British HIV Association guidelines for HIV-associated malignancies 2014
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HIV Medicine March 2014
Scope and purpose
The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection and malignancy. The scope includes the management of diagnosed malignancies in people living with HIV but does not address screening for malignancies in this population. This is covered elsewhere in other BHIVA guidance where evidence is available to support it .
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.
Guideline development process
BHIVA revised and updated the Association's guideline development manual in 2011 . 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 [3,4]. Full details of the guideline development process, including conflict of interest policy, are outlined in the manual.
The scope, purpose and guideline topics were agreed by the Writing Group. Questions concerning each guideline topic were drafted and a systematic literature review undertaken by an information scientist. BHIVA HIV-associated malignancy guidelines were last published in 2008 . For the 2013 guidelines the literature search dates were 1 January 2008 to 16 July 2013 and included MEDLINE, Embase and the Cochrane Library. Abstracts from selected conferences were searched between 1 January 2009 and 16 July 2013. 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 (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, 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 and conducted.
BHIVA views the involvement of patient and community representatives in the guideline development process as essential. The Writing Group included two patient representatives appointed through the UK HIV Community Advisory Board (UK-CAB) who were involved in all aspects of the guideline development process. In addition, two meetings with patients and community representatives were held to discuss and receive feedback and comments on the proposed guideline recommendations. The first was held before the Writing Group's consensus meeting and the second as part of the public consultation process.
The GRADE Working Group  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, 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, and (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 the benefits clearly outweigh the risks (or vice versa) for most, if not all patients. Most clinicians and patients should and 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. Most clinicians and patients would want to follow a weak or conditional recommendation but many would not. 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.
The quality of evidence is graded from A to D and for the purpose of these guidelines is defined as follows:
Grade A evidence means high-quality evidence that comes from consistent results from well-performed randomized controlled trials (RCTs), or overwhelming evidence of some other sort (such as well-executed observational studies with consistent strong effects and exclusion of all potential sources of bias). Grade A implies confidence that the true effect lies close to the estimate of the effect.
Grade B evidence means moderate-quality evidence from randomized trials that suffer from serious flaws in conduct, inconsistency, indirectness, imprecise estimates, reporting bias, or some combination of these limitations, or from other study designs with special strengths such as observational studies with consistent effects and exclusion of most potential sources of bias.
Grade C evidence means low-quality evidence from controlled trials with several very serious limitations or observational studies with limited evidence on effects and exclusion of most potential sources of bias.
Grade D evidence on the other hand is based only on case studies, expert judgement or observational studies with inconsistent effects and a potential for substantial bias, such that there is likely to be little confidence in the effect estimate.
Good practice points
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 emphasize 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 emphasized that GPPs are not an alternative to evidence-based recommendations.
Dissemination and implementation
The following measures have/will be undertaken to disseminate and aid implementation of the guidelines:
1. E-publication on the BHIVA website and the journal HIV Medicine.
2. Publication in the journal HIV Medicine.
3. Shortened version detailing concise summary of recommendations.
4. E-learning module accredited for CME.
5. Educational slide set to support local and regional educational meetings.
6. National BHIVA audit programme.
Guideline updates and date of next review
The guidelines will be next fully updated and revised in 2018. 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.
HIV infection is associated with three AIDS-defining malignancies (Kaposi sarcoma, high grade B-cell non-Hodgkin lymphoma and invasive cervical cancer) as well as an increased risk of many other malignancies. The clinical care of patients with these tumours requires a multidisciplinary approach drawing on the skills and experience of all healthcare professional groups. Moreover, optimal care can only be achieved by the close co-operation of oncologists, haematologists and HIV physicians, and unless all these clinicians are intimately involved in the care of patients it is likely that the outcome will be less favourable. Patients with HIV-associated malignancies should therefore only be managed in a centre dealing with large numbers of patients with these tumours.
The minimum number of patients that an HIV oncology service should manage has not been defined. Several studies and a Cochrane review have shown that the more HIV patients treated by a centre, the better the outcomes [6–8]. Similarly, Improving outcomes in haematological cancer published by NICE in 2003 included a systematic review of published evidence suggesting that higher patient volumes are associated with improved outcomes and that outcomes in specialist centres are better. They advocated that all patients with haematological cancer should be managed by a multidisciplinary haemato-oncology team serving a population of at least 500 000 . An audit study in North London confirmed the better management of patients with AIDS-related lymphomas in HIV centres with cohorts of >500 patients . An audit from Canada also showed that clinicians treating larger numbers of patients with AIDS-related lymphoma provided better care  and a recent cohort study in the US published in 2013 attributed poorer results in some centres to a lack of access to optimal intergrated cancer and HIV care . An additional benefit of centralization could be greater uptake of HIV testing amongst patients diagnosed with cancers including lymphomas as advocated in BHIVA testing guidelines  and in the US . This remains a concern since UK lymphoma clinicians are often overly reluctant to adopt universal testing  and uptake remains low even for AIDS-defining malignancies .
In line with national cancer waiting times, all patients with suspected cancers must be referred urgently and seen within 2 weeks of referral. Moreover, the NHS Cancer Plan sets out the goal that no patient should wait longer than 1 month from an urgent referral with suspected cancer, to the start of treatment .
We recommend that all patients with HIV and malignancy should be referred to centres that have developed expertise in the management of these diseases (level of evidence 1B). The multidisciplinary team managing these patients must include HIV physicians, oncologists, haematologists and palliative care physicians along with clinical nurse specialists, specialist HIV pharmacists and specialist chemotherapy pharmacists.
· We recommend that all patients with HIV and malignancy should be referred to centres that have developed expertise in the management of these diseases (level of evidence 1B).
· We recommend that clinical networks supporting regional centres of excellence for the treatment of both AIDS-defining and non-AIDS-defining cancers should be developed as advocated by the Standards of Care for People Living with HIV 2013  (level of evidence 1D).