The Role of Palliative Care in the Current HIV Treatment Era in Developed Countries CME

Abstract

The goal of palliative care is to minimize and prevent suffering and maximize physical function and quality of life in patients with serious illness. In the early years of the AIDS epidemic in developed countries, prognosis was poor and palliative care was often inseparable from HIV care. Despite the advent of effective antiretroviral therapy and its availability in developed countries, patients with HIV disease still present many palliative care challenges and opportunities. The cases of 3 HIV-infected patients who embody these challenges will be presented in this article: an older patient with numerous medical comorbidities, chronic pain, and severely impaired physical function; a patient with psychiatric illness and substance abuse, difficulties with adherence to antiretroviral therapy and retention in HIV primary care, and cryptococcal meningitis; and a patient with stable HIV disease and hepatitis C virus–related liver failure. These cases are being presented to stimulate a discussion between HIV and palliative care practitioners about potential areas of clinical and research collaboration.

The goal of palliative care is to alleviate and prevent suffering in patients with serious illness. Early in the AIDS epidemic in developed countries, prognosis was universally poor. HIV care and palliative care were seen as one and the same, and HIV practitioners, by necessity, became experts in palliative care. Patients dying with AIDS needed palliative care to help ease their suffering at the end of life; suffering related to pain and other symptoms experienced during the dying process, and eventually, suffering related to toxic antiretroviral medications used in the early treatment era. This era, the pre–potent antiretroviral therapy era, is an era that the field of HIV medicine was glad to leave behind.

The AIDS epidemic has changed dramatically over the past 20 years. With the introduction of effective antiretroviral therapy and its widespread uptake in developed countries, the epidemic has matured. By 2015, 50% of patients with HIV disease in the United States will be older than 50 years.1,2 In addition, patients with HIV disease often have numerous comorbidities, such as cardiovascular, renal, or liver disease, and non–AIDS-defining malignancies. This has been described as a process of “accelerated aging.”3 The combination of a “graying” epidemic and multimorbidity likely contributes to the high prevalence of pain and symptoms still seen in patients with HIV disease. Estimates of pain occurrence in the current HIV treatment era in studies from the United States range from 39% to 55%.4-13 Physical symptoms such as nausea and fatigue and psychological symptoms such as depressed mood and anxiety are also common.7, 9-11, 13-16 Data from the pre–potent antiretroviral treatment era suggest that pain is underrecognized and undertreated.17-19 Adding to this complexity, psychiatric illness and substance abuse are common in HIV-infected patients.20-22 All of this is compounded by an aging population, in which the complications of HIV as a chronic disease now intersect with the added challenges of geriatric care. These myriad issues lead to growing clinical complexity and impaired quality of life for HIV-infected patients.

Despite advances in therapeutics, patients with HIV infection still die, even in settings in which antiretroviral therapy is widely available. Deaths attributable to AIDS in an era of antiretroviral therapy have shifted “from fate to tragedy,” often relating to late diagnosis or failures in adherence to antiretroviral therapy or retention in HIV primary care.23 Today, AIDS-related deaths account for less than half of all deaths in patients with HIV disease; the remainder are primarily due to other comorbidities such as liver disease and non–AIDS-defining malignancies.24 Many HIV-infected patients are now being cared for by a generation of physicians who did not experience the epidemic of suffering, dying, and death in the pre–potent treatment era, and who may not be as attuned to the palliative aspects of HIV disease.

Palliative care as a medical specialty has also evolved over the past 20 years. It emerged from the hospice movement and is often employed near the end of life. However, palliative care has been increasingly understood as an approach to minimize and prevent suffering while maximizing physical function in the face of serious illness, irrespective of stage of illness or prognosis (Figure).25,26 Palliative care has been successfully integrated in the early stages of illness in patients with complex diseases such as heart failure, chronic obstructive pulmonary disease (COPD), and cancer.27-30

Figure 1.

Palliative care’s place in the course of illness. Adapted from World Health Organization.53

Palliative care has recently been recognized as a medical specialty in the United States, requiring fellowship training and board certification for physicians who practice in this area. The palliative care skill set includes pain and symptom management and communication about physical, emotional, psychosocial, and spiritual suffering in the context of serious illness. In particular, palliative care specialists have specific expertise in communicating about goals of care. Common goals of care include functional improvement, comfort, and caregiver support and are considered an essential part of discussions with patients with serious illness.31

Palliative care is, by definition, interdisciplinary in nature. Physicians, nurses, psychologists, social workers, chaplains, physical and massage therapists, and counselors with special expertise and training in palliative care work together with patients’ primary practitioners to help patients who are suffering achieve their care goals. When appropriate, palliative care can also help patients whose health is rapidly declining, or who are nearing the end of life.

Therefore, palliative care is a natural fit to address suffering and maximize function and quality of life for patients living with HIV disease, and for patients with HIV disease who are nearing the end of life.32 Unfortunately, palliative care for patients with HIV disease in the current treatment era in developed countries has received little attention in the HIV literature or at national and international HIV conferences. This is a missed opportunity. Inpatient and ambulatory palliative care programs are growing rapidly, with more than 60% of US hospitals now providing a palliative care team.33 HIV clinicians have the opportunity to collaborate with and learn from their palliative care colleagues, to integrate palliative care with disease-specific care for patients with HIV in order to improve their quality of life and HIV-related clinical outcomes. Three cases are presented that illustrate opportunities for integration of palliative care with disease-specific care for patients with HIV throughout the course of their illness. The intent is to stimulate a dialogue between HIV and palliative care practitioners and researchers and to challenge us to consider novel ways to reduce patient suffering while improving their physical function and quality of life.

Cases

Case 1: Aging With HIV

Mr A, a 65-year-old white man, was diagnosed with HIV infection in 1996 during an episode of Pneumocystis jiroveci pneumonia. Mr A has a history of good adherence to antiretroviral therapy and retention in HIV primary care. He is currently taking a regimen of emtricitabine, tenofovir, and ritonavir-boosted darunavir, his CD4+ count is 350 cells/μL, and his viral load is undetectable. Over the past 10 years, Mr A has developed several comorbidities. He has diabetes, requiring oral hypoglycemic therapy and insulin. Although he is not overweight, he has central adiposity, and his total cholesterol and triglycerides are elevated. He also has peripheral neuropathy, which may be secondary to a combination of early treatment with stavudine, diabetes, and HIV itself. His neuropathy improved somewhat after initiation of gabapentin but still affects his quality of life. Last year, he began to have hip pain and was diagnosed with bilateral severe hip osteonecrosis. The pain has severely limited Mr A’s mobility and he is unable to participate in activities that he previously enjoyed, such as working in his garden or playing with his nieces. While undergoing an evaluation for a bilateral total hip replacement, he had an episode of chest pain and a positive stress test, resulting in a cardiac catheterization and stent placement. Over the past few years, Mr A has also begun to appear more frail; he is thinner, has less muscle mass, has a slow gait, and has begun to show signs of cognitive decline.

Mr A lives with his 85-year-old mother and has become increasingly dependent on her for some activities of daily living, such as grocery shopping and other errands. She has cardiovascular disease and suffers from arthritis, which impairs her mobility. Mr A notes that his mother’s health has been declining over the past year, and notably, they share many of the same comorbidities.

Commentary

This case illustrates the numerous challenges that may be faced when caring for aging HIV “survivors.” At this point in Mr A’s illness trajectory, diabetes and cardiovascular disease have surpassed HIV infection itself as drivers of functional impairment. An HIV practitioner, seeing this patient in a 15-to 30-minute office visit, is likely to focus on the biggest threats to Mr A’s health: his cardiovascular risk factors and glycemic control. However, there are other pressing issues that must be addressed, including Mr A’s disabling pain, his increasingly challenging family environment, his cognitive decline, and possibly his mood.

Research on the impact of chronic pain in patients with HIV disease and the approaches to its management in the current treatment era is limited. There is some evidence that pain impacts retention, adherence, virologic suppression, and physical function in HIV-infected patients.10, 12, 34, 35 The goal of successful chronic pain management is to restore physical function. This involves a combination of pharmacologic management and the use of psychologic-based therapeutic techniques. In this case, Mr A’s peripheral neuropathy is only somewhat improved with gabapentin. Numerous other pharmacologic agents (Table 1), in addition to cognitive behavioral therapy and supportive psychotherapy,36 are effective in the treatment of this painful disorder. In addition, although not a factor in this case, psychiatric illnesses such as mood disorders and substance abuse must be addressed when present, as these often impact the patient’s pain and response to therapy.37

Table 1.

Agents Used in the Treatment of Peripheral Neuropathy in HIV-Infected Patients

Agent	Comments
Gabapentina	In a randomized controlled trial of gabapentin vs placebo in 26 HIV-infected patients, 44% of subjects reported improvement in neuropathic pain and 48% reported improvement in sleep in the gabapentin group, and no improvements were reported in the placebo group.44
Pregabalin	A randomized controlled trial of pregabalin vs placebo in 302 HIV-infected patients showed lack of superiority of pregabalin.45 However, based on its similarity to gabapentin, and its ease of administration and superior tolerability, it is often prescribed for the treatment of peripheral neuropathy.
Amitriptyline	Randomized trials of amitriptyline, mexiletine, or placebo46 and a 2 x 2 factorial design of amitriptyline and acupuncture47 found no difference between amitriptyline and placebo. However, due to its efficacy in other populations (eg, diabetic neuropathy), amitriptyline and other tricyclic antidepressants are often used to treat neuropathy in HIV-infected patients.
Capsaicina	Two similarly designed randomized controlled trials in which high-dose capsaicin (8%) was compared with a low-dose control (0.04%) demonstrated efficacy. Analysis of combined data from both trials showed an improvement of 27% with the high dose vs 16% with the low dose (n = 239 and n = 100, respectively).48
Lidocaine	A randomized, controlled, crossover study of topical lidocaine in 64 participants found it to be no more effective than placebo in HIV-infected patients with peripheral neuropathy.49
Opioids	There are no studies of opioids in HIV-infected patients with peripheral neuropathy. However, opioids are commonly used in the treatment of chronic nonmalignant pain and, in particular, have been shown to have at least some efficacy in the treatment of neuropathic pain in non–HIV-infected patients.50 They are sometimes used in the management of peripheral neuropathy in HIV-infected patients.

Based on the literature for diabetic neuropathy, duloxetine or valproic acid may be considered for second-line management of peripheral neuropathy in HIV-infected patients. aProven efficacy for HIV peripheral neuropathy in at least 1 randomized controlled trial. Compiled from Hahn et al,44 Simpson et al,45 Kieburtz et al,46 Shlay et al,47 Brown et al,48 Estanislao et al,49 and Eisenberg et al.50

Mr A’s chronic pain and declining health impact his relationship with his mother, who is also ailing. Mr A may wonder what will happen if his mother can no longer take care of him, or of herself. Mr A’s mother may be experiencing a high degree of caregiver burden from caring for an adult child who is declining.

Consultation with a palliative care specialist could assist Mr A with the activities and issues that are most important to him. It is becoming more common for palliative care providers to see patients with chronic pain in the ambulatory setting.38 A palliative care approach to this patient’s chronic pain could include pharmacologic management, including opioids and drugs specifically targeted at peripheral neuropathy (ie, gabapentin, pregabalin, or other anticonvulsants); setting realistic functional goals with the patient; using advanced therapeutic techniques such as cognitive behavioral therapy and motivational interviewing to help him achieve his goals; assessing the patient for cognitive decline and mood disorders such as depression and anxiety; and testing for hypogonadism, given the patient’s frailty and declining muscle mass. Addressing the patient’s declining health, planning for the future, treating his comordibities and increasing frailty, and anticipating advanced care planning for an ailing parent are all part of the palliative care skill set.

Additionally, palliative care is provided in the context of an interdisciplinary approach, which includes nurses, social workers, and chaplains with palliative care training or expertise. The focus of the palliative care team’s efforts is not only on the patient but on the patient’s entire family or support system. In the case of Mr A, team members could be involved in a variety of ways, including emotional and spiritual support to him and his mother, which is an often neglected but important part of decision making for patients with life-threatening illness,39 and identifying community resources such as meal preparation programs or caregiver support.

Case 2: Retention and Adherence

Ms B is a 22-year-old African American woman who was diagnosed with HIV infection during a pregnancy 5 years ago and placed on antiretroviral therapy. She gave birth to a healthy, HIV-seronegative girl. Her CD4+ count at antiretroviral therapy initiation was 200 cells/mL and was 300 cells/mL with an undetectable viral load at the time she gave birth. She was encouraged to continue on antiretroviral therapy and was connected to a Ryan White HIV/AIDS Program clinic to receive ongoing HIV care. Ms B has suffered from addiction to cocaine since the age of 16 years. During her pregnancy, she lived in a recovery house and was able to deliver her baby cocaine-free. However, after giving birth, she suffered from depression and relapsed. Her daughter was removed from her care by social services and taken to live with the patient’s parents. Despite numerous calls from the clinic social workers and other staff trying to locate her, Ms B disappeared from the clinic. When she reappeared a year later, it was at a dual diagnosis unit where she was hospitalized for depression and cocaine relapse. After discharge, she was referred back to the Ryan White clinic. Laboratory samples were drawn, and a 1-month follow-up visit to discuss reinitiation of antiretroviral therapy was scheduled. Ms B missed that visit and clinic staff were later notified that she was in the hospital again. She had been found unresponsive in a local park; her urine tested positive for cocaine, and a lumbar puncture revealed an opening pressure of 30 cm and a white blood cell count of 100/μL. Her cerebrospinal fluid tested positive for cryptococcal antigen and an India ink stain showed yeast forms. She was hospitalized for 2 weeks, during which time she suffered from severe headaches, nausea, and vomiting. She received therapy with liposomal amphotericin and flucytosine and daily lumbar punctures. She was discharged with a prescription for fluconazole and an appointment to see her HIV care practitioner in 1 month to initiate antiretroviral therapy. She was readmitted after only 2 weeks, once again with a urine drug screen that tested positive for cocaine, a full bottle of fluconazole in her pocket, and a relapse of cryptococcal meningitis.

Commentary

This is an all too common scenario and is likely to cause distress not only for the patient and her family but for the medical team involved in the patient’s care. This patient is young and has the potential to be relatively healthy. Unfortunately, this patient has experienced a high burden of illness secondary to depression and substance abuse, which have impacted key health behaviors: retention in HIV primary care and adherence to antiretroviral therapy. She now has cryptococcal meningitis, which if not treated properly is universally fatal. Her prognosis could be excellent, but given her psychiatric and substance abuse comorbidities is likely poor.

Ms B’s suffering is multifaceted. In palliative care, this is often conceptualized as “total pain,” which includes suffering that is not only physical but also psychologic, social, emotional, and spiritual.40 She has a high burden of physical pain and nausea, which, regardless of their cause or the fact that they could have been prevented, can be treated with careful selection of analgesics and antiemetics (Table 2). The assessment and management of symptoms in a patient with altered mental status may be particularly complex but can be achieved. The patient’s psychiatric illness and substance abuse are also likely to be contributing to her suffering and must be directly addressed; given the barriers to accessing mental health services in the United States, it is often difficult to address these issues. Ms B and her family may also experience a high degree of emotional and existential suffering, and even grief, over how their lives have been changed so dramatically by Ms B’s illness.

Table 2.

Mechanisms and Locations of Action of Common Antiemetic Therapies

Etiology	Pathophysiology	Therapy
Brain metastases, meningeal irritation	Increased intracranial pressure	Steroids
Movement	Vestibular stimulation	Anti-acetylcholine (scopolamine)
Anxiety	Cortical	Anxiolytics (benzodiazepines)
Medications (chemotherapy, opioids)	CTZ, vestibular stimulation	Antidopaminergics (haloperidol, metoclopramide), antihistamines (diphenhydramine, meclizine), serotonin antagonists (ondansetron), anti-acetylcholine
Motility (opioids, ileus, other medications)	Gastrointestinal	Prokinetic agents (metoclopramide), stimulant laxatives (sennosides)
Mechanical obstruction	Constipation, tumor, stricture	Manage constipation, surgery when appropriate, steroids, inhibit secretions with octreotide
Metabolic (hypercalcemia, hyponatremia, hepatic or renal failure)	CTZ	Antidopaminergics, antihistamines, fluids, steroids

CTZ indicates chemoreceptor trigger zone (medulla). Adapted from Glare et al51 and International Palliative Care Resource Center.52

These are complex issues that may be difficult to address in the context of an inpatient hospital stay. Two central themes of the palliative care approach are identifying the patient’s and the family’s goals of care, and identifying and treating their suffering, not only physical but spiritual, emotional, and psychosocial. This approach is especially well-suited to situations like Ms B’s, which are both medically and socially complex. Communicating with patients about goals of care and suffering under such complex circumstances is often challenging; palliative care interdisciplinary team members must be highly skilled communicators. By understanding the patient’s and family’s goals, the palliative care team can help guide the patient, family, and other clinicians through complex medical decision making.

It is often necessary to call on psychiatric and addiction specialist colleagues to collaborate in cases when mental illness itself has become a barrier to effective HIV treatment. Regardless of the patient’s goals of care, treatment of psychiatric illness and addiction as core causes of suffering is essential and must not be overlooked.

Case 3: Liver Failure in an HIV-Infected Patient

Mr D is a 55-year-old white man who was infected with HIV in his 30s when he injected heroin. He was diagnosed with HIV in 2002 and had a CD4+ count of 600 cells/μL. His hepatitis C virus (HCV) antibody test was also positive, with a viral load of 1 million IU/mL. Because of bouts of depression and alcohol abuse, he was deemed to be a poor candidate for HCV treatment with peginterferon alfa and ribavirin and was not started on antiretroviral therapy owing to concerns about adherence. He was observed off antiretroviral therapy until 2009, when his CD4+ cell count was 300/μL, and his HCV viral load was 2 million IU/mL. His laboratory test results were unremarkable, except for a platelet count of 90/μL and an albumin level of 3 g/dL. At that time, he also had a liver ultrasound, which showed results consistent with cirrhosis. Mr D was started on antiretroviral therapy with emtricitabine, tenofovir, and efavirenz for his HIV infection, but due to his advanced liver disease, no HCV therapy was initiated. Over the subsequent 3 years, Mr D developed decompensated cirrhosis. Most troubling was the detection of large-volume ascites that caused the patient abdominal pain and shortness of breath, and hepatic encephalopathy, resulting in numerous hospital admissions and difficulty with his activities of daily living. Mr D also admits to drinking alcohol up until 3 months before his most recent visit and therefore is not a candidate for liver transplant. Mr D is estranged from his wife, whom clinic staff have tried unsuccessfully to locate. He has no other family and does not have a health care proxy.

Commentary

Cirrhosis leading to liver failure is the second most common cause of non–AIDS-related comorbidity and death in patients infected with HIV.41,42 This patient is not a transplant candidate, because of his alcohol use, and his decompensated cirrhosis and poor functional status make survival to the point of transplantation unlikely. This patient’s prognosis is likely a life expectancy of only a few months. As with many patients in this type of situation, Mr D’s HIV infection is well controlled, whereas his HCV infection is the primary driver of morbidity and ultimately mortality.

Palliative care involvement, during one of Mr D’s many hospital admissions or in the outpatient setting, could be beneficial in several ways. Mr D’s symptom burden is high. The use of pharmacologic approaches to relieve his shortness of breath, such as low-dose opioids or benzodiazepines, is challenging for patients with liver disease but achievable with close monitoring. The addition of nonpharmacologic measures, such as forced oxygen treatment or a fan, yoga to help the patient with positioning, relaxation therapy, cognitive behavioral therapies, and paracentesis or peritoneal drain placement, may prove helpful. Addressing his symptoms may help the patient to focus on the things he wants to do during the last stage of his life, such as saying goodbye to the people who are close to him, addressing any outstanding financial issues, and achieving existential or spiritual closure.

Mr D has had bouts of depression and, until very recently, was actively drinking alcohol. Mood disorders and addiction are often ongoing sources of suffering for patients and their families near the end of life. Therefore, it is important to assess these issues, recognizing that the way they should be addressed may be different for patients who have a life-limiting illness than for those who do not; eg, engaging in recovery may not be feasible given the severity of illness; if life expectancy is very short, then a selective serotonin reuptake inhibitor may not be practical; and stimulants like methylphenidate may be used.43 The interdisciplinary palliative care team, in collaboration with psychiatric and addiction specialists when appropriate, can help address the sources of suffering during the last phase of Mr D’s life.

Identifying a health care proxy for patients with serious medical illness is extremely important, especially for patients where no “natural proxy” (ie, easily identifiable next of kin such as a spouse or partner) exists. Mr D should discuss with his proxy his medical condition and what his wishes might be should his condition worsen. The question of artificial nutrition and hydration (eg, a feeding tube) may arise, since Mr D’s worsening condition will likely lead to an inability to swallow medications, including lactulose, or eat. The risks and benefits of such interventions in dying patients must be carefully considered. The medical team should explore whether Mr D would like a team member to be present for his conversation with his health care proxy to assist with communication about these difficult issues. Many patients at the end of life also wish to communicate final thoughts with their families, such as “please forgive me,” “I forgive you,” “thank you,” “I love you,” and sometimes, “goodbye” (see http://www.thefourthings.org).

Finally, the question of if and when to stop antiretroviral therapy in patients like Mr D who are dying of a comorbidity, or in patients dying with AIDS, is a challenging one. Many factors must be taken into consideration, including pill burden, cost (especially if hospice care is being considered, as some hospices cannot afford to continue providing antiretroviral drugs), patient and family preference, adverse effects, and whether there are any remaining potential benefits of the medications.

Summary

Palliative care is a specialty that may be applied to the practice of HIV medicine in the current treatment era. Challenges faced by patients and practitioners, such as aging, multimorbidity, complex decision making for seriously ill patients with AIDS, and caring for patients with HIV infection who are dying of causes other than HIV, may be aided by a palliative care approach. These cases are meant to prompt discussion between HIV and palliative care practitioners about potential areas of clinical and research collaboration.

Acknowledgements

We thank Sarah Goodlin, MD, Associate Professor and Chief of Geriatrics, Portland VA Medical Center, Portland, Oregon, for her help in developing the concept for this paper and her review of an earlier version of the manuscript.