Background: In HIV-infected patients, the immunogenicity of hepatitis B vaccines is impaired. In this randomised controlled study (RCT), we investigated the effect of Fendrix® versus double-dose Engerix® vaccination in previously non-responsive HIV-infected subjects. Methods: Patients included those who were HIV-infected and non-responders to a primary (single-dose hepatitis B (HBV) vaccination) and a subsequent double-dose HBV revaccination schedule. Subjects were randomised 1:1 to receive Fendrix® (t = 0, 4, 8, 24 weeks) or double-dose Engerix® (t = 0, 4, 24 weeks) vaccinations. Primary efficacy, defined as anti-HBs response ≥ 10 IU/l, was evaluated at week 28 in both study arms. Results: A subset of 48 patients non-responsive to HBV vaccination was selected, from a cohort of patients at our institution, who underwent HBV vaccination unsuccessfully either in a previous RCT or through standard care. The anti-HBs ≥ 10 IU/l response rate at week 28 in the Fendrix® arm and the Engerix® arm were 85.7% and 65.0%, respectively (p = 0.09). There was no significant difference between the two used vaccine types in the anti-HBs levels reached. In our institution, the overall response rate after initial standard-dose vaccination schedule and double-dose revaccination in our cohort was 75%. In this study, combining the effects of Fendrix and Engerix resulted in a 75% response rate in the 25% remaining non-responders on initial and double-dose revaccination series. This yielded an absolute 19% increase and an overall response to HBV vaccination in HIV-infected patients of around 94% in our cohort. Conclusion: These results together, suggest that continuing HBV vaccination in non-responders to a first course of single-dose vaccine and a double-dose revaccination scheme is worth the effort. No superiority of one of the investigated hepatitis B vaccines was shown in this cohort but an appropriate number of patients needed to achieve reliable answers was not achieved.

INTRODUCTION:HIV-infected patients are more than 100-fold greater at risk for developing malignant AIDS-related lymphoma (ARL) compared to the general population. Most ARLs are EBV related. The main purpose of this study was to investigate whether a high peak EBV DNA load in HIV-infected patients is predictive of ARL, including classical Hodgkin lymphoma. METHODS:From an ongoing prospective HIV positive cohort study, we conducted a case-control study between 2004 and 2016 among patients from whom at least one EBV DNA load in serum or plasma was available. We compared peak EBV DNA load between patients with (49 cases) and without ARL (156 controls). RESULTS:The geometric mean of the peak EBV DNA load measured before diagnosis of malignant lymphoma was 52,565 IU/mL in EBER-positive lymphoma patients vs. 127 IU/mL in controls (p < .001). Patients with EBV DNA loads >100,000 IU/mL have an increased risk for diagnosis of malignant lymphoma compared to patients with EBV DNA loads ≤100,000 IU/mL (adjusted OR 12.53; 95%CI: 4.08; 38.42). In the longitudinal study, including 13 patients with at least three left-over plasma samples available for retesting, measurements of EBV-DNA during the preceding 12 months proved to be of poor value for predicting subsequent lymphoma diagnosis. CONCLUSIONS:A EBV DNA load >100,000 IU/mL can be useful in clinical setting to accelerate time to diagnosis and treatment. EBV-DNA loads in samples taken during the preceding year of ARL diagnosis showed to be of poor predictive value.

Background: To obtain maximal benefit of combination antiretroviral therapy (cART), HIV-infected patients should be retained in medical care. Missed clinical visits are independently associated with all-cause mortality among HIV-infected patients. Our objective was to identify risk factors and patient-reported reasons for nonattendance at outpatient clinic appointments. Design and methods: We conducted a cross-sectional case-control study among 447 HIV-infected patients attending the outpatient clinic between March and July 2014. Patients with missed appointments from January 2013 onwards were included as cases and compared to a random selection of same-day controls without missed appointments during the same period. Clinical and socio-demographic characteristics were collected from clinical records and an interviewer-administered questionnaire. Additionally, reasons for nonattendance and possible solutions for future better attendance were addressed in the questionnaire. Multivariable logistic regression analysis was used to determine independent risk factors for nonattendance. Results: A total of 224 cases and 223 controls were included. Independent risk factors for nonattendance were: (i) age <30 years (odds ratio (OR) 7.2; 95% CI: 3.2-16.3 versus 50 years); (ii) African region of origin (OR 2.8; 95% CI: 1.5-5.0 versus Western origin); (iii) having children <12 years of age (OR 2.1; 95% CI: 1.1-4.1); (iv) history of drugs- or alcohol abuse (OR 4.4; 95% CI: 1.8-10.8); (v) no cART (OR 2.5; 95% CI: 1.1-5.3) or HIV-RNA >400 copies/ml while receiving cART (OR 3.5; 95% CI: 1.3-9.6). The main reason given for nonattendance was failure to remember the appointments (44%). Most patients would prefer to receive an appointment reminder by SMS (80% of the cases and 55% of the controls). Conclusion: Missing outpatient clinic appointments were associated with available clinical characteristics. Nonattendance may be prevented by sending routine SMS reminders prior to the next appointment.

Background: Maternal transmission is the most common cause of HCV infection in children. HIV co-infection and high levels of plasma HCV-RNA have been associated with increased HCV transmission rates.Objectives: We assessed the vertical HCV transmission rate in the HIV-HCV co-infected group of pregnant women on cART.Study design: We conducted a retrospective study in a Dutch cohort of HIV-positive pregnant women and their children. We identified co-infected mothers. Results of the HCV tests of the children were obtained.Results: All 21 women were on cART at the time of delivery. We analyzed data of the 24 live-born children at risk for mother-to-child transmission (MTCT) of HCV between 1996 and 2009. HIV-RNA was <500 copies/ml during 18/24 [75%] deliveries, the median CD4(+) cell count was 419 cells/mu l (290-768). There was no transmission of HIV. The median plasma HCV-RNA in our cohort of 23 non-transmitting deliveries in 21 women was 3.5x10E5 viral eq/ml (IQR 9.6x104-1.5x106 veq/mL). One of 24 live-born children was found to be infected with HCV genotype 1. At the time of delivery the maternal plasma HIV-RNA was <50 copies/ml, the CD4(+) cell count was 160 cells/mu l and maternal plasma HCV-RNA was 4.6x10E6 veq/ml. This amounted to a prevalence of HCV-MTCT of 4%.Conclusion: In this well-defined cohort of HIV-HCV co-infected pregnant women, all treated with cART during pregnancy, a modest rate of vertical HCV transmission was observed. (C) 2015 Elsevier B.V. All rights reserved.

BACKGROUND:The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice.METHODS:A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm.RESULTS:Efficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count <200 cells/mm³ (P < 0.001), GSS <3 (P = 0.002) and use of lamivudine (P < 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT).CONCLUSIONS:In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3.

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.

Background: In recent years chronic hepatitis E virus (HEV) infections have been reported in immunosuppressed patients, including HIV-positive patients with low CD4 cell counts. Because of delayed anti-HEV seroconversion in patients with CD4 cell count <200 cells/ml it is difficult to draw firm conclusions on HEV-seroprevalence in a population of HIV positive patients.Objectives: To determine the HEV seroprevalence in a population of HIV infected patients.Study design: We retrospectively analysed the HEV prevalence in a population of 256 HIV infected patients with liver enzyme elevations (LEEs), using HEV specific antibody testing and HEV-RNA detection.Results: Within this cohort we observed a HEV-seroprevalence of 11.7%, without any anti-HEV IgM positive or HEV-RNA positive cases. HEV seropositivity was equally prevalent among different CD4(+) cell count groups.Conclusion: Although HIV infected patients in the Netherlands are at risk of acquiring HEV, the number of acute infections is low and no chronic cases were found. (C) 2014 Elsevier B.V. All rights reserved.

BACKGROUND:Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection.AIM:To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome.METHODS:All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case–control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed.RESULTS:On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3–2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1–19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2–22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003).CONCLUSIONS:HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation

Background: The incidence of anal intraepithelial neoplasia (AIN) and anal cancer is increased in HIV-positive men who have sex with men (MSM). Persistent high-risk human papillomavirus (HPV) infection is an important etiologic agent. Methods: In this study, a group of 250 HIV-positive MSM was included to determine the prevalence of AIN and to investigate the role of highly active antiretroviral therapy (HAART), high-risk HPV, and other risk factors possibly associated with this prevalence. Results: Among patients included, 108 (43.2%) had lesions suspicious for AIN. Histologic analyses showed AIN 1 in 24 patients (22.2%), AIN 2 in 6 patients (5.6%), and AIN 3 in 10 patients (9.3%). In multivariable analyses, the use of HAART was associated with the absence of AIN (P = 0.045). In MSM without HAART, HPV infection was detected significantly more often compared with those who used HAART (P = 0.010). AIN was associated with HPV types 16 and 6. Conclusions: In this cross-sectional study in 250 HIV-positive MSM, the use of HAART was associated with lower prevalence of AIN and a significantly lower prevalence of HPV. This association between the prevalence of AIN and the absence of HAART may contribute to the current debate on when to start HAART in HIV-infected individuals.

Purpose of the studyIdiopathic non‐cirrhotic portal hypertension (INCPH) has been reported increasingly in patients with chronic HIV infection. However, several aspects of this disorder remain to be elucidated. The aim of our study was to evaluate the prevalence and risk factors of HIV associated INCPH.MethodsAll adult HIV patients attending the outpatient clinic between February and September 2011 underwent sonographical spleen size determination and assessment of portosystemic collaterals. Patients with splenomegaly underwent an extensive ultrasound examination. Gastroscopy was performed when additional signs of portal hypertension or collaterals were observed. All children with HIV infection underwent extensive ultrasound examination. INCPH was diagnosed according to the general definition. Differences between INCPH cases (group 1) and HIV patients treated with didanosine (ddI) without portal hypertension (group 2) were assessed at HIV diagnosis, start of ddI and INCPH diagnosis.Summary of resultsFour out of 1010 screened adult HIV patients were diagnosed with INCPH (prevalence of 4‰). Hundred of the 1010 screened patients were treated with ddI. All INCPH patients were treated with ddI, representing an INCPH prevalence of 4% in patients exposed to ddI. In The Netherlands, 7000 patients were treated with ddI and only 17 are diagnosed with INCPH, suggesting underdiagnosis in 260 patients. No differences in clinical characteristics predictive for the development of INCPH could be demonstrated between group 1 and group 2 at HIV infection or start of ddI treatment. INCPH patients were treated longer with ddI [86 vs. 51 months, p<0.01] and concomitant treatment with ddI and stavudine [21 vs. 4 months, p<0.01]. Corrected for age and duration of follow‐up of HIV, active protein c [0.64 vs. 1.13, p<0.01] and active protein s [0.67 vs. 1.01, p<0.01] levels were lower in the INCPH group. None of the 38 children with HIV infection were diagnosed with INCPH. None of these children were ever treated with ddI.ConclusionsIn our study HIV‐associated INCPH only occurred in patients exposed to ddI. Awareness for this disorder is warranted considering the suggested underdiagnosis based on these study results. Risk factors are long term treatment with ddI and concomitant treatment with stavudine and screening for signs of portal hypertension in this subgroup may be recommended. A possible pathophysiological role for thrombophilia remains to be elucidated. image

OBJECTIVES:The aim of the study was to gain more insight into the relationship between transmitted singletons found at HIV diagnosis by population sequencing and the possible presence of clinically relevant viral minorities containing additional resistance mutations. METHODS:We studied the viral quasispecies and therapy response in 10 individuals with transmitted single nucleoside reverse transcriptase inhibitor (NRTI)-related resistance mutations as detected by population sequencing. RESULTS:Ultra-deep pyrosequencing did not reveal additional drug-resistance mutations in nine of 10 patients. In these nine patients, no breakthrough with resistant viruses was observed despite the use of low genetic nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in the majority of patients. CONCLUSIONS:These data suggest that viral minority variants containing additional resistance mutations may be rare in patients with transmitted NRTI singletons in the Netherlands. Larger studies are required to confirm these findings and to determine the therapeutic consequences.

VIRAL HEPATITIS -b) HEPATITIS C -EXPERIMENTAL (VIROLOGY) S123 interval.After the second DC-injection, tumors were analyzed by flow cytometry.Results: Co-culture with Ad-CD40L-transduced DC enhanced significantly the cytotoxicity against Hepa129-cells of splenocytes in comparison to co-culture with Ad-IL-2 or Ad-LacZ-transduced DC (p < 0.05).Combination of CD40L/IL-2-expressing DC inhibited the tumor-growth significantly compared to mice treated with control DC or IL-2-DC (p < 0.05).However, the antitumoral activity of the combination was not stronger compared to DC transduced only with Ad-CD40L.Furthermore, CD40L-DC showed even a stronger inhibition of tumor growth than the combination of CD40L/IL-2-DC: the mean tumor volume was 361.4±118.5 mm 3 in CD40L-DC-treated animals vs. 868.2±510.5 in CD40L/IL-2-or 1805±309.7 mm 3 in LacZ-DC-treated mice.Flow cytometry of tumors treated with CD40L-expressing DC revealed higher tumor-infiltration with CD4+-, CD8+-T-cells and NK-cells than tumors treated with CD40L/IL-2 DC.Conclusions: The combination of CD40L/IL-2-expressing DC can significantly inhibit the tumor-growth, activating both acquired and innate immunity.However, this effect seemed not to be synergistic, as treatments with CD40L-DC seemed to have even stronger antitumoral effects than the combination of CD40L-and IL-2-DC.These data underline the potential of the co-stimulation on CD40/CD40L-interaction in DC-based approaches against tumor disease.

During peginterferon-alfa-2a/ribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IU/mL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCV/HIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2a/ribavirin-treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (Delta0-48), the slope (lambda(1)) and the efficiency factor (epsilon) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIV/HCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIV/HCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIV/HCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger Delta0-48 and steeper lambda(1) (-1.77log(10) IU/mL +/- 0.66 and -2.04/day +/- 0.76) compared to nine non-RVR patients (-0.66log(10) IU/mL +/- 0.39; P = 0.019 and -0.76/day +/- 0.41; P = 0.019). When divided by SVR, a greater Delta0-48 and steeper lambda(1) were also seen in both HCV mono-infected and HIV/HCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.

Purpose: To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiveness of ATV in maintaining virus suppression. Methods: Retrospective cohort study in patients with viral suppression, comparing patients switching to ATV with those continuing combination antiretroviral therapy (cART). Outcome measures were 48-week total (TC), high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) changes, stratified for dyslipidemia and lipodystrophy and virological failure (time to first of two consecutive detectable HIV RNA). Results: 225 patients switched to ATV (193 [85.8%] RTV boosted), and 3120 continued cART. In patients with baseline TC >6.2 mmol/L, those switching had greater mean (95% CI) TC decreases compared to those continuing cART (-1.26 [-1.63 to -0.89] and -0.54 [-0.64 to -0.44] mmol/L, p=.002). Likewise greater TG changes were observed in patients with high (>2.3 mmol/L) baseline TG (-1.44 [-2.05 to -0.83] and -0.54 [-0.70 to -0.38] mmol/L, p=.002). Effects were seen irrespective of presence of lipodystrophy. Patients switching to ATV had virological failure more often (17/224 [7.8%]) than those continuing cART (73/3100 [2.4%], p<.0001). Conclusions: Patients with virological suppression, including those with lipodystrophy, may benefit from switching to ATV with lipid profile improvement, especially if baseline lipid levels are high. This should be balanced against a possible higher virological failure risk.

ObjectivesOptimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother-to-child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations.MethodsWe included all HIV-1-infected women for whom NVP plasma concentrations were available as part of routine patient care at two university hospitals. Plasma NVP concentrations were compared for pregnant (n=45) and non-pregnant (n=152) women. Univariate and multivariate linear regression analyses were used to identify and adjust for other confounding factors associated with NVP plasma concentrations. For pregnant women who had a plasma NVP concentration available both during and outside pregnancy, a paired analysis was performed.ResultsSteady-state NVP plasma concentrations were lower in pregnant women: 5.2 mg/L (interquartile range 3.9-6.8) vs. 5.8 mg/L (4.3-7.7) (P=0.08). After adjusting for confounders, both pregnancy (regression coefficient=-0.90 mg/L, P=0.046) and African descent (regression coefficient=+1.13 mg/L, P=0.005) influenced NVP concentrations significantly. The paired analysis showed mean concentrations of 4.8 mg/L during pregnancy and 5.8 mg/L outside pregnancy (paired t-test, P=0.073).ConclusionsPregnancy has a moderate but significant lowering effect on NVP plasma concentrations. Being of African descent compensates for the lowering effect of pregnancy on NVP concentrations.