<scp>B</scp>ritish <scp>HIV</scp> Association guidelines for <scp>HIV</scp>‐associated malignancies 2014

Introduction Scope and purpose Methodology Guideline development process Patient involvement GRADE Good practice points Dissemination and implementation Guideline updates and date of next review Summary Key recommendations References Summary of Recommendaations/good practice points and auditable outcomes Kaposi sarcoma (KS) Diagnosis, staging and prognosis Management Prevention Local therapy Radiotherapy Other local therapies Systemic therapy HAART Cytotoxic chemotherapy Liposomal anthracyclines Taxanes Immunotherapy Other systemic therapies Summary of recommendations References Systemic AIDS-related non-Hodgkin lymphoma (ARL) Introduction Diagnosis, staging and prognosis Recommendation Management First-line chemotherapy for DLBCL in HIV-infected individuals Localized disease Disseminated disease Rituximab for DLBCL Treatment for high-risk patients The effect of adding HAART Recommendations for DLBCL Burkitt lymphoma/leukaemia Recommendations for BL Prevention of secondary CNS lymphoma Recommendations for IT prophylaxis Supportive care Treatment of relapsed/refractory AIDS-related lymphoma Recommendations for patients with relapsed/refractory aggressive ARL Response evaluation and follow-up References Primary central nervous system lymphoma (PCNSL) Introduction Diagnosis, staging and prognosis Treatment of HIV-associated primary cerebral lymphoma Recommendations References Primary effusion lymphoma (PEL) Introduction Pathogenesis Presentation Diagnosis Prognosis and management Recommendations References Plasmablastic lymphoma Introduction Morphology Pathogenesis Clinical presentation Treatment Recommendation References Cervical intraepithelial neoplasia (CIN) and cervical cancer Introduction Screening for cervical cancer and pre-cancer The effect of HAART on the natural history of CIN Diagnosis and management of CIN Diagnosis, staging, management and prognosis of cervical cancer Key recommendations References Anal cancer Introduction Key recommendations of BHIVA, BASHH and FFPRHC 2008 guidelines on anal cancer in HIV Key recommendations of NICE 2004 guidelines on anal cancer Epidemiology Diagnosis Staging Management First-line treatment for anal cancer Benefit of adding antiretrovirals to anal cancer treatment Best treatment of relapse of anal cancer Best response evaluation and follow-up in anal cancer Summary of guidance References Hodgkin Lymphoma (HL) Introduction Diagnosis, staging, prognostic factors Do antiretrovirals reduce the risk of HL? What is the best treatment for HL? Recommendations What is the benefit of adding ARVs to chemotherapy in HL? Recommendations What is the benefit of adding rituximab to chemotherapy in HL? What is the best treatment in second line for HL? Recommendation What is the benefit of adding opportunistic infection prophylaxis in HL? Recommendation What is the best response evaluation and follow-up in HL? Recommendations References Multicentric Castleman's disease Introduction Diagnosis Recommendations Staging Prognosis Observations Management Combination antiretroviral therapy (cART) Rituximab Chemotherapy Immunotherapy (excluding rituximab) Anti-human herpes virus-8 therapy Surgery Recommendations Auditable outcomes References Non-AIDS-defining malignancies Introduction Testicular germ cell cancers Introduction Diagnosis, staging, prognostic factors Management Stage I disease Metastatic disease Relapsed disease Summary Non-small cell lung cancer Introduction Prognosis Management Operable disease Locally advanced disease Metastatic disease HAART Screening Summary Hepatocellular cancer Introduction Presentation and diagnosis Management Localized therapies Transplantation Sorafenib Screening for HCC in patients with hepatitis and HIV co-infection Summary Other cancers Colorectal cancer Skin cancer Merkel cell carcinoma (MCC) Cutaneous lymphoma Penis precancer and cancer Others Summary References Opportunistic infection prophylaxis in HIV-associated malignancy Introduction PCP prophylaxis MAC prophylaxis Fungal prophylaxis Bacterial prophylaxis Antiviral prophylaxis Recommendations References Acknowlegements Conflicts of interest statements List of appendices Appendix 1 Summary modified GRADE system 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 [1]. 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 revised and updated the Association's guideline development manual in 2011 [2]. 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 [5]. 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 [4] 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. 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. 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 [9]. An audit study in North London confirmed the better management of patients with AIDS-related lymphomas in HIV centres with cohorts of >500 patients [10]. An audit from Canada also showed that clinicians treating larger numbers of patients with AIDS-related lymphoma provided better care [11] 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 [12]. 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 [13] and in the US [14]. This remains a concern since UK lymphoma clinicians are often overly reluctant to adopt universal testing [15] and uptake remains low even for AIDS-defining malignancies [16]. 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 [17]. 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. 1 Asboe, D, Aitken, C, Boffito, M et al. British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011. HIV Med 2012; 13: 1– 44. 2 BHIVA. British HIV Association (BHIVA) Guideline Development Manual. 13 September 2011. Available at: http://www.bhiva.org/GuidelineDevelopmentManual.aspx (accessed December 2013). 3 Guyatt, GH, Oxman, AD, Kunz, R et al. Going from evidence to recommendations. BMJ 2008; 336: 1049– 1051. 4 Development and Evaluation (Short GRADE) Working Group. The grading of recommendations assessment. Available at http://www.gradeworkinggroup.org (accessed December 2013). 5 Bower, M, Collins, S, Cottrill, C et al. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Med 2008; 9: 336– 388. 6 Curtis, JR, Bennett, CL, Horner, RD et al. Variations in intensive care unit utilization for patients with human immunodeficiency virus-related Pneumocystis carinii pneumonia: importance of hospital characteristics and geographic location. Crit Care Med 1998; 26: 668– 675. 7 Handford, CD, Rackal, JM, Tynan, A-M et al. The association of hospital, clinic and provider volume with HIV/AIDS care and mortality: systematic review and meta-analysis. AIDS Care 2012; 24: 267– 282. 8 Rackal, JM, Tynan, A-M, Handford Curtis, D et al. Provider training and experience for people living with HIV/AIDS. Cochrane Database Syst Rev 2011; 6: CD003938. 9 National Institute for Clinical Excellence. Guidance for Commissioning Cancer Services. Improving outcomes in haematological cancers: the research evidence. Available at: http://www.nice.org.uk/nicemedia/live/10891/28787/28787.pdf (accessed December 2013). 10 Brook, MG, Jones, K, Bower, M, Miller, RF. Management of HIV-related lymphoma in HIV treatment centres in North Thames Region. Int J STD AIDS 2004; 15: 765– 766. 11 Cheung, MC, Imrie, KR, Leitch, HA et al. Physician perceptions and preferences in the treatment of acquired immunodeficiency syndrome (AIDS)-related lymphoma. Ann Hematol 2007; 86: 631– 638. 12 Dunleavy, K, Wilson, WH. Implications of the shifting pathobiology of AIDS-related lymphoma. J Natl Cancer Inst 2013; 105: 1170– 1171. 13 Palfreeman, A, Fisher, M, Ong, E et al. Testing for HIV: concise guidance. Clin Med 2009; 9: 471– 476. 14 Chiao, EY, Dezube, BJ, Krown, SE et al. Time for oncologists to opt in for routine opt-out HIV testing? JAMA 2010; 304: 334– 339. 15 Bowman, CA, Olarinde, O, Wright, J. Routine HIV testing in lymphoma patients. Overcoming the challenges. HIV Med 2010; 11( Suppl 1): 59 [Abstract P122]. 16 Lebari, D, Kaczmarski, E. HIV testing in cancer: experience from a tertiary oncology hospital. HIV Med 2012; 13( Suppl 1): 34 [Abstract P70]. 17 Department of Health. The NHS plan. A plan for investment. A plan for reform. Cm 4818-I. London: HMSO, July 2000. Available at: http://pns.dgs.pt/files/2010/03/pnsuk1.pdf&ei=NJHKUpqHIqiR7AbFl4GwAw&usg=AFQjCNHQ7SYdrNz7Kv-Vcv77eIZYy1wkhw&bvm=bv.58187178,d.bGQ 18 BHIVA. Standards of Care for People Living with HIV 2013. Available at: http://www.bhiva.org/documents/Standards-of-care/BHIVAStandardsA4.pdf (accessed December 2013). Kaposi sarcoma is still the most common tumour in people with HIV infection, is an AIDS-defining illness and is caused by the Kaposi sarcoma herpesvirus (KSHV). The diagnosis is usually based on the characteristic appearance of cutaneous or mucosal lesions and should be confirmed histologically since even experienced clinicians misdiagnose KS [1] (level of evidence 1C). Lesions are graded histopathologically into patch, plaque or nodular grade disease. Visceral disease is uncommon, affecting about 14% at diagnosis [2] and CT scans, bronchoscopy and endoscopy are not warranted in the absence of symptoms (level of evidence 2D). The AIDS Clinical Trial Group (ACTG) staging system for AIDS-related KS was developed in the pre-HAART era to predict survival and includes tumour-related criteria (T), host immunological status (I) and the presence of systemic illness (S) (see Table 3.1) [3,4]. The ACTG also established uniform criteria for response evaluation in AIDS KS (see Table 3.2) [3]. In the era of HAART, the prognostic value of this staging system has been questioned and one study suggested that only the T and S stages identify patients with poor survival [5], whilst another study from Nigeria found that I and S stages but not T stage were of prognostic significance [6]. However, a comprehensive evaluation of prognostic factors in 326 patients diagnosed with AIDS KS in the era of HAART, externally validated on 446 patients from the US HIV/AIDS Cancer Match Study, has established a prognostic scoring scheme [7] and more detailed immune subset analysis does not provide additional prognostic information [8]. Having KS as the first AIDS-defining illness (-3 points) and increasing CD4 cell count (-1 for each complete 100 cells/μL in counts at KS diagnosis) improved prognosis, whereas age at KS ≥50 years old (+2) and S1 stage (+3) conveyed a poorer prognosis. On the basis of this index it was suggested that patients with a poor risk prognostic index (score >12) should be initially treated with HAART and systemic chemotherapy together, whilst those with a good risk (score <5) should be treated initially with HAART alone, even if they have T1 disease. Over time, there has been a rise in the CD4 cell count at diagnosis of KS, and the impact of initiation of treatment may also change [9–12]. In addition to prognostic factors identified in the model, blood levels of Kaposi sarcoma herpesvirus (KSHV) DNA are a surrogate marker of tumour burden and are of prognostic significance. In 144 patients followed in the Swiss HIV Cohort study, detectable levels of KSHV DNA in the blood were an indicator of a poor prognosis [13]. Patients in Zimbabwe initiated on ART for advanced AIDS-KS, also had a poorer outcome when pretreatment plasma KSHV levels were high [14]. The introduction of HAART was associated with a substantial reduction in the incidence of KS in many large cohorts [15–21], although some of this decline in incidence appears to have preceded the introduction of HAART [22]. A population-based, record-linkage study of 472,378 individuals living with AIDS described a fall in the cumulative incidence of KS from 14.3% during 1980–1989, to 6.7% during 1990–1995, and a fall to during Similarly, survival from KS have during this In KS to be a significant in although it is that with increasing access to HAART, outcomes will The decline in incidence of KS has been shown to be to HAART, and are as as in KS Moreover, the study patients to or use of by CD4 cell and it found that patients ART had of KS as well as of opportunistic and The optimal to start HAART for HIV infection is still and is in the of Treatment study, an to the risks and benefits including of KS, of HAART than therapies the of KS, may also be in the of KS but published cohort studies are A UK cohort study of people living with HIV showed that the risk of KS was by and but not However, from a cohort of living with AIDS found that to and not reduce the risk of KS A randomized controlled of in the and of KSHV but this to levels therapy HAART results in significant in the levels of whereas and have only a effect that is not with HAART Local are most for managing or KS lesions or for However, local therapies are limited by to large or to the development of lesions in the pre-HAART had an important and established in the management of cutaneous KS, including the of treatment of lesions on and An randomized study of for cutaneous KS showed that response and of local were better with in and in 10 with an although and patient were A second study of patients found no significant in response between 16 in 4 and 8 in a A study of patients including some with KS treated with a of 8 an response of In another study of patients with KS of the a of 3 at to a of the response was with a complete response of A randomized two in 12 and in 5 with and in patients of were on were 13 patients before A of in patients were on the with a area treated of response and were in with a to response of 3 An important large randomized study from Zimbabwe has evaluated for in patients who were not treated with antiretroviral This showed that not overall survival or quality of to care In higher numbers of of to only benefits and are more as well as less for patients. In a effect of it is not clear if this is of clinical Radiotherapy effects in patients with AIDS have been as more although a recent review of and cancer patients treated with or not any significant in for HIV-positive to patients and close to including of and use of may The use of has since the introduction of HAART, although it may still be for KS at for is an and treatment for and lesions in effects on and cell and can KS cell in is a therapy in the US and some for the treatment of randomized trials a of evaluated 12 weeks of The response in the 12 weeks were and to and in the by to In studies, of were HAART and this not the In another study of patients, of treated lesions to of the The may and at the are seen even in patients with low CD4 cell counts and weeks has also been is only in the UK for In a study of patients on the response was although the of the HAART is is the most for KS and of were in the pre-HAART era lesions usually and although do not A randomized study in 16 patients or in the treatment of KS in with no significant differences of such as have also shown but are In one study of patients, complete were in of lesions treated with and the of the response was more than 6 In addition, greater than of KS was in this pre-HAART era study can have a An alternative approach is which is based by of a that in tumour such as KS A of patients with a of KS lesions to patients were on HAART and of the lesions to therapy and complete and

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