British HIV Association guidelines for the management of hepatitis viruses in adults infected with HIV 2013

Introduction Scope and purpose Methodology Guideline development process Patient involvement GRADE Good practice points Dissemination and implementation Guideline updates and date of next review Resource use References Summary of recommendations Patient involvement in care Introduction Good practice points Auditable outcome Rationale References Screening, prevention and immunisation Introduction Screening investigations at diagnosis Recommendations Good practice points Auditable outcomes Rationale Assessment of liver disease Recommendations Good practice point Auditable outcomes Rationale Immunisation Recommendations Good practice points Auditable outcomes Rationale References Antiretroviral therapy Introduction Recommendations Good practice points Auditable outcome Rationale References Hepatitis B (HBV) Introduction Natural history HBV resistance, genotype testing and treatment response Recommendations Good practice point Rationale Thresholds for ART treatment Recommendations Good practice points Auditable outcome Rationale Antiviral treatment: CD4 count ≥500 cells/μL (Algorithm 1) Recommendations Rationale Pegylated interferon (PEG-IFN) Adefovir Antiviral treatment: CD4 count <500 cells/μL (Algorithm 2) Recommendations Good practice points Auditable outcomes Rationale Antiviral treatment: Acute HBV Recommendations Auditable outcome Rationale References Hepatitis delta (HDV) Introduction Recommendations Good practice point Auditable outcome Rationale References Hepatitis C (HCV) Introduction Natural history Diagnosis of HCV after high-risk exposure Recommendations Good practice points Auditable outcomes Rationale Thresholds and timing of treatment Recommendations Good practice points Auditable outcome Rationale Choice of ART Recommendations Good practice point Auditable outcomes Rationale Assessment and investigation Good practice points Auditable outcome Rationale Antiviral treatment: genotype 1 Recommendations Good practice points Auditable outcomes Rationale Antiviral treatment: genotypes 2 and 3 Recommendations Good practice points Auditable outcomes Rationale Antiviral treatment: other genotypes Good practice points Auditable outcomes Rationale Acute hepatitis C Recommendations Good practice points Auditable outcomes Rationale References Hepatitis E Recommendations Auditable outcome Rationale References End-stage liver disease Introduction Recommendations Good practice points Auditable outcomes Rationale References Acknowledgements Conflicts of interest statements List of Abbreviations List of Appendices Summary modified GRADE system Literature search Questions and PICO criteria Search protocols The purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV and viral hepatitis coinfection. The scope includes: i) guidance on diagnostic and fibrosis screening; ii) preventative measures including immunisation and behavioural intervention; iii) ARV therapy and toxicity; iv) management of acute and chronic HBV/HIV and HCV/HIV; v) monitoring and management of coinfection-related end-stage liver disease (ESLD) including transplantation; and vi) discussion on HDV/HIV and HEV/HIV infection. The guidelines are aimed at clinical professionals involved in and responsible for the care of adults with HIV and viral hepatitis coinfection, and at community advocates responsible for promoting the best interests and care of adults with coinfection. They should be read in conjunction with other published BHIVA and hepatitis guidelines. BHIVA revised and updated the Association's guideline development manual in 2011 [1]. BHIVA has adopted the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for the assessment, evaluation and grading of evidence and the development of recommendations [2–3]. The guideline was developed by a Writing Group comprising professional group members and an elected community representative. The scope, purpose and guideline topics were agreed by the Committee and key questions concerning each guideline topic were drafted (Table 1.1) and a systematic literature review undertaken by an information scientist. Full details of the guideline development process are outlined in the appendices to this document. Review questions were developed in a PICO (patient, intervention, comparison and outcome) framework. This framework guided the literature-searching process, critical appraisal and synthesis of evidence, and facilitated the development of recommendations by the Guideline Writing Group. Eleven review questions were identified. Full literature searches and critical appraisals were completed for all specified questions. Because of a lack of comparative data for any of the priority questions in hepatitis/HIV coinfection, no separate meta-analyses were conducted. Members of the Guideline Writing Group declared their conflicts of interests prior to the commencement of the writing process, and if a vote was necessary any member whose declared interests made this inappropriate did not participate. BHIVA hepatitis coinfection guidelines for hepatitis B and C were last published in 2010 [4]. For the 2013 guidelines the literature search dates were 1 January 2009 to 30 October 2012, and included Medline, Embase and the Cochrane library. Abstracts from selected conferences (see Appendix 2) were searched between 1 January 2009 and 30 October 2012. For each topic and health care question, evidence was identified and evaluated by Guideline Writing Group members with expertise in that field. Using the modified GRADE system (Appendix 1), panel members were responsible for assessing and grading the quality of evidence for predefined outcomes across studies and developing and grading the strength of recommendations. An important aspect of evaluating evidence is an understanding of the design and analysis of clinical trials including the use of surrogate marker data. For a number of questions, GRADE evidence profile and summary of findings tables were constructed using predefined and rated treatment outcomes (Appendix 2) to achieve consensus for key recommendations and aid transparency of process. Prior to final approval by the Writing Group the guidelines were published online for public consultation and external peer review commissioned. BHIVA views the involvement of patient and community representatives in the guideline development process as essential. The Writing Group included one patient representative who was involved in all aspects of the guideline development process and was responsible for liaising with all interested patient groups. The GRADE Working Group [3] has developed an approach to grading evidence that moves from initial reliance on study design to consider the overall quality of evidence across outcomes. BHIVA has adopted the modified GRADE system for the Association's guideline development. The advantages of the modified GRADE system are: (i) the grading system provides an informative, transparent summary for clinicians, patients and policy makers by combining an explicit evaluation of the strength of the recommendation with a judgement of the quality of the evidence for each recommendation; (ii) the two-level grading system of recommendations has the merit of simplicity and provides clear direction to patients, clinicians and policy makers. A Grade 1 recommendation is a strong recommendation to do (or not do) something, where benefits clearly outweigh risks (or vice versa) for most, if not all, patients. Most clinicians and patients would want to follow a strong recommendation unless there is a clear rationale for an alternative approach. A strong recommendation usually starts with the standard wording 'We recommend'. A Grade 2 recommendation is a weaker or conditional recommendation, where the risks and benefits are more closely balanced or are more uncertain. Alternative approaches or strategies may be reasonable depending on the individual patient's circumstances, preferences and values. A weak or conditional recommendation usually starts with the standard wording 'We suggest'. The strength of a recommendation is determined not only by the quality of evidence for defined outcomes but also the balance between desirable and undesirable effects of a treatment or intervention, differences in values and preferences, and where appropriate resource use. Each recommendation concerns a defined target population and is actionable. In addition to graded recommendations, the BHIVA Writing Group has also included good practice points (GPP), which are recommendations based on the clinical judgement and experience of the working group. GPPs emphasise an area of important clinical practice for which there is not, nor is there likely to be, any significant research evidence. They address an aspect of treatment and care that is regarded as such sound clinical practice that health care professionals are unlikely to question it and where the alternative recommendation is deemed unacceptable. It must be emphasised that GPPs are not an alternative to evidence-based recommendations. The following measures have, or will be undertaken, to disseminate and aid implementation of the guidelines: i) e-publication on the BHIVA website and the Journal HIV Medicine; ii) publication in the journal HIV Medicine; iii) e-learning module accredited for CME; iv) an educational slide set to support local and regional educational meetings; and v) National BHIVA Audit Programme. The guidelines will be reviewed and updated as required on a 6-monthly basis with a plan for an extensive rewrite in 2016. The Writing Group will continue to meet regularly to consider new information from high-quality studies and publish amendments and addendums to the current recommendations prior to the full revision date where this is clinically important data developed to ensure continued best clinical practice. The BHIVA Writing Group recognises that cost-effectiveness data are important in the formulation of guidelines and it was agreed as a critical outcome for certain priority questions (Table 1.1). There are limited cost-effectiveness data in the UK comparing different antiretroviral drugs in HIV mono-infection and none examining different antiretroviral drugs or anti-HBV or anti-HCV therapies in adults with HBV/HIV or HCV/HIV infection or different screening strategies for hepatitis viruses in HIV infection. Hence, the intervention was deemed cost-effective if it was both less costly in terms of likely resource use and more clinically effective compared with other relevant alternative strategies within the data available to the expert(s) writing the specific guideline. However, the Writing Group believes that reducing management costs should not be at the cost of increased risk of poorer outcomes and quality of care. 1 BHIVA Guideline Development Manual, September 2011. Available at: www.bhiva.org/GuidelineDevelopmentManual.aspx (accessed 3 May 2013). 2 Guyatt, GH, Oxman, AD, Kunz, R et al. Going from evidence to recommendations. BMJ 2008; 336: 1049– 1051. 3 The Grading of Recommendations Assessment, Development and Evaluation (short GRADE) Working Group. Available at: www.gradeworkinggroup.org (accessed 3 May 2013). 4 Brook, G, Main, J, Nelson, M et al. for the BHIVA Viral Hepatitis Working Group. British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010. HIV Med 2010; 11: 1– 30. BHIVA views the involvement of patient and community representatives in the guideline development process as essential. The Writing Group includes a patient representative appointed through the UK HIV Community Advisory Board (UK-CAB) who was involved in all aspects of the guideline development process. Studies that have evaluated patient perspectives on ART therapy in HIV have shown that trust, a good-quality relationship, and good communication skills between doctor and patient are associated with better adherence and treatment outcomes [1–5]. Also, adherence is affected by patient beliefs about the necessity, efficacy and side effects of treatment, the practicability of taking it, and their ability to adhere to therapy [6–9]. Before starting ART or anti-hepatitis treatments in adults with coinfection, clinicians should consider the factors outlined in Box 3.1. Community advocacy and peer support are helpful in supporting and educating patients in their understanding of ART and anti-hepatitis therapy and guide the patient in treatment decisions. Working in collaboration with healthcare professionals, community organisations in the UK have been instrumental in providing a range of patient information resources and peer-support services for both hepatitis and HIV. These include published and web-based information materials, telephone advice lines, treatment advocates and peer-support groups. They are an important and essential adjunct to clinic-based services. A number of patient factors may affect adherence, adverse effects and treatment outcomes for both ART and anti-hepatitis treatments. Depression, alcohol and recreational drugs are associated with poor ART adherence [10–13] and provision of social support has been shown to influence experience and reporting of adverse events in hepatitis C treatment [14]. Patients should be screened for mental health illness in the clinic (particularly depression) including specific enquiry about alcohol and recreational drug use with the offer of support to moderate or manage it [15–16]. In addition, clinicians should be aware of each patient's socio-economic status and refer to social support where necessary, as this has been shown to have a direct effect on treatment adherence and other healthcare behaviours. Practical issues such as financial and transport support for the increased number of clinic visits necessary when undergoing treatment for HCV is also important to assess prior to initiation of treatment. Improved ART adherence has been associated with positive experiences of quality of life such as having a meaningful life, feeling comfortable and well cared for, using time wisely, and taking time for important things [17]. Patient self-management skills and courses that facilitate this have been associated with both improved adherence and better clinical outcomes in a number of studies [18–20] and it may be helpful to inform patients of these and other psychological support options which are locally available in line with the BPS/BHIVA Standards for Psychological Support for Adults Living with HIV [21]. Clinicians should establish what level of involvement the patient would like and tailor their consultation style appropriately. They should also consider how to make information accessible and understandable to patients (e.g., with pictures, symbols, large print and different languages) [22], including linguistic and cultural issues. Youth is consistently associated with lower adherence to ART, loss to follow-up, and other negative healthcare behaviours [23] and some studies have found an independent association between poorer adherence and attendance and female gender [24], so information and consultation style should be age and gender appropriate for the patient. Neurocognitive impairment is more common in adults with HCV/HIV infection, and clinical assessment should be made prior to treatment. If there is a question about the patient's capacity to make an informed decision, this should be assessed using the principles in the Mental Capacity Act 2005 [25]. Patients presenting at the clinic may be at different stages of readiness to take ART therapy [26] and the clinician's first task is to assess their readiness, by means of open questions rather than closed, before supporting and furthering patients' decisions on therapy. The benefits of treating HCV or HIV first and of treating HCV now or deferring in the absence of significant liver disease require careful explanation and, where there is clinical equipoise, patients should be given the necessary time and assistance to make a decision. However, if a patient presents in circumstances that necessitate starting ART or HCV treatment urgently, then doctors should explain the reasons carefully and provide regular support for the patient's adherence, especially through the first few weeks. Recognising and appropriately managing symptoms that can be attributed to ART or HCV treatment side effects might avoid loss of adherence and deterioration of trust in the patient–provider relationship [27–28]. This will be especially important when initiating anti-HCV treatment because of the increased likelihood of side effects, hospital visits, and venepunctures; contact details for the treatment unit should be provided. Supporting patients requires good communication not just between clinician and patient but also between all healthcare staff involved with their care, including those in their HIV and hepatitis services, their GP, and any clinicians involved in management of further conditions. Patients should be offered copies of letters about them sent to their primary care doctor (GP) and other physicians. The advantages of disclosure of their conditions to the patient's GP should be discussed and considered best practice, as several situations require consensual clinical decision-making. A patient's decision not to disclose to their GP, one or more of their conditions, however, should always be respected, subject to the clinician's duty to protect vulnerable individuals. 1 Schneider, J, Kaplan, SH, Greenfield, S et al. Better physician-patient relationships are associated with higher reported adherence to antiretroviral therapy in patients with HIV infection. J Gen Intern Med 2004; 19: 1096– 1103. 2 Kremer, H, Ironson, G. To tell or not to tell: why people with HIV share or don't share with their physicians whether they are taking their medications as prescribed. AIDS Care 2006; 18: 520– 528. 3 Roberts, KJ. Physician-patient relationships, patient satisfaction, and antiretroviral medication adherence among HIV-infected adults attending a public health clinic. AIDS Patient Care STDS 2002; 16: 43– 50. 4 Owens, DM, Nelson, DK, Talley, NJ. The irritable bowel syndrome: long-term prognosis and the physician–patient interaction. Ann Intern Med 1995; 122: 107– 112. 5 Vermeire, E, Hearnshaw, H, Van Royen, P et al. Patient adherence to treatment: three decades of research. A comprehensive review. J Clin Pharm Ther 2001; 26: 331– 342. 6 Horne, R, Buick, D, Fisher, M et al. Doubts about necessity and concerns about adverse effects: identifying the types of beliefs that are associated with non-adherence to HAART. Int J STD AIDS 2004; 15: 38– 44. 7 Horne, R, Cooper, V, Gellaitry, G et al. Patients' perceptions of highly active antiretroviral therapy in relation to treatment uptake and adherence: the utility of the necessity-concerns framework. J Acquir Immune Defic Syndr 2007; 45: 334– 341. 8 Gonzalez, JS, Penedo, FJ, Llabre, MM et al. Physical symptoms, beliefs about medications, negative mood, and long-term HIV medication adherence. Ann Behav Med 2007; 34: 46– 55. 9 Maasoumy, B, Manns, MP. Optimal treatment with boceprevir for chronic HCV infection. Liver Int 2013; 33( Suppl 1): 14– 22. 10 Gonzalez, JS, Batchelder, AW, Psaros, C et al. Depression and HIV treatment non-adherence: a review and meta-analysis. J Acquir Immune Defic Syndr 2011; 58: 181– 187. 11 Hendershot, CS, Stoner, SA, Pantalone, DW et al. Alcohol use and antiretroviral adherence: review and meta-analysis. J Acquir Immune Defic Syndr 2009; 52: 180– 202. 12 Reback, CJ, Larkins, S, Shoptaw, S. Methamphetamine abuse as a barrier to HIV medication adherence among gay and bisexual men. AIDS Care 2003; 15: 775– 785. 13 Halkitis, PN, Kutnick, AH, Borkowski, T et al. Adherence to HIV medications and club drug use among gay and bisexual men. XIV International AIDS Conference. Barcelona, Spain. July 2002 [Abstract ThPeE7856]. 14 Lima, VD, Geller, J, Bangsberg, DR et al. The effect of adherence on the association between depressive symptoms and mortality among HIV-infected individuals first initiating HAART. AIDS 2007; 21: 1175– 1183. 15 Yun, LW, Maravi, M, Kobayashi, JS et al. Antidepressant treatment improves adherence to antiretroviral therapy among depressed HIV-infected patients. J Acquir Immune Defic Syndr 2005; 38: 432– 438. 16 Arroll, B, Khin, N, Kerse, N. Screening for depression in primary care with two verbally asked questions: cross sectional study. BMJ 2003; 327: 1144– 1146. 17 Holzemer, WL, Corless, IB, Nokes, KM et al. Predictors of self-reported adherence in persons living with HIV disease. AIDS Patient Care STDS 1999; 13: 185– 197. 18 Smith, SR, C et al. A medication self-management to adherence to HIV therapy Patient 2003; et al. of to self-management skills of with J Acquir Immune Defic Syndr 18: et al. that a chronic disease self-management can health status reducing a Med Care 1999; British Psychological British HIV for AIDS and Standards for psychological support for adults living with HIV. 2011. Available at (accessed 2013). National for and adherence: adults and in decisions about National Guideline Available at: (accessed 2013). D, S et al. Patient adherence to HIV medication a review of published and Patient 2002; T et al. gender lower and adherence to antiretroviral therapy in a of 2011; 11: on good capacity issues. 2010. Available at: (accessed In search of how people to S, B, et al. for the Group. symptoms after initiation of a in HIV-infected patients and their on adherence to HAART. HIV Clin 2001; 38– M, et al. for the Group. and of deterioration of a relationship among HIV-infected persons with antiretroviral therapy. J Acquir Immune Defic Syndr 2008; The following recommendations the prevention and screening for, viral hepatitis in the of including immunisation and drug use to and For the assessment and evaluation of evidence, priority questions were agreed and outcomes were important and not by members of the Writing Group. key questions were identified by the Writing Group in relation to acute HCV i) should screening be for HCV in adults with HIV infection 6 or 12 and ii) should the screening be HCV or HCV HCV cost and A further key question was whether liver or is the investigation of in the assessment of fibrosis of disease of from no adverse effects, cost and patient of the search and literature review are in Appendix Screening for viral hepatitis infection has been shown to be in HIV-infected with a to at both diagnosis and reported in a number of including a BHIVA recommendations to do so within guidelines Hepatitis A is in and is to It is a disease and HIV-infected individuals should be screened for and if hepatitis B virus (HBV) infection is associated with chronic liver disease including HBV as 10 genotypes with a such that an genotype will the genotype of their of There is evidence that genotypes different of chronic disease and genotype testing may have in outcome if treatment with interferon (PEG-IFN) is considered this is no in (see of HBV is defined as the of in for more than 6 The of in HIV patients in a study from the UK HIV was associated with a positive in this study were of having a history of or as when compared to This study an of HBV infection of of with acute infection to hepatitis B infection in of The risk of HBV infection was higher for than for and higher for than for in the absence of other of HBV infection or and is a common in the of HIV infection. The of may a HBV infection by loss of to or a positive HBV has been to between the two (see A less likely is a acute infection after loss of and before of will be Development of in of patients with and is by use of ART and CD4 but not by of drugs with HBV or self-reported HBV These data support the that a of HIV-infected patients with have prior HBV infection with that is at an level to The long-term of is not with a positive with HCV are more likely to for is to a infection and can positive for to 2 after acute infection. of those with long-term follow-up, which may be an of HBV or HBV infection. is in this (see The of HBV of usually level HBV in individuals testing depending on the population and including of the In the the of HBV are and there is no association with clinical this is in the of HBV infection. The is in individuals who negative for but have of HBV and evidence of liver disease (see with HCV among those with HIV has as an important of and mortality [25]. HCV in drug with exposure to and through and other The of HCV in individuals in the UK is reported at with risk of infection in