), 291 (IQR 187-413) and 234 (IQR 106-444)cells/µL. The predictive values of different tropism assays were comparably high: at Month 24, 92.9% (Trofile and GTT) and 100.0% (MT-2) of patients had plasma HIV-RNA <50 copies/mL. Three patients stopped MVC treatment because of suspected side effects. Five patients died during follow-up. In this heavily pre-treated cohort, treatment with MVC was well tolerated and resulted in good immunological and virological responses. Results generated by the different tropism assays correlated well with each other and had a high predictive value.

Favourable SVR12 rates with boceprevir or telaprevir triple therapy in HIV/HCV coinfected patients.

BACKGROUND: Recent publications have reported superior efficacy of telaprevir- or boceprevir-based triple therapy over conventional peginterferon-alfa/ribavirin therapy, albeit with varying rates of adverse events and treatment discontinuations in HIV/HCV coinfected patients. Therefore, the aim of this study is to describe the effectiveness of triple therapy in an HIV/HCV coinfection cohort in the Netherlands. METHODS: HIV-infected patients with chronic HCV genotype 1 starting triple therapy including either boceprevir or telaprevir were enrolled, 26% had F3-F4 fibrosis. Data were assessed at Week 4, 8, 12, 24, 48 and SVR12 (i.e. absence of detectable plasma HCV RNA 12 weeks after completion of treatment). Failure was defined as discontinuation of treatment due to virological failure, adverse events or loss to follow-up. RESULTS: A total of 53 HIV/HCV coinfected patients started peginterferon-alfa/ribavirin therapy with either boceprevir (n = 29) or telaprevir (n = 24). SVR12 was achieved in 19 (66%) of the boceprevir-treated and 15 (63%) of the telaprevir-treated patients. Both prior relapse and achievement of a rapid virological response were associated with a higher SVR12 rate. Non- response, breakthrough and relapse occurred in 4, 1 and 5 patients on boceprevir and 3, 2, 2 on telaprevir, respectively. One patient was lost to follow-up and one patient died due to progression of liver failure. Except for these two patients, no treatment discontinuations were observed due to adverse events. CONCLUSION: In HIV/HCV coinfected patients, boceprevir or telaprevir triple therapy was well tolerated and resulted in favourable SVR12 rates comparable with previous publications concerning HCV mono-infected patients.

Low serum hyaluronic acid levels associated with spontaneous HBsAg clearance.

PURPOSE: The pathophysiological underlying mechanism of spontaneous HBsAg clearance in hepatitis B virus (HBV) infected patients is largely unknown. However, serum hyaluronic acid (sHA) plays a role in liver fibrosis progression and reversely could serve as a potential biomarker for HBsAg clearance. This study investigates whether low sHA is associated with HBsAg loss in non-Asian HBV patients. METHODS: Non-Asian women living in Amsterdam with known chronic HBV infection between 1990-2003 were invited for a single follow-up visit at the Municipal Health Service Amsterdam between September 2011 to May 2012. Serum hyaluronic acid and liver stiffness measurement together with clinical evaluation, biochemical and virologic blood tests were performed. RESULTS: Of the 160 women, HBsAg loss occurred in 38 (23 %) patients between diagnosis and follow-up. sHA levels were lower in HBsAg negative patients compared to HBsAg positive patients (14.5 [9.4-27.2] ng/mL vs 25.0 [12.3-42.5] ng/mL, p <0.01). A similar distinction in sHA between low and high HBV DNA was noted. sHA had a significant discriminatory ability to differentiate between HBsAg positive and HBsAg negative patients, (AUC 0.65 [95 % CI 0.55-0.75], p < 0.01). In multivariable analysis only sHA level was associated with HBsAg loss (OR 0.4 [0.2-0.9]). Finally, F3-F4 fibrosis (cut-off >8.1 kPa) was diagnosed in 3 % in HBsAg negative patients compared to 10 % in HBsAg positive patients (p = 0.15). CONCLUSION: Serum HA levels are lower in patients who experience spontaneous HBsAg loss compared to HBsAg positive patients.

Primary resistance to integrase strand-transfer inhibitors in Europe.

OBJECTIVES: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. METHODS: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score ≥ 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing. RESULTS: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score ≥ 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score ≥ 10 were found in 8 (14.3%) individuals. CONCLUSIONS: No signature InSTI-resistant variants were circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years.

Current knowledge and future perspectives on acute hepatitis C infection.

Acute hepatitis C virus (HCV) infections are frequently seen worldwide in certain risk groups, with an annual incidence rate varying between 0.08% and 66%. Although this incidence is substantial, a delayed diagnosis during chronic infection is most often made in the absence of clinical symptoms in the acute phase of the infection. Currently used methods to diagnose acute HCV infection are IgG antibody seroconversion and repeated HCV RNA measurements, although no definitive diagnostic test is currently available. Progress in the field of adaptive and innate immune responses has aided both advances in the field of HCV vaccine development and a more basic understanding of viral persistence. The rapid changes in the treatment of chronic HCV infection will affect therapeutic regimens for acute HCV infection in the coming years, leading to shorter treatment courses and pegylated interferon-free modalities. This review gives an overview of the current knowledge and uncertainties, together with some future perspectives on acute hepatitis C epidemiology, virology, immunology, and treatment.

Extensive thoracolumbosacral vertebral osteomyelitis after Lemierre syndrome.

PURPOSE: To present a unique case of multilevel vertebral osteomyelitis after Lemierre syndrome. METHODS: A previously healthy 27-year-old man presented in the Emergency Department in septic shock because of Lemierre syndrome for which he was subsequently treated with intravenous benzylpenicillin for 2 months. Two and a half months later, the patient was readmitted with severe back pain without neurological deficits or fever. Imaging revealed an extensive vertebral osteomyelitis of the complete thoracic, lumbar and sacral spine. RESULTS: Although the blood cultures obtained at the initial admission for Lemierre syndrome revealed Fusobacterium species and Streptococcus milleri, the cultures from the spinal biopsies remained negative. Histology of the spinal biopsies showed a purulent sclerosing osteomyelitis. The patient was successfully treated with intravenous piperacillin and tazobactam. Despite persisting back pain, no recurrence of infection was seen at 3 years of follow-up. CONCLUSION: Lemierre syndrome and an extensive thoracolumbosacral vertebral osteomyelitis are rare but serious infections. Clinicians must maintain a high index of suspicion for infectious metastases leading to vertebral osteomyelitis when a patient presents with back pain after an episode of life-threatening septicaemia caused by Lemierre syndrome.

A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

OBJECTIVES: The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). METHODS: An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/µL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/µL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). RESULTS: For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. CONCLUSIONS: A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

ELF-test less accurately identifies liver cirrhosis diagnosed by liver stiffness measurement in non-Asian women with chronic hepatitis B.

BACKGROUND: The enhanced liver fibrosis test (ELF-test) has been validated for several hepatic diseases. However, its performance in chronic hepatitis B virus (CHB) infected patients is uncertain. OBJECTIVE: This study investigates the diagnostic value of the ELF test for cirrhosis identified by liver stiffness measurement (LSM) in non-Asian women with CHB. STUDY DESIGN: Women of non-Asian origin with perinatally acquired CHB infection, detected during pregnancy in the period 1990-2003, returned to our center between September 2011 and May 2012 for LSM and blood sampling to perform an ELF test and to calculate, APRI and FIB-4 scores. Fibrosis stages were classified by the METAVIR system. RESULTS: A total of 119 women were included in this study with a median age of 43 years, all ALT levels being <2× ULN and all being HBeAg negative. The overall median LSM (IQR) stiffness and ELF test were 5.5kPa (4.0-6.8) and 8.4 (7.8-9.2) respectively. LSM and ELF test classified 14 (12%) and 19 (16%) patients with severe fibrosis to cirrhosis (≥F3, i.e. liver stiffness >8.1kPa), however in only 4 (3%) patients there was an agreement between LSM and ELF test. With LSM as reference, the area under receiver operating characteristic curve (AUROC) for detection of ≥F3 fibrosis was for ELF 0.65 (95% CI 0.51-0.80; p=0.06), APRI 0.66 (0.50-0.82; p=0.07) and FIB-4 0.66 (0.49-0.82; p=0.07). CONCLUSION: The ELF test less accurately discriminates severe fibrosis or cirrhosis when compared to LSM in our cohort of non-Asian women with CHB.