British HIV Association guidelines for the treatment of <scp>HIV</scp>‐1‐positive adults with antiretroviral therapy 2015

Abstract

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection on antiretroviral therapy (ART). The scope includes: (i) guidance on the initiation of ART in those previously naïve to therapy; (ii) support of people living with HIV (PLWH) on treatment; (iii) management of individuals experiencing virological failure; and (iv) recommendations in specific populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals directly involved with and responsible for the care of adults with HIV infection, and at community advocates responsible for promoting the best interests and care of HIV-positive adults. They should be read in conjunction with other published BHIVA guidelines. BHIVA fully revised and updated the association's guideline development manual in 2011. Further updates have been carried out subsequently 1. Full details of the guideline development process, including conflict of interest policy, are outlined in the manual. BHIVA has adopted the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for the assessment, evaluation and grading of evidence and development of recommendations (see below and Appendix 1) 2, 3. The scope, purpose and guideline topics were agreed by the writing group. Questions concerning each guideline topic were drafted and a systematic literature search was undertaken by an information scientist. Details of the search questions and strategy (including the definition of populations, interventions and outcomes) are outlined in Appendix 2. BHIVA guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy were last published in 2013 4. For the 2015 guidelines Medline, Embase and the Cochrane library were searched between October 2011 and August 2014. Abstracts from selected conferences (see Appendix 2) were searched between 1 January 2011 and July 2015. For each topic and healthcare question, evidence was identified and evaluated by writing group members with expertise in the field. Using the modified GRADE system, writing group 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. Decisions regarding the clinical importance of difference in outcomes are made by the writing group. For a number of questions, GRADE evidence profile and summary of findings tables were constructed, using predefined and rated treatment outcomes (Appendix 3), to help achieve consensus for key recommendations and aid transparency of the process. Before final approval by the writing group, the guidelines were published online for public consultation and an external peer review was commissioned. BHIVA views the involvement of PLWH and community representatives in the guideline development process as essential. The writing group included two representatives appointed through the UK HIV Community Advisory Board (UK-CAB) who were involved in all aspects of the guideline development process. Community groups were invited to participate in the draft guideline consultation process and a community consultation was held on 6th August 2015. The GRADE Working Group 3 has developed an approach to grading evidence that moves away from initial reliance on study design to consider the overall quality of evidence across outcomes. BHIVA has adopted the modified GRADE system for its guideline development. The advantages of the modified GRADE system are (i) the grading system provides an informative, transparent summary for clinicians, PLWH 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, and (ii) the two-level grading system of recommendations has the merit of simplicity and provides clear direction to PLWH, clinicians and policy makers. The strength of recommendation is graded as 1 or 2 as follows: 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. The quality of evidence is graded from A to D and for the purpose of these guidelines is defined as the following: 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 healthcare 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: The guidelines will be next fully updated and revised in 2017. However, 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 before the full revision date where this is thought to be clinically important to ensure continued best clinical practice. The primary aim of ART is the prevention of the mortality and morbidity associated with chronic HIV infection at low cost of drug toxicity. Treatment should improve the physical and psychological well-being of PLWH. The effectiveness and tolerability of ART has improved significantly over the last 15 years. The overwhelming majority of PLWH attending HIV services in the UK and receiving ART experience long-term virological suppression and good treatment outcomes 5, which compare very favourably with other developed countries. Notably, in 2013 around 90% of those diagnosed with HIV in the UK had initiated ART, with 93% of those on ART having a suppressed viral load 5. A UK analysis of individuals commencing ART between 2000 and 2010 demonstrates that the expected age at death for HIV-positive men from ART start was 68, 73 and 77 years at exact ages 20, 35 and 50 years, respectively, compared with 77, 78 and 79 years in the general population 6. The corresponding expected age at death for HIV-positive women was 69, 74 and 78 years, compared with 81, 82 and 83 years in the general population. The same study shows that life expectancy in men and women with an undetectable viral load and CD4 cell count greater than 350 cells/μL is the same as, or slightly better than, that for the general population 6. Modelling has suggested that for HIV-positive men who have sex with men (MSM) living in a developed country with extensive access to HIV care and assuming a high rate of HIV diagnosis, the life expectancy is 75 years 7. The authors concluded that the greatest risk of excess mortality is due to delays in HIV diagnosis. Decreasing late diagnosis (and consequently starting ART earlier), maintaining individuals in care and reducing long-term drug toxicity and non-aquired immune deficiency syndrome (AIDS) co-morbidities are crucial to further improving life expectancy and the well-being of people living with HIV infection. A further aim of treatment is the reduction in sexual transmission of HIV. The use of ART to prevent mother-to-child transmission is universally accepted and best practice is addressed in the BHIVA guidelines for the management of HIV infection in pregnant women 8. Recently, the size of the effect of ART on reducing the risk of sexual transmission of HIV has been estimated at >95% 9, 10. The PARTNER study investigated the risk of HIV transmission within serodifferent couples where the HIV-positive partner was on suppressive ART (viral load less than 200 copies/mL) and demonstrated no transmissions compared with a predicted 86 new infections had the positive partner not been on effective ART 11. The upper 95% confidence interval for risk of transmission was 0.4 per 100 couple years for any sex and 1.0 per 100 couple years for anal sex. At a population level, ART is likely to be important in reducing the incidence of HIV infection. ART is extremely cost-effective and compares favourably with the cost of management of many other chronic diseases. Estimates of the cost-effectiveness of ART have been assessed in studies in North America and Europe 12-14. Their findings have been consistent with an estimated incremental cost-effectiveness ratio of about US$20,000 per quality adjusted life year (QALY) for combination ART compared with no therapy based on drug costs and treatment patterns in the USA and Europe 15. The primary aim of these guidelines is to summarise and base recommendations on the clinical benefits of ART and different ART options. The number of people living with HIV in the UK continues to increase and by the end of 2013 was estimated to be 107,800 (95% credible interval 101,600–115,800), of whom 24% were undiagnosed. In 2013, 90% (73,290/81,510) of people seen for HIV care were prescribed ART 5. With ongoing HIV transmission, increased HIV testing and a reduction in the undiagnosed fraction, the number of people diagnosed with HIV and accessing HIV services will continue to increase. It has been estimated that the annual population treatment and care costs rose from £104 million in 1997 to £483 million in 2006, rising to a projected annual cost of £721 million in 2013 16. It is likely this estimated projected cost is an overestimate due to various factors, including earlier diagnosis and a lower proportion of individuals with symptoms. However, in the current economic climate containing and reducing costs without affecting the current high standards of care and treatment outcomes will be an immense challenge to commissioners, healthcare professionals and PLWH alike. A collaborative approach is required. In the UK, higher annual treatment and care costs have been associated with late diagnosis and initiation of ART at lower CD4 cell counts than the BHIVA guidelines recommend 17, 18. In addition to earlier diagnosis and initiation of ART, reducing inpatient episodes, decreasing drug toxicity, preventing HIV-associated co-morbidities and innovations in models of care are likely to have a beneficial effect on costs. However, the cost of antiretroviral (ARV) drugs remains the major factor contributing to treatment and care costs. With the increasing availability of generic drugs and the introduction of a standard tariff for HIV services (in England), commissioners and the NHS will be faced with difficult choices about the value and benefit of different ARV drugs. The BHIVA writing group recognises that cost of drugs is an important issue in the choice of ART regimens. In addition to drug acquisition costs there are costs associated with, for example, multidisciplinary team meetings, switching ART, co-morbidities and management of drug–drug interactions. There are limited cost-effectiveness data in the UK comparing different ARV drugs and for this reason we did not include cost-effectiveness as an outcome in ART comparisons. However, the writing group believes that decreasing the risks of virological failure, drug resistance and drug-associated toxicity are likely to have a beneficial impact on long-term cost-effectiveness and resource use. In the setting of similar virological efficacy, determining the acceptable threshold at which differences in the risk of toxicity, tolerability and convenience outweigh differences in resource use and cost will be important. These thresholds may differ among clinicians and PLWH alike. In developing the recommendations in these guidelines, we have taken into account differences in critical treatment outcomes between different drug regimens in determining preferred and alternative treatment regimens. We recognise and support that commissioning arrangements and local drug costs will and should influence ART choice where outcomes, across a range of clinical measures, are similar between individual drugs in the treatment of defined populations. However, we believe that reducing treatment costs should not be at the cost of an increased risk of poorer treatment outcomes and quality of care, not least as these are likely to have a detrimental impact on long-term cost. In reviewing quality of evidence, guidelines will identify areas of treatment and care where there is an absence of evidence or limited confidence in the size of effect to influence choice of treatments or determine treatment and management strategies. For this reason, it is not the intention of these guidelines to stifle clinical research but rather to help promote continued research with the aim to further improve clinical care and treatment outcomes. The development and provision of HIV clinical trials within the UK are supported, and participation in a clinical trial should be open and offered to PLWH where appropriate. Table 5.1.1 Summary recommendations for choice of ART NB. The viral load advice for abacavir/lamivudine and rilpivirine applies only to initiating these agents in individuals with a detectable viral load – when these agents are used as a switch option in the context of viral load suppression the baseline viral load can be disregarded. Table 8.2.1 Summary recommendations for the treatment of hepatitis B and C co-infection PLWH should be given the opportunity to be involved in making decisions about their treatment 1. Studies show that trust, a good-quality relationship and good communication skills between doctor and PLWH are associated with better adherence and treatment outcomes in HIV and in other disease areas 2-8. Studies have shown that beliefs about the necessity, efficacy and side effects of ART, the practicability of taking it, and ability to adhere to therapy, all affect adherence 7-9. Before prescribing ART (treatment initiation or switching), clinicians should assess the individual's readiness to take therapy, including: Community advocacy and peer support, including clinic-based peer support, are helpful in supporting an individual's understanding and confidence around treatments, and may also help increase readiness to start therapy. Community organisations in the UK have been instrumental in providing a range of information resources for PLWH and peer-support services, including published and web-based information materials, telephone advice lines, treatment advocates and peer-support groups, working in collaboration with healthcare professionals. They are an important and essential adjunct to clinic-based services and are helpful in addressing the issues discussed below. Peer support is particularly important at diagnosis but there may be other crucial times whe peer support in particularly important such as starting/switching ART, disclosing to others or planning a family. A number of factors may affect adherence, adverse effects and treatment outcomes, including social and cultural beliefs. Depression is significantly associated with low adherence 10, 11 and some studies report an independent association between depression and mortality in people with HIV 12. Adherence can be improved by treating depression 13, so all PLWH should be screened for depression before starting therapy, using simple screening tools such as the Arroll two question quick screen 14. HIV-positive individuals should also be screened for anxiety and for cognitive impairment using validated tools (see the BHIVA guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011; www.bhiva.org/Guidelines.aspx). Current problematic alcohol and recreational drug use are also associated with low adherence 15-17, although a history of injecting drug use, even current use, does not necessarily predict poor adherence 18. PLWH should be asked about alcohol and recreational drug use and offered support to moderate or manage it if desired. Conversely, 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 19. Self-management skills and courses that teach these to PLWH have been associated with both improved adherence and better clinical outcomes in a number of studies 20-22. It may be helpful to PLWH to inform them of these and other psychological support options locally available, in line with the BPS/BHIVA/MedFASH Standards for Psychological Support for Adults Living with HIV 23. An individual's socio-economic status has a direct effect on adherence. For instance, a US study found that poverty had a direct effect on adherence, largely due to food insufficiency 24. A 2010 report on poverty in people with HIV in the UK found that 1-in-6 people with HIV was living in extreme poverty, in many cases due to unsettled immigration status 25. In addition, the ASTRA study revealed that after adjustment for demographic factors, increasing financial hardship, non-employment, non-homeownership, non-university education and lack of supportive network were associated with higher risk of virological rebound in ART-treated individuals 26. Clinicians should be aware of the socio-economic status of HIV-positive individuals and refer to social support where necessary. Clinicians should establish what level of involvement the HIV-positive individual would like and tailor their consultation style appropriately. They should also consider how to make information accessible and understandable to PLWH (e.g. with pictures, symbols, large print and different languages) 1, including addressing linguistic and cultural issues. Youth is consistently associated with lower adherence to ART, loss to follow-up and other negative healthcare behaviours 27 and some studies have found an independent association between poorer adherence and attendance and female gender 28, so information and consultation style should be age and gender appropriate for the individual. If there is a question about an individual's capacity to make an informed decision, this should be assessed using the principles in the Mental Capacity Act 2005 29. PLWH presenting at the clinic may be at different stages of readiness to take therapy 30 and clinicians' first task is to assess their readiness, by means of open (rather than closed) questions. However, if an HIV-positive individual presents in circumstances that necessitate starting ART immediately, for example with an AIDS diagnosis or very low CD4 cell count, then doctors should prescribe ART and provide support for their adherence, especially through the first few weeks. Recognising symptoms that individuals attribute to ART side effects might avoid loss of adherence and deterioration of trust in the patient–provider relationship 31, 32. A 'perceptions and practicalities' approach should be used to tailor support to meet the needs of the individual, to identify both the factors as beliefs about and factors as capacity and adherence 1, 8. In of PLWH for ART it is important to and the for ART, adverse adherence is essential and the of and appropriate of the of ART and how different drugs HIV may help the for combination therapy and it is so important to take the drugs in the at the A review of the individual's social support, social life, options to ART, ability to any food understanding of drug–drug and where to advice are important. The impact of or taking ART on to others should be information or to online resources should be as should access to peer The for ART will from to the next and the multidisciplinary team should be as PLWH good communication not between and the HIV-positive individual but also between all healthcare involved with their care, including those in their HIV services, their general and any clinicians involved in management of PLWH should be offered of about them to their and other of HIV status to the should be best practice and should be However, an individual's not to their status to their should be to the to BHIVA that individuals with chronic HIV infection should start ART before the CD4 count to below 350 cells/μL 1. recommendation was based on evidence from studies that demonstrated an increased risk of disease in individuals who ART their CD4 count was below 350 cells/μL and the absence of evidence from in which the intervention, and populations were similar to setting trials have people with a CD4 cell count cells/μL to start or to The HIV trial individuals to ART at a CD4 cell count between 350 and or ART at a CD4 cell count below the study a benefit to earlier ART those in the treatment at a significantly lower CD4 cell count than in the UK 15. study is likely to overestimate the benefits of treatment compared with starting at A further the trial in 2015. in the with a CD4 cell count cells/μL to ART or to of ART to for initiation of therapy times over the of the the trial demonstrated a clinical benefit associated with earlier ART the CD4 cell count at ART initiation in the is likely to be lower than would be clinically acceptable in the the population in the trial in the with a high incidence of is different to the UK of the study have been and published study adults with CD4 cell counts cells/μL CD4 cell count in 35 and them to start ART or to ART the CD4 count below 350 The risk of developing a or of death as the primary was by in those who were to start after a follow-up of 3 years. The were similar in when compared to and and by a difference in of AIDS particularly and ART was not associated with higher risk of or on virological efficacy, drug resistance and toxicity, and the of effects on and and quality of life outcomes have not been these a benefit of ART at CD4 counts of and that if individuals are to to taking ART, it should be of the CD4 when an individual to start ART are addressed in 7. It is important to recognise that the significant reduction in risk of disease associated with ART, the risk of ART was In this of individuals in the in the treatment a over 3 years of The risk of therapy should be when making individual recommendation is largely based on the study that demonstrated AIDS and improved cost-effectiveness when ART was within compared with initiation after of treatment for the infection 1, 2. with as the primary infection were from this and the majority of individuals had The were well to informed and to take and the findings may not be to those who are or who data a benefit for HIV-positive who are on ART in the care but the data are to make a recommendation in this group 4. There was no increase in the incidence of immune or adverse with ART initiation in 1, 5. However, those with infections may be to immune with ART data that should be with two studies from have demonstrated an increased mortality with ART both were in very different healthcare from the UK and regimens that would not be preferred 5, 7. The study that those with an or with of were at higher risk of death with ART initiation 7. It is important to that immune can be difficult to and across presenting with and are discussed in 8. HIV infection is defined as HIV infection within a of from the estimated time of HIV It can be diagnosed based on in the setting of a clinical sexual history 1. In the setting of the from the and trials, there is no when all individuals diagnosed with these studies clinical benefit to starting ART over In the context of there are to take into account when best is a where symptoms consistent with at a time of the of to with a new HIV diagnosis. diagnosed with with low initial CD4 cell counts high viral HIV and within of a negative 9, have a rate of disease than others without these at and ART initiation should be ART should be only when the individual to However, there are clinical of where ART initiation should be We recommend starting ART as as for presenting with any of the following to be associated with morbidity or very disease The and of ART initiation with a to long-term therapy should be and to any individual diagnosed with ART should be as due to the increased mortality from treatment in the study which was seen of CD4 cell Table The and of starting ART in The for ART initiation individuals diagnosed with There is likely to be a trial in comparing ART that is to a as such a study would to recommendations of best management of are based on surrogate of mortality and CD4 cell evidence has identified both and of surrogate of the immune system in of CD4 cell count and ratio for individuals initiating ART to the time of HIV transmission compared to ART A analysis demonstrated lower of a CD4 cell count if treatment initiation was than after even the circumstances where ART is starting within 1 year of diagnosis is 18. or ART initiation for and those with very high viral will clinical symptoms and the