Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Overcoming the False Dichotomy of Curative vs Palliative Care for Late-Stage HIV/AIDS Michael W. Rabow, MD Education Guides Editor

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. “Let me live the way I want to live, until I can’t.” HIV/AIDS

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Mr C’s Story A 33-year-old man with advanced human immunodeficiency virus (HIV) infection –Diagnosed 11 years prior –CD4 cell count of less than 200/μL (20 × 10 9 /L) –HIV viral load of higher than copies/mL despite ongoing antiretroviral therapy He has a history of many past opportunistic infections –Pneumocystis jiroveci pneumonia –Cryptococcal meningitis –Cytomegalovirus retinitis –Disseminated Mycobacterium avium complex

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Mr C’s Story He also has had multiple other complications –Rectal carcinoma –Scrotal carcinoma in situ –Peripheral neuropathy –Chronic wasting syndrome Treatment-related complications have included –Thrombocytopenia after chemotherapy and radiation for rectal carcinoma –A ruptured globe after multiple intravitreal ganciclovir implants for chronic cytomegalovirus retinitis –Uveitis secondary to rifabutin –Chronic renal insufficiency secondary to tenofovir

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Mr C’s Recent Medications Didanosine Ritonavir Saquinavir Efavirenz –The above 4 medications were recently suspended because of worsening nausea and anorexia and concerns about possible lactic acidosis Levofloxacin Ethambutol –Also recently suspended because of gastrointestinal intolerance

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Mr C’s Recent Medications Fluconazole Trimethoprim-sulfamethoxazole Valacyclovir Azithromycin Long-acting morphine sulfate Dronabinol Zolpidem Sertraline Famotidine Filgrastim Erythropoietin

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Mr C’s Story Dr K (Mr C’s HIV physician) wonders whether Mr C has consistently adhered to antiretroviral therapy regimens –Mr C has had a persistently elevated viral load Over the years, Mr C was admitted and discharged from hospice programs several times –He has had conflicting feelings about advance directives concerning life-prolonging interventions

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Challenges of HIV/AIDS as a Chronic Disease In developing countries, HIV/AIDS is more likely to follow the grimly predictable, stereotypic, and rapidly fatal course seen in the early phase of the epidemic –In the United States in the early 1980s, the median time from AIDS diagnosis to death was often less than 1 year Access limitations in developing countries –Basic health care –Antiretroviral therapy

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Challenges of HIV/AIDS as a Chronic Disease AIDS has become a chronic disease in the United States and other industrialized countries –Its prevalence has increased, as people live longer with it –It is now a prolonged illness with exacerbations and remissions –There is a growing cumulative disease burden –There are significant therapy ‑ related toxic effects –There are increasing medical and psychiatric comorbidities

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Challenges of HIV/AIDS as a Chronic Disease Its symptom burden –Is comparable to other serious chronic illness such as chronic heart, lung, and renal disease –Requires palliative care

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Challenges of HIV/AIDS as a Chronic Disease Still, AIDS ultimately remains a life-threatening illness –There have been deaths per year since 1997 –It is a leading cause of death among young adults aged years, especially among African Americans and Hispanics –It requires end-of-life care

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Challenges of HIV/AIDS as a Chronic Disease HIV/AIDS is both a chronic disease and a life- threatening disease –It is a false dichotomy to focus on either disease management or symptom management Its treatment plan must integrate both –Curative or disease ‑ specific interventions Highly active antiretroviral therapy (HAART) Treatment of opportunistic infections –Symptom palliation

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Late ‑ Stage HIV Disease Late-stage disease is defined as longstanding, symptomatic HIV disease It is associated with –Severe immunosuppression –Significant cumulative morbidity –Failure of or inability to tolerate antiretroviral therapy

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Cumulative Disease Burden Life ‑ prolonging treatment can create morbidities –Decline in physical functioning –Poorer quality of life –Worse appearance Adverse effects of disease ‑ specific therapy –eg, nausea or vomiting, neuropathy, uveitis, renal insufficiency, hyperamylasemia, lactic acidosis Hazards of longstanding HIV ‑ associated immunosuppression –eg, cancer

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Comorbid Illnesses Comorbid illnesses have a major impact on morbidity and mortality in patients with HIV/AIDS –Hepatitis B –Hepatitis C –Non–AIDS ‑ defining cancers –Psychiatric disorders –Substance abuse–related sequelae Some comorbid illness can account for a burden of mortality comparable to or greater than the total mortality of AIDS itself –Malignancy –Cirrhosis or liver failure

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Aging There is a growing prevalence of age-related comorbidities –Degenerative joint disease –Osteoporosis –Psychiatric disorders, especially mood and anxiety disorders –Cognitive decline HIV-related cognitive disorders Age-related cortical impairments –Immunologic senescence –Age-associated increased cancer risk –Increasing prevalence of metabolic disorders –Increasing prevalence of cardiovascular disease

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Aging Polypharmacy –Common in elderly patients in general –Has implications for HIV-related therapies Risk of increasing social isolation –Common in elderly patients in general –Is potentially compounded by the stigma and isolation related to HIV/AIDS Impact of long-term survival on maintaining safer sex behaviors –Fatigue with respect to self-regulatory behavior

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Pain and Other Symptoms High prevalence of pain and other symptoms –Especially in the later stages –May be underrecognized, undertreated, or both

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Prevalence of Symptoms in Patients With AIDS SymptomPercentage Range Fatigue or lack of energy 48 ‑ 85 Weight loss 37 ‑ 91 Pain 29 ‑ 76 Anorexia 26 ‑ 51 Anxiety 25 ‑ 40 Insomnia 21 ‑ 50 Cough 19 ‑ 60 Nausea or vomiting 17 ‑ 43 Dyspnea or respiratory symptoms 15 ‑ 48 Depression or sadness 15 ‑ 40 Diarrhea 11 ‑ 32 Constipation 10 ‑ 29

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Symptoms Symptom management –May improve adherence to HIV ‑ specific therapies –Has been demonstrated effective in limited research Patient self-care symptom management strategies with documented utility in AIDS include –Exercise –Meditation –Prayer –Complementary and integrative practices

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Symptoms The best palliation may be –Disease-specific therapy eg, fluconazole for cryptococcal meningitis –Symptom-specific therapy eg, antiemetics for medication-induced nausea

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Psychiatric Symptoms Psychotic, anxiety, or mood disorders can cause significant morbidity They may also shorten longevity –They may affect patients’ motivation and capacity to adhere to medical treatment

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Psychiatric Symptoms Cognitive disorders in late ‑ stage HIV disease –Confound the clinical picture –Limit information processing and decision making Useful interventions include –Psychiatrists and other mental health professionals –Support groups Randomized controlled trials demonstrate less depression and feelings of meaninglessness and better spiritual well- being

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Combining Disease ‑ Specific and Palliative Approaches AIDS care cannot readily be dichotomized into curative vs palliative approaches However, there is a disconnect between the paradigms of HIV care and palliative care –At the XIV International Conference on AIDS in 2002, less than 1% of nearly 6000 abstracts focused primarily on palliative care–related topics –At the 14th Annual Assembly of the American Academy of Hospice and Palliative Medicine in 2002, only 2% of the 105 abstracts dealt primarily with HIV/AIDS

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Combining Disease ‑ Specific and Palliative Approaches Comprehensive HIV/AIDS care must include scrupulous management of HAART medications, but also of symptoms and psychiatric disease The clinician must be aware of the potential for drug interactions between palliative and HIV medications –eg, certain opioids, antidepressants, anticonvulsants, and benzodiazepines interact with the protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and rifamycins

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Medical Challenges: Combining Disease ‑ Specific and Palliative Approaches Some medications that are not routinely used in HIV/AIDS treatment may be needed for palliation –eg, short-term use of corticosteroids for anorexia, malaise, fevers, fatigue, or nausea is not deleterious and may improve quality of life for patients with late ‑ stage disease Clinicians must remain aware of ongoing inequalities in access and integration of care for patients with AIDS

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Prognostic Challenges: Clinical Markers Pre-HAART mortality was readily and uniformly predicted by –Occurrence of specific opportunistic infections –Surrogate markers CD4 T ‑ lymphocyte cell counts HIV viral loads

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Prognostic Challenges: Clinical Markers Now, prognostic markers are much less reliable in late ‑ stage disease –Any of the traditional prognostic markers may be overridden by the potential impact of HAART –US National Hospice Organization guidelines no longer predict 6 ‑ month mortality accurately

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Prognostic Challenges: Clinical Markers Better predictors of prognosis in advanced HIV –Functional deficits Impaired activities of daily living Cognitive impairments on mental status examination –Existence of other life ‑ threatening conditions Cancer End ‑ organ failure New prospective studies are needed to develop prognostic variables for late ‑ stage HIV disease in the HAART era

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Prognostic Challenges: Discontinuation of HAART There are detailed guidelines for the initiation of HAART But there are no guidelines to guide the discontinuation of HAART in the setting of treatment failure The clinician must weigh the potential benefits and risks of its discontinuation

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Potential Benefits of HAART in Late-Stage HIV Selection for less fit virus (ie, less pathogenic than wild type virus), even in the presence of elevated viral loads Protection against HIV encephalopathy or dementia Relief or easing of symptoms possibly associated with high viral loads (eg, constitutional symptoms) Continued therapeutic effect, albeit attenuated Psychological and emotional benefits of continued disease ‑ combating therapy

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Potential Risks of HAART in Late-Stage HIV Cumulative and multiple drug toxic effects may occur in the setting of therapeutic futility There may be diminished quality of life from the demands of the treatment regimen There may be therapeutic confusion (ie, use of future ‑ directed, disease ‑ modifying therapy in a dying patient)

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Potential Risks of HAART in Late-Stage HIV Distraction from end ‑ of ‑ life and advance care planning issues, with a narrow focus on medication adherence and monitoring Evidence is lacking for some of the potential benefits mentioned although they are commonly considered in clinical decision making

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Advance Care Planning Physician discussion of advance directives and life ‑ limiting interventions is less common with HIV/AIDS patients There are multiple barriers to advance care planning in HIV/AIDS –Physicians’ discomfort with discussing death –Physicians’ reluctance to undermine hope –Availability of HAART

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Advance Care Planning The clinician must address the patient’s concern that palliative care is somehow less than standard care – AIDS is concentrated in vulnerable populations African Americans have been noted to be less likely to consider withdrawal or cessation of life ‑ prolonging measures than certain other racial or ethnic groups –There is a persistent societal stigma associated with AIDS

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. Shift Toward Palliation The shift toward palliation is an ongoing iterative process in which the potential benefits, risks, and burdens of particular therapies are repeatedly assessed –The range of disease ‑ specific treatments narrows eg, might continue PCP prophylaxis but not HAART –The focus of treatment may become primarily palliative There is no rigid template for this process –It requires a specific, individualized treatment plan –It must be consistent with the patient’s expressed goals of care –The goals may evolve over time

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. The “Chronic” Caregiver Caregiver emotions have intensified in the chronic disease era –Feelings of anger, dread, relief, guilt, isolation, and feelings of loss of control –Burdens of exhaustion, anxiety, and uncertainty Physicians should proactively address these issues –Normalize the need for caregiver help –Refer to support groups –Inform caregivers about respite programs that hospice services may provide

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. The Physician’s Role Clinician frustration in advanced HIV in the HAART era includes –Being aware of what the therapy can provide and then being confronted with the evidence of its failure The possibility of greater hope is darkened by disappointment, regret, guilt, and second ‑ guessing –More of the responsibility for the disease’s outcome is placed in the hands of the patient and the physician Patients and families may blame physicians for the disease outcome Physicians may blame patients for non-adherence Physicians may blame themselves for failed treatments

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. The Physician’s Role There is an ongoing, even deepening role for the physician with patients dying of HIV/AIDS The experience can be moving and life-changing for physicians as well –Many physician-authors have described personal pain, transcendence, and growth –“If you listen carefully to your patients, they will tell you not only what is wrong with them, but also what is wrong with you.” —Walker Percy in Love in the Ruins

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. The End of the Story Mr C developed worsened mobility –Neuropathy and loss of vision progressed –He began to rely on a motorized scooter to move around outside his home Ms D (Mr C’s aunt, his primary caregiver) and Dr K both noted a progressive cognitive deterioration during the next several months

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. The End of the Story Unable to eat or drink at home, Mr C was admitted to the hospital for comfort care Two days later (11 years after his diagnosis of HIV), Mr C died from hepatic and respiratory failure –Likely secondary to aspergillosis and toxic effects from his therapeutic regimen

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. This Education Guide slide set has been created as a part of Care at the Close of Life: Evidence and Experience Michael W. Rabow, MD University of California, San Francisco Education Guides Editor Stephen J. McPhee, MD; Margaret A. Winker, MD; Michael W. Rabow, MD; Steven Z. Pantilat, MD; Amy J. Markowitz, JD Care at the Close of Life: Evidence and Experience Editors

Care at the Close of Life: Evidence and Experience Copyright © American Medical Association. All rights reserved. | JAMA | The McGraw-Hill Companies, Inc. HIV/AIDS Selwyn PA, Forstein M. Overcoming the false dichotomy of curative vs palliative care for late- stage HIV/AIDS. In: McPhee SJ, Winker MA, Rabow MW, Pantilat SZ, Markowitz AJ, eds. Care at the Close of Life: Evidence and Experience. New York, NY: McGraw-Hill; 2010:

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