Prevention and Treatment of Hepatitis B Virus Infection in HIV-Infected Patients

We describe in a multicenter study the feasibility and effectiveness of an accelerated hepatitis B vaccination schedule compared to the standard regimen in HIV-infected patients. The results show that the compliance with an accelerated schedule is significantly better, although its efficacy is only non-inferior in patients with a CD4+ cell-count >500 cells/mm3. In all HIV-infected patients a better response rate is provided in patients on HAART with undetectable HIV-RNA load, longer duration of HAART use, female gender and younger age. Around 50% of our HIV-infected cohort responded on initial HBV vaccination. In an attempt to achieve a higher response rate we prospectively revaccinated all non-responders three times at monthly intervals with double dose HBV vaccine. An additional 51% responded in the revaccination series. This response was more likely in patients younger than 40 years of age, irrespective of viral load, while in patients older than 40 years an undetectable HIV-RNA load is associated with a better response rate. We studied the possible relationship between HBV and influenza vaccination in HIV-infected patients. A trend for higher geometric mean titers, both in pre- and post- influenza immunization was found in HBV vaccination responders. We also retrospectively investigated the long-term efficacy of tenofovir administered as a part of antiretroviral therapy in a large cohort of HIV/HBV co-infected patients. It is shown that after five years of follow-up, approximately 90% of patients achieved undetectable HBV-DNA load. There was no significant difference between patients with or without lamivudine resistance at baseline. Furthermore, no confirmed genotypic substitutions in the HBV polymerase gene associated with decreased sensitivity to tenofovir have been identified in our cohort

Patient experiences with value-based healthcare interventions at the HIV outpatient clinic of the Erasmus Medical Centre

Background One of the aims of value-based healthcare (VBHC) is to deliver more patient-centred care. However, little is known about the effect of VBHC interventions on patient experiences. We aim to explore how patients experience VBHC as implemented in an HIV outpatient clinic in an academic hospital in the Netherlands. Methods The HIV outpatient clinic of the Erasmus MC, Rotterdam, the Netherlands, an academic tertiary hospital, implemented a VBHC intervention consisting of 1) implementation of a generic quality of life questionnaire, administered before each visit, 2) a change in consultation schedule; from twice a year face-to-face to one face-to-face double consultation and one remote consultation per year, and 3) a change in consultation structure; from a single face-to-face consultation with the infectious diseases (ID) specialist to a double consultation in which the patient visits both the nurse and the ID specialist. Semi-structured interviews were held with Dutch or English-speaking adult patients, that had been a patient within Erasmus MC for more than 5 years, on their experiences with the implemented changes. Results Thirty patients were interviewed. Patients had no objections towards completing the questionnaires especially if it could provide the professionals with additional information. Patients were primarily positive about the change in consultation schedule. For the yearly remote consultation they preferred a telephone-consultation above a video-consultation. The change in consultation structure ensured that more topics, including psychosocial and medical aspects could be discussed. Some patients did not see the added value of talking to two professionals on the same day or completing the quality of life questionnaire before their consultation. Conclusion Patients are generally positive towards the VBHC interventions implemented at the HIV outpatient clinic. Our findings may inform further optimization of VBHC interventions and improve patient-centred care in outpatient HIV clinics.</p

Patient experiences with value-based healthcare interventions at the HIV outpatient clinic of the Erasmus Medical Centre

Background One of the aims of value-based healthcare (VBHC) is to deliver more patient-centred care. However, little is known about the effect of VBHC interventions on patient experiences. We aim to explore how patients experience VBHC as implemented in an HIV outpatient clinic in an academic hospital in the Netherlands. Methods The HIV outpatient clinic of the Erasmus MC, Rotterdam, the Netherlands, an academic tertiary hospital, implemented a VBHC intervention consisting of 1) implementation of a generic quality of life questionnaire, administered before each visit, 2) a change in consultation schedule; from twice a year face-to-face to one face-to-face double consultation and one remote consultation per year, and 3) a change in consultation structure; from a single face-to-face consultation with the infectious diseases (ID) specialist to a double consultation in which the patient visits both the nurse and the ID specialist. Semi-structured interviews were held with Dutch or English-speaking adult patients, that had been a patient within Erasmus MC for more than 5 years, on their experiences with the implemented changes. Results Thirty patients were interviewed. Patients had no objections towards completing the questionnaires especially if it could provide the professionals with additional information. Patients were primarily positive about the change in consultation schedule. For the yearly remote consultation they preferred a telephone-consultation above a video-consultation. The change in consultation structure ensured that more topics, including psychosocial and medical aspects could be discussed. Some patients did not see the added value of talking to two professionals on the same day or completing the quality of life questionnaire before their consultation. Conclusion Patients are generally positive towards the VBHC interventions implemented at the HIV outpatient clinic. Our findings may inform further optimization of VBHC interventions and improve patient-centred care in outpatient HIV clinics.</p

Vaccination with Fendrix of prior nonresponding patients with HIV has a high success rate

Background: Patients with HIV have a poor serological conversion rate with the standard vaccination strategy against hepatitis B virus (HBV) of around 50%. Vaccination with Fendrix confers much better results in these patients. In this study, we tested the effect of revaccination with Fendrix in prior nonresponding patients with HIV and aimed to determine which factors are associated with seroconversion. Methods: Eight Dutch HIV treatment centers participated in this retrospective study. Patients infected with HIV-1 and nonresponding to prior course of vaccination against HBV (anti-HBs <10 IU/ml) and who had Fendrix as a second, third or fourth effort to achieve seroconversion were eligible for inclusion. Primary outcome was the proportion of patients with seroconversion after revaccination with Fendrix. Univariate binary logistic regression analyses were used to determine which factors could be used as predictors for seroconversions. Results: We included 100 patients with HIV. The mean age was 47.3 (11.0) years and 86% were men. Revaccination with Fendrix showed a seroconversion rate of 81% (95% confidence interval 72–88%). Median nadir CD4þ cell count was 300 (20–1040) cells/ ml and median CD4þ cell count at the time at starting vaccination with Fendrix was 605 (210–1190) cells/ml. Regression analyses showed no significant factor associated with seroconversion. Conclusions: Revaccination with Fendrix of patients prior nonresponding to other hepatitis B vaccination strategies has a high success rate. Eighty-one percentage responded with seroconversion, irrespective of CD4þ cell count

Suppression of HBV by Tenofovir in HBV/HIV coinfected patients : a systematic review and meta-analysis

Background: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone

Viral Hepatitis and Rapid Diagnostic Test Based Screening for HBsAg in HIV-infected Patients in Rural Tanzania.

\ud \ud Co-infection with hepatitis B virus (HBV) is highly prevalent in people living with HIV in Sub-Saharan Africa. Screening for HBV surface antigen (HBsAg) before initiation of combination antiretroviral therapy (cART) is recommended. However, it is not part of diagnostic routines in HIV programs in many resource-limited countries although patients could benefit from optimized antiretroviral therapy covering both infections. Screening could be facilitated by rapid diagnostic tests for HBsAg. Operating experience with these point of care devices in HIV-positive patients in Sub-Saharan Africa is largely lacking. We determined the prevalence of HBV and Hepatitis C virus (HCV) infection as well as the diagnostic accuracy of the rapid test device Determine HBsAg in an HIV cohort in rural Tanzania. Prospectively collected blood samples from adult, HIV-1 positive and antiretroviral treatment-naïve patients in the Kilombero and Ulanga antiretroviral cohort (KIULARCO) in rural Tanzania were analyzed at the point of care with Determine HBsAg, a reference HBsAg EIA and an anti-HCV EIA. Samples of 272 patients were included. Median age was 38 years (interquartile range [IQR] 32-47), 169/272 (63%) subjects were females and median CD4+ count was 250 cells/µL (IQR 97-439). HBsAg was detected in 25/272 (9.2%, 95% confidence interval [CI] 6.2-13.0%) subjects. Of these, 7/25 (28%) were positive for HBeAg. Sensitivity of Determine HBsAg was rated at 96% (95% CI 82.8-99.6%) and specificity at 100% (95% CI, 98.9-100%). Antibodies to HCV (anti-HCV) were found in 10/272 (3.7%, 95% CI 2.0-6.4%) of patients. This study reports a high prevalence of HBV in HIV-positive patients in a rural Tanzanian setting. The rapid diagnostic test Determine HBsAg is an accurate assay for screening for HBsAg in HIV-1 infected patients at the point of care and may further help to guide cART in Sub-Saharan Africa

Unsuccessful therapy with adefovir and entecavir-tenofovir in a patient with chronic hepatitis B infection with previous resistance to lamivudine: a fourteen-year evolution of hepatitis B virus mutations

<p>Abstract</p> <p>Background</p> <p>Complex mutants can be selected under sequential selective pressure by HBV therapy. To determine hepatitis B virus genomic evolution during antiviral therapy we characterized the HBV quasi-species in a patient who did no respond to therapy following lamivudine breakthrough for a period of 14 years.</p> <p>Case Presentation</p> <p>The polymerase and precore/core genes were amplified and sequenced at determined intervals in a period of 14 years. HBV viral load and HBeAg/Anti-HBe serological profiles as well as amino transferase levels were also measured. A mixture of lamivudine-resistant genotype A2 HBV strains harboring the rtM204V mutation coexisted in the patient following viral breakthrough to lamivudine. The L180M+M204V dominant mutant displayed strong lamivudine-resistance. As therapy was changed to adefovir, then to entecavir, and finally to entecavir-tenofovir the viral load showed fluctuations but lamivudine-resistant strains continued to be selected, with minor contributions to the HBV quasi-species composition of additional resistance-associated mutations. At the end of the 14-year follow up period, high viral loads were predominant, with viral strains harboring the lamivudine-resistance signature rtL180M+M204V. The precore/core frame A1762T and G1764A double mutation was detected before treatment and remaining in this condition during the entire follow-up. Specific entecavir and tenofovir primary resistance-associated mutations were not detected at any time. Plasma concentrations of tenofovir indicated adequate metabolism of the drug.</p> <p>Conclusions</p> <p>We report the selection of HBV mutants carrying well-defined primary resistance mutations that escaped lamivudine in a fourteen-year follow-up period. With the exception of tenofovir resistance mutations, subsequent unselected primary resistance mutations were detected as minor populations into the HBV quasispecies composition during adefovir or entecavir monotherapies. Although tenofovir is considered an appropriate therapeutic alternative for the treatment of entecavir-unresponsive patients, its use was not effective in the case reported here.</p

Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets.

OBJECTIVE: Triomune Baby and Junior have been developed in response to the urgent need for appropriate paediatric fixed-dose combination antiretroviral tablets, with higher nevirapine to stavudine and lamivudine ratios than adult tablets, in accordance with paediatric recommendations. We determined whether this ratio results in optimal exposure in the target population. METHODS: Seventy-one Zambian children were treated with Triomune Baby or Junior dosed according to weight bands. After 4 weeks or more, a 12-h pharmacokinetic curve was recorded. Antiretroviral plasma concentrations were assayed by high-performance liquid chromatography. RESULTS: Six children were excluded because of poor adherence. Of the remaining 65, 24 (37%) were female, 24 (37%) weighed less than 15 kg and most were malnourished. Mean (range) nevirapine C12h, Cmax and AUC12h of 6.0 (1.4, 16.9) mg/l, 10.0 (3.8, 22.5) mg/l and 94.4 (32.1, 232) mg/l per hour were higher than those reported in adults. Nevirapine C12h was subtherapeutic (< 3.0 mg/l) in four children (6%). Mean stavudine and lamivudine C12h, Cmax, AUC12h (< 0.015 mg/l, 0.45 mg/l, 1.05 mg/l per hour and 0.09 mg/l, 1.33 mg/l, 5.42 mg/l per hour) were comparable to adults. There was no evidence of a difference in nevirapine AUC12h across weight bands (P = 0.2), whereas the difference in stavudine (P = 0.0003) and lamivudine AUC12h (P = 0.01) was driven by the single weight band with unequal dosing. CONCLUSION: Nevirapine concentrations were higher but more variable than in adults; the pharmacokinetic parameters of stavudine and lamivudine were comparable to adults. As nevirapine underdosing is of greater concern than overdosing, the Triomune Baby and Junior ratio appears to be appropriate for children weighing 6 kg and over. Further research is required for children under 6 kg

A case series of familial ARID1B variants illustrating variable expression and suggestions to update the ACMG criteria

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses