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INTRODUCTION — Palliative care is an interdisciplinary medical specialty that focuses on preventing and relieving suffering and on supporting the best possible quality of life for patients facing serious illness and their families. The primary tenets are symptom management; establishing goals of care that are in keeping with the patient’s values and preferences; consistent and sustained communication between the patient and caregivers; and psychosocial, spiritual, and practical support, both to patients and their caregivers. For patients with a variety of advanced illnesses, palliative care is applicable early in the course of the disease in conjunction with disease-modifying therapies (the simultaneous care model); it is not limited to end of life care . (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
In the early days of the human immunodeficiency virus (HIV) epidemic, all care for individuals with HIV-related disease was, by definition, palliative. With the introduction of tolerable, effective antiretroviral therapy (ART), HIV infection was transformed from a terminal disease with a uniformly poor prognosis to a serious chronic illness, at least in resource-rich settings among individuals who know their HIV status and are adherent to ART . (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient" and "The natural history and clinical features of HIV infection in adults and adolescents".)
However, even in the modern treatment era, individuals with HIV fit well within the “serious illness” paradigm for which early integration of palliative care plays a complementary role to active treatment of the underlying disease. These patients have a substantial burden of medical and psychiatric comorbidities, pain, and other symptoms throughout the course of the disease, and a wide-ranging need for psychosocial, family, and care-planning support. Although no studies have investigated this to date, it is possible that treatment of these comorbidities could improve HIV outcomes, such as adherence to ART, retention in HIV primary care, and virologic suppression.
This topic review describes an approach to palliative care in patients with HIV/acquired immunodeficiency syndrome (AIDS) in resource-rich settings that is based on the available literature and our clinical experience. The specific areas in which palliative care principles and expertise might assist in the care of individuals with HIV infection include establishing goals of care, advance care planning, making decisions about continuing or discontinuing ART as the end of life approaches, and symptom management.
OVERVIEW OF HIV STAGES AND TREATMENT — HIV infection can be divided into the following stages:
●Acute HIV infection (also called primary HIV infection or acute seroconversion syndrome) (see "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Acute and early HIV infection')
●Chronic HIV infection (see "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Chronic HIV infection, without AIDS' and "The natural history and clinical features of HIV infection in adults and adolescents", section on 'AIDS and advanced HIV infection')
•Early symptomatic HIV infection (previously known as AIDS-related complex [ARC] or Class B)
•AIDS characterized by a CD4 cell count <200 cells/microL or the presence of any AIDS-defining condition (table 1)
•Advanced or late HIV infection characterized by a CD4 cell count <50 cells/microL
Antiretroviral therapy (ART) is recommended for all HIV infected individuals. The goal of ART is to inhibit viral replication, decreasing viral load and allowing the patient’s immune system to recover. ART also decreases the risk and/or slows the development of AIDS-defining conditions and non-AIDS-defining complications (table 2), lessens the risk of HIV transmission, and prolongs life. (See "When to initiate antiretroviral therapy in HIV-infected patients".)
HIV treatment has changed dramatically since the early 1990s. Modern ART generally consists of two or more drugs of different classes in combination to prevent the acquisition of drug resistance (table 3). Many combinations are available in a single pill, which decreases the pill burden. Adherence is important because nonadherence can lead to viral replication in the presence of ineffective levels of one or more of the drugs used in the regimen, causing the virus to mutate and reducing susceptibility to current drugs used to treat HIV. (See "Overview of antiretroviral agents used to treat HIV".)
Prophylactic antimicrobial therapy is administered to certain HIV infected patients with the goal of preventing a clinically significant opportunistic infection. Such treatment is typically initiated as the individual’s cell-mediated immunity (ie, CD4 cell count) declines. For certain infections, the decision to initiate antimicrobial therapy also depends upon prior exposure to the pathogen. (See "Overview of prevention of opportunistic infections in HIV-infected patients".)
BURDEN OF HIV — The HIV epidemic has reached every country and nearly all populations throughout the world. Globally, an estimated 37 million individuals are HIV infected, with just over 1 million of those in the United States . (See "Global epidemiology of HIV infection", section on 'Worldwide statistics'.)
Advances in antiretroviral therapy (ART) have resulted in significant changes in the survival rate and quality of life of HIV infected individuals over the past 20 to 25 years. In resource-rich settings, HIV infected adults who are aware of their diagnosis, are linked to and stay in ongoing care, adhere to ART treatment, and are virologically suppressed have expected life spans approaching that of the general population [4-8]. This increase in life expectancy is attributable to the decreased incidence of opportunistic infections (OIs) because of early initiation of ART and improved care for those with HIV-related complications, which has led to an increase in five-year survival after an AIDS-defining OI [9-11]. (See 'Prognostication and the influence of ART' below.)
However, this dramatically increased life expectancy has also contributed to a rapidly aging HIV infected population. A Dutch modeling study projected that the percentage of individuals with HIV over age 50 would increase from an already sizable 28 percent of the population in 2010 to 73 percent by 2030 . Additionally, individuals of all ages with HIV are at risk for premature age-related comorbidities, as compared with the general population . Therefore, despite gains in life expectancy, individuals with HIV shoulder a large burden of morbidity. (See 'Comorbidity and multimorbidity' below and "HIV infection in older adults".)
Furthermore, despite advances in ART, complications of end-stage HIV disease are still prevalent because of undiagnosed cases and difficulties with adherence to ART and/or with retention in care. Roughly one-third of individuals living with HIV in the United States are diagnosed late in the disease course, at a time when they already have a CD4 count below 350 cells/microL or an AIDS-defining illness . Risk factors associated with these challenges include substance abuse (alcohol, intravenous drug use), depression, the stigma of HIV infection, lack of social support, and younger age [15-19]. The challenges inherent in managing these patients are discussed in more detail below. (See 'Challenges in caring for patients with advanced HIV/AIDS' below.)
Challenges also remain in resource-limited countries. Despite advances in ART provision in such settings, a large proportion of HIV infected patients still do not have access to or are otherwise not receiving ART. (See "The impact of antiretroviral therapy on morbidity and mortality of HIV infection in resource-limited settings".)
Causes of death — Despite advances in treatment, AIDS-defining illnesses cause a sizable proportion of deaths among HIV infected individuals :
●In a study examining mortality among 49,731 participants in the Data Collection of Adverse Events of HIV Drugs (D:A:D) study, the most common causes of death were AIDS-related causes (29 percent), followed by non-AIDS-related cancers (15 percent), liver disease (13 percent), and cardiovascular disease (11 percent) .
●In another study of 230 HIV infected patients (89 percent with a prior AIDS-defining illness) in a United States palliative care program, 36 percent died of AIDS, 19 percent died of a non-AIDS-defining cancer, 18 percent died of bacterial pneumonia or sepsis, and 13 percent died of liver failure .
●Approximately 25 to 35 percent of all deaths in HIV infected individuals are related to malignancies, especially non-Hodgkin lymphomas [23,24]. (See "HIV infection and malignancy: Epidemiology and pathogenesis".)
Comorbidity and multimorbidity — Patients with HIV infection have a high degree of comorbidity and multimorbidity. Comorbidity, as it relates to HIV infection, can be defined as any disease or risk factor that interacts with HIV, making either condition worse . Multimorbidity, which is defined by the World Health Organization (WHO) as two or more chronic health conditions , is an evolving concept in HIV disease. Multimorbidity is sometimes referred to as polypathology .
Compared with matched controls in the general population, individuals with HIV infection have higher rates of age-related comorbidities, such as hypertension, diabetes mellitus, renal failure, cardiovascular disease, and fractures, which occur an average of 10 years earlier . Other common comorbidities include osteoporosis , frailty [28,29], liver disease , and neurocognitive impairment . These comorbid conditions are thought to be related to a myriad of factors, including direct toxicity from the virus, chronic inflammation, chronic immunosuppression, toxicity related to ART, and elevated rates of high-risk health behaviors in this population [29,32-36]. HIV-specific risk factors for developing comorbidities include lower nadir CD4 cell count and prolonged ART exposure. (See "Primary care of the HIV-infected adult", section on 'Monitoring for complications'.)
Notably, these medical comorbidities are in addition to the relatively high rates of psychiatric illness and substance use disorders in individuals with HIV infection [37-40]. As an example, in one study, rates of psychiatric illness were twice as high in individuals with HIV infection as in the general population . Psychiatric comorbidities are associated with suboptimal adherence to ART [42-44]. In addition, studies of individuals with HIV infection have shown that patients with substance use disorders have worse health outcomes . (See "Overview of the neuropsychiatric aspects of HIV infection and AIDS" and "Depression, mania, and schizophrenia in HIV-infected patients" and "Substance abuse and addiction in HIV-infected patients".)
CHALLENGES IN CARING FOR PATIENTS WITH ADVANCED HIV/AIDS
Prognostication and the influence of ART — Prognosis and disease trajectory in individuals with advanced HIV or AIDS are highly variable and depend on many factors, including the ability to successfully treat with antiretroviral therapy (ART), the immunologic response to ART, response to therapy for opportunistic infections (OIs), and the presence and type of malignancy, if present. Since many patients with advanced HIV/AIDS have not yet begun ART or have had past challenges with adherence or retention, the likelihood of long-term success of treatment of the acute condition in these patients is often uncertain. In our view, in the current treatment era, any attempt at prognostication that does not address whether the patient has had an adequate trial of ART would be ill-informed and inaccurate.
Some important prognostic indices for individuals with HIV have been developed from contemporary observational cohorts. These indices incorporate combinations of HIV-specific and non-HIV-specific biologic, behavioral, and demographic variables and offer prognostic information about risk and survival. For example, one of the most widely cited indices, the Veterans Aging Cohort Study (VACS) index, combines seven variables to predict mortality in HIV infected individuals: age, CD4 cell count, HIV viral load, hemoglobin, Fibrosis-4 Index , presence of hepatitis C, and glomerular filtration rate [47-49].
However, such indices neglect a critical factor in individuals with AIDS who are not on ART: ART can have a determinative impact on long-term survival. This is true even when patients present with advanced AIDS-related conditions that meet criteria for hospice admission, such as central nervous system toxoplasmosis or progressive multifocal leukoencephalopathy (PML) . (See 'Hospice' below.)
In the current treatment era of potent ART, resistance to treatment leading to inability to find a fully active regimen is uncommon. Therefore, when individuals with HIV infection in resource-rich settings are dying of AIDS or AIDS-related illnesses, the root cause is typically a breakdown in what is known as the HIV treatment cascade. These patients are not taking ART because they are either unaware they have HIV and have been diagnosed with advanced disease, know they have HIV but are not linked to HIV care, or are linked to care but are not adherent to ART .
ART management in advanced disease — Given the uncertainties with prognosis in the patient with advanced HIV/AIDS, which depends substantially on the success of ART, we recommend the following general approach to ART management in individuals with advanced HIV/AIDS:
●For individuals without an AIDS-defining illness who are not on ART due to late diagnosis or challenges with adherence or retention, every attempt should be made to fully engage them in care and begin ART, with close attention to adherence. (See "When to initiate antiretroviral therapy in HIV-infected patients", section on 'Benefits of antiretroviral therapy' and "Patient monitoring during HIV antiretroviral therapy", section on 'Adherence'.)
●For individuals with an AIDS-defining illness who are not on effective ART, we strongly recommend a trial of ART. ART should be initiated in consultation with an HIV specialist; the optimal time to initiate ART varies by clinical situation (see individual topic reviews for recommendations about initiation of ART in the setting of OIs). This trial should last for at least six months.
In such patients, the short-term prognosis depends on the severity of the acute illness, particularly in cases such as cryptococcal meningitis requiring shunt placement, extensive Kaposi sarcoma, or pneumocystis pneumonia requiring mechanical ventilation, which are associated with high mortality rates, even when treated aggressively. However, long-term prognosis typically depends not only on following patients through their acute medical issues, but also upon whether patients can maintain lifelong retention in HIV primary care and adherence to ART. Since many patients with AIDS-related illnesses have not yet begun ART or have had past challenges with adherence or retention, the likelihood of long-term success in these patients is often uncertain.
Determining with certainty which patients will be able to achieve long-term ART adherence, retention, and virologic suppression when they present with an AIDS-related illness is an impossible task. Therefore, it should be assumed that all individuals with HIV have the potential to achieve long-term success until clearly demonstrated otherwise.
Frank conversations with patients and their families in these situations are essential. Optimistic messages about availability of effective ART regimens should be communicated alongside the realities of the severity of the patient’s acute illness and what would be necessary in order for the patient to achieve long-term success in terms of life-long ART adherence and retention in HIV primary care.
This discussion should prompt a discussion of the patient’s goals of care. Some patients may have goals that focus on quality of life over quantity; other patients may be focused on treating the acute illness aggressively, regardless of the invasiveness of the treatments required; still others may fall somewhere in between. It is the provider’s responsibility to respect the patient’s choice, tailor the plan of care to the patient’s goals, and revise the plan of care as often as necessary as these conversations evolve. A subspecialty palliative care consultation may facilitate these discussions. (See 'Advance care planning' below and 'Primary versus secondary (subspecialty) palliative care' below and "Discussing goals of care".)
It is important that all such patients have continuity, ideally with an experienced HIV primary care provider. Therefore, if such discussions occur in an inpatient setting, they should be done in consultation with an HIV specialist. Upon discharge, that specialist should facilitate the patient’s linkage with outpatient HIV care and clearly communicate the patient’s treatment plan as part of this hand-off.
Notably, the factors that lead to late diagnosis or that lead to suboptimal adherence to ART or retention in care include mental illness, substance use disorders, and lack of social support. These are serious comorbidities and concerns in and of themselves, and they can often continue to pose a barrier to restoring a patient’s health. They should be addressed directly whenever possible.
In rare instances, high-level HIV drug resistance leaves a patient with no available fully active salvage regimen. Continuing a patient on a partially active regimen may control their disease enough to prolong their survival until a new drug or class of drugs is available. Occasionally, no such partially active regimen is available, and it may be appropriate to discontinue ART. This decision should be made in close consultation with an HIV specialist.
Even more rarely, there are instances in which individuals with advanced AIDS are unable to benefit from ART due to extenuating clinical circumstances. As an example, all current standard agents are only available in oral form. Therefore, gastrointestinal malabsorption, severe hypoalbuminemia, or other mechanical or functional barriers to adequate bioavailability of ART exist. Occasionally, for patients who have a functioning gastrointestinal tract but cannot ingest the medication (eg, are unable to swallow or have intractable nausea/vomiting), clinicians may consider time-limited percutaneous endoscopic gastrostomy (PEG) placement in order to deliver the antiretroviral effectively. However, in such cases, this must be done in concert with the patient’s wishes about artificial feeding and, if done primarily for a trial of ART, should be managed in this time-limited context (eg, not left in place and used indefinitely if not in accord with the patient’s intentions).
In general, once an individual is successfully on suppressive ART, they should continue it as long as it is consistent with the goals of care. Issues related to discontinuation of ART or prophylaxis at the end of life are discussed below. (See 'Continuation versus discontinuation of HIV-related medications' below.)
UTILIZATION AND BENEFITS OF PALLIATIVE CARE — The primary goal of palliative care is to improve quality of life for the patient and their family through relief of emotional and physical symptoms. Other key services are establishing goals of care that are based on the patient’s values and preferences; advance care planning (ACP); psychosocial, spiritual, and bereavement support; and coordination of care. (See "Benefits, services, and models of subspecialty palliative care" and "Palliative care and hospice outside of the United States".)
Empirical support for the benefit of early palliative care intervention in the management of serious illness comes from randomized trials showing that palliative care, when delivered alongside disease-modifying treatment, enhances quality of life, lowers the costs of care, and may improve survival. Much of the data are derived from patients with advanced cancer, but an increasing body of evidence supports the benefits of early palliative care intervention in a variety of diseases. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
Individuals with HIV infection in the modern treatment era fit well within the “serious illness” paradigm for which early integration of palliative care plays a complementary role to active treatment of the underlying disease for the following reasons:
●Despite therapeutic advances, AIDS and its associated comorbidities remain important causes of death among patients infected with HIV. (See 'Causes of death' above.)
●Individuals with HIV/AIDS often have a substantial burden of medical and psychosocial comorbidities, as well as pain and other symptoms, throughout the course of the disease. Additionally, the population of individuals with HIV is itself aging and has a high prevalence of comorbidity and multimorbidity. As patients survive longer, they may in fact have a greater need for comprehensive symptom management and a wide-ranging need for psychosocial, family, and care-planning support. (See 'Comorbidity and multimorbidity' above.)
●Uncertainty about prognosis and the limitations of ART (especially side effects and compliance) has made decision-making about ACP and end of life issues more complex and difficult than when the disease course was more uniform, rapid, and predictable .
In fact, both the World Health Organization (WHO)  and the Joint United Nations Program on HIV/AIDS (UNAIDS)  specify the importance of offering palliative care across the spectrum of illness for all patients with HIV/AIDS. (See "Primary care of the HIV-infected adult" and "Overview of the neuropsychiatric aspects of HIV infection and AIDS" and "HIV infection in older adults".)
There is very little literature, especially in resource-rich settings, on the contemporary state of palliative care in individuals with HIV infection, and what data there are suggest that palliative and hospice care are underutilized in this population . In one retrospective cohort study of 367 HIV patients hospitalized in a large urban safety net hospital in 2010, 28 percent died during that hospitalization, but only 6 percent received a palliative care consultation, and 6 percent were enrolled in hospice. Of the patients who received hospice care, the mean time to death after enrollment was only 11 days.
While the benefits of specific palliative care interventions for individuals with HIV infection have not been tested in randomized controlled trials, early results from programs allowing for early integration of palliative care services into HIV primary care are promising [51,56-62]. As an example, one early systematic review included 17 studies evaluating outcomes or satisfaction with care in persons living with HIV who received services that specifically addressed symptom control, pain management, psychosocial support, and/or end of life care . While acknowledging the significant methodologic challenges associated with the evidence base (one randomized trial, two observational studies with control groups, seven single-group longitudinal studies, and one cross-sectional study), the authors concluded that home palliative care and inpatient hospice programs resulted in better pain and non-pain symptom control, reduced anxiety and enhanced spiritual wellbeing, and improved disease insight. The sole randomized trial, which compared an integrated multidisciplinary home care approach with standard home care in 57 patients with AIDS, showed potentially meaningful benefits (in quality of wellbeing and survival), but the differences were not statistically significant .
An important point is that among the obstacles to ART adherence are lack of financial resources, housing instability, difficulties with transportation, and symptom burden, including fatigue, confusion, and pain [58,65-67]. Optimizing symptom control and addressing psychosocial issues that might impact treatment compliance are both elements of comprehensive palliative care. (See 'ART management in advanced disease' above and "Overview of comprehensive patient assessment in palliative care".)
A “false dichotomy” between curative and palliative care in individuals with HIV has been described. However, optimally, palliative care should be delivered alongside potentially curative treatments. Individuals may receive life-prolonging treatment, such as treatment directed at the AIDS-related illness and/or ART, while also receiving treatment for pain and other symptoms, and engaging in goals of care conversations .
Primary versus secondary (subspecialty) palliative care — Hospice and Palliative Medicine is now recognized as a medical subspecialty by the American Board of Medical Specialties (ABMS), as well as in Canada, England, Ireland, Australia, and New Zealand. Many other European countries are also in the process of developing certification for palliative care. (See "Palliative care and hospice outside of the United States".)
In most jurisdictions, palliative care is provided by an interdisciplinary team of specially trained physicians, nurses, social workers, chaplains, and other specialists with advanced training in palliative care who work with a patient’s other clinicians to provide an “extra layer” of support. Clinicians who are specifically trained in palliative care (subspecialty palliative care) can provide in-depth pain and symptom management, communication regarding goals of care, and care coordination across settings and over time. Subspecialty palliative care services are most available in high-income countries, as exemplified by the United States. The availability of subspecialty palliative care services in low-income countries is generally quite limited. (See "Benefits, services, and models of subspecialty palliative care" and "Palliative care and hospice outside of the United States".)
Patients with all stages of HIV disease have complex care needs, including overlapping medical, psychiatric, and psychosocial comorbidities . In order for a large number of patients with advanced life-threatening illness, such as HIV/AIDS, to benefit from palliative care, it is important that supportive services not only be provided by specialists, but also be incorporated into the practices of all clinicians who are caring for individuals with HIV infection. Some term this “primary” palliative care to distinguish it from “secondary” or “subspecialty” palliative care . Primary palliative care encompasses any type of supportive care that is delivered by all health care professionals caring for patients with serious life-threatening illness.
While primary care and infectious disease physicians caring for patients with advanced HIV/AIDS are able to manage most of their patients’ palliative care issues, consultation with a palliative care specialist may be beneficial in certain situations. Indications for a formal palliative care consultation have not been established for patients with advanced HIV/AIDS. However, general criteria for a palliative care assessment at the time of admission to the hospital are available (table 4).
Optimal palliative care for patients with advanced HIV/AIDS should ideally incorporate both primary and subspecialty palliative care. Clinicians caring for these patients need to attain competence in providing comprehensive supportive care.
What are the important components of palliative care? — Important components of a comprehensive palliative care assessment include exploring the patient’s understanding about his or her illness and prognosis; assessing and managing symptoms; counseling and establishing goals of care that are consistent with the patient’s values and preferences; ACP; providing psychosocial, spiritual, and practical support, both to patients and their family caregivers; coordination across sites of care issues that are affecting access to and compliance with care; and helping plan end of life care, including determining the need and timing of hospice care. (See 'Hospice' below and "Overview of comprehensive patient assessment in palliative care".)
Assessing and managing symptoms — Symptom burden, especially pain, is high for HIV infected patients. As an example, in an analysis of data from 124 patients seen in an outpatient palliative care clinic embedded within an HIV primary care clinic, pain was the most common reason for referral (95 percent); most (90 percent) was chronic . Other commonly addressed problems were depression (48 percent), anxiety (21 percent), insomnia (30 percent), and constipation (32 percent).
Symptom burden does not appear to be associated with CD4 cell count [69,70], except among patients with AIDS or CD4 cell counts <200 cells/microL [70,71]. The relationship between symptom burden and viral load is less clear . However, adherence to ART is associated with a lower symptom burden [73,74], while on the other hand, a persistent symptom burden while on ART has been associated with reduced adherence to ART . (See 'ART management in advanced disease' above.)
A comprehensive approach to symptom assessment in palliative care populations, including tools to measure symptom burden and intensity, is discussed in detail elsewhere. (See "Approach to symptom assessment in palliative care".)
An approach to specific symptoms that are prevalent in late-stage HIV/AIDS (chronic pain, fatigue, fever, and anorexia/tissue wasting) is presented below. (See 'Specific symptoms' below.)
Advance care planning — ACP is the process of discussing choices and preferences for care at the end of life . It includes general conversations about patient goals, values, and preferences, and more specific formal planning, such as creation of advanced directives (eg, drafting a living will, appointing a health care power of attorney). (See "Advance care planning and advance directives".)
Discussing goals of care is an important component of ACP, and this starts with exploring what is important to the patient. Some patients feel that living as long as possible is most important, even if it means that they have to undergo highly burdensome interventions, such as prolonged mechanical ventilation, that impair their quality of life. Others may want to spend their remaining time at home with their loved ones, without having to go to the hospital, even if this compromises their survival. The best possible care should support patients in living the rest of their lives according to their informed wishes. A stepwise approach to the discussion of goals of care is presented elsewhere. (See "Discussing goals of care", section on 'REMAP: A stepwise approach'.)
There are few prospective studies addressing disease-specific ACP for the palliative care needs of adult patients with HIV . The evolving literature in the ART era suggests that ACP in individuals with HIV infection is highly variable, but in general, patients with HIV/AIDS are less likely than HIV uninfected individuals with other life-threatening illnesses to have discussed ACP with their health care providers [77-84]. One review of 11 studies of HIV infected adults conducted between 1996 and 2015 found that between 8 and 47 percent had advance directives, and between 36 and 54 percent had some type of end of life communication . Lack of ACP was most commonly associated with low income, followed by lower illness severity, low education level, black or Hispanic race, female sex, younger age, injection drug use, and social isolation. Factors associated with having an ACP included severity of illness, malignancy, or cardiovascular, neurologic, or chronic kidney disease.
Other potential reasons for low rates of ACP prevalence in individuals with HIV/AIDS are the significant discrepancies between patients and health care providers with respect to what “end of life” really means in the context of HIV infection, the degree to which they believe that living a long life with HIV infection is possible, and their perspectives on patient autonomy in the decision-making process about end of life care .
When to initiate the discussion — A major unresolved question is the optimal time to initiate discussion on ACP and preferences for end of life care in individuals with HIV infection. Some have pointed out that having these conversations too early can be problematic, as individuals’ preferences change over time, and the concepts discussed can seem too abstract. On the other hand, having these conversations too late can result in receipt of care that does not match patient preferences or in the patient being too sick or cognitively impaired to actively participate in decision-making .
Therefore, finding the optimal time can be challenging but may be informed by the best available prognostic information . However, as described above, prognostication in individuals with HIV infection who have the potential to get better with adherence to ART or who have multiple medical comorbidities may be especially challenging. (See 'Prognostication and the influence of ART' above.)
There is no formal guidance regarding when to initiate ACP discussions in individuals with HIV infection, and no consensus on this issue. Specifically, the Infectious Diseases Society of America HIV primary care guidelines and the European AIDS Clinical Society do not address ACP. However, based on our clinical experience, we recommend following the guidance of the well-established “Respecting Choices” paradigm [86,87], which recommends a three-stage, prognosis-informed approach, as outlined elsewhere. (See "Advance care planning and advance directives", section on 'Facilitating the ACP'.)
Challenges in end of life care — In this section, we will discuss two major challenges that commonly arise in individuals with HIV infection at the end of life: continuation versus discontinuation of HIV-related medications, and HIV hospice entry criteria and their applicability in the current treatment era.
Continuation versus discontinuation of HIV-related medications — The shift towards end of life palliation often involves discontinuation of many disease-specific therapies. When disease-specific therapies contribute to comfort at the end of life, they may be continued after careful discussion with the patient and family. (See "Palliative care: The last hours and days of life", section on 'Reviewing medication orders'.)
For patients with HIV/AIDS who are approaching the end of life, one of the most important decisions is whether and when to discontinue ART. This is a particularly difficult decision for patients and their families as it may be seen as “giving up.” There are no guidelines to inform clinicians and patients about when to stop ART or routine prophylaxis for opportunistic infections (OIs), and one must weigh the risks (burdens such as cost, side effects, and pill burden) and benefits of continuing ART and OI prophylaxis. Especially as more patients die from conditions such as liver failure or cancer (ie, dying with, rather than from, HIV/AIDS), decisions regarding the role of ART become more complex.
Each situation is unique; however, there are potential benefits for continuing ART, even in late-stage disease :
●In individuals who are virologically suppressed and dying from a condition besides AIDS, discontinuing ART will lead to uncontrolled viremia, which could contribute to symptom burden
In the rare individual dying of AIDS and on a salvage ART regimen, even though this regimen may only be partially active in late-stage disease, treatment could select for a less “fit” virus, even in the presence of elevated viral loads . This could help stave off burdensome symptoms (eg, fatigue, weight loss, neuropathy ) caused by the direct effects of the virus.
●ART may help sustain cognitive functioning, as systemic viral load does not always correlate with central nervous system viral load [90,91].
There are also many reasons to consider discontinuing ART or OI prophylaxis:
●Continuing medications might contribute to anxiety for patients who had trouble taking medications prior to late-stage disease, cause confusion about goals, and distract from ACP .
●Pill burden and potential drug-drug interactions with common palliative care medications are also important to consider. For example, some antiretrovirals, such as ritonavir, increase levels of some opioids (eg, oxycodone) while decreasing the levels of other opioids (eg, methadone) . Patients should be monitored for signs and symptoms of overdose or withdrawal, and if needed, the opioid dose should be adjusted.
Clinicians should initiate these discussions early with patients and their families and continue the conversation about goals of care and when the burdens of therapy outweigh the risks throughout the course of treatment.
Hospice — Hospice services in the United States are provided for patients who have an estimated life expectancy of six months or less under the Medicare hospice benefit. (See "Hospice: Philosophy of care and appropriate utilization in the United States".)
Current hospice admission criteria are not evidence-based and were last written in 1996, prior to the introduction of modern ART; they are outlined in the table (table 5). Non-disease-specific eligibility requirements, which must be used in conjunction with the disease-specific criteria, are outlined in the table (table 6).
In our experience, providers may be reluctant to refer patients with AIDS who have any of these conditions to hospice given the prognostic uncertainty described above. (See 'Prognostication and the influence of ART' above.)
Another barrier to hospice referral in patients with AIDS is payment for ART. If the hospice diagnosis is AIDS, Medicare may not pay for ART. Despite these barriers, we assert that individuals with AIDS in the current treatment era can be successfully referred to hospice. However, it is critical to work with a hospice that understands that goals of care and prognosis are in flux, and when needed, is willing to pay for ART. If the patient improves, he/she may be disenrolled from hospice.
In the current treatment era, comorbid conditions, rather than AIDS, may be the primary reason for referral to hospice. For example, an individual with HIV infection and cardiovascular disease might meet hospice criteria based on his/her New York Heart Association Class IV heart failure (table 7) with significant symptom burden. Notably, in this situation, as the admitting diagnosis is heart failure, Medicare would still pay for ART.
Chronic pain — Chronic pain is pain that lasts for more than three months, beyond the period of normal tissue healing . Acute pain, such as pain that occurs with injury or acute inflammation, is an adaptive process that is necessary to alert the body to danger. However, pain that persists is the result of abnormal pain processing in the brain and spinal cord. A detailed discussion regarding the pathogenesis of chronic pain is presented separately. (See "Definition and pathogenesis of chronic pain", section on 'Chronic pain'.)
●Prevalence – Chronic pain is common in individuals with HIV infection. Although existing studies have significant methodologic limitations , the best evidence suggests that chronic pain affects 39 to 85 percent of individuals with HIV infection [69,95-101]. This is generally higher than prevalence estimates in the general population, which are closer to 25 to 30 percent . There is also abundant evidence that chronic pain is often underdiagnosed and undertreated in this population .
●Etiology – Historically, pain in individuals with HIV infection was primarily neuropathic in origin. (See "Epidemiology, pathogenesis, and clinical features of HIV-associated neuropathies" and "Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated peripheral neuropathy" and "Diagnosis, treatment, and prognosis of HIV-associated neuropathies".)
However, this appears to be changing in the current treatment era. Contemporary studies report a substantial burden of musculoskeletal pain in individuals with HIV/AIDS, which may be regional (eg, low back pain) or more widespread [56,57,96,101,104]. As an example, in one study from a palliative care clinic for individuals with HIV infection and chronic pain, the most common pain location was the back (21 percent) . Twelve percent of patients reported neuropathic pain, and the remainder of individuals reported some type of regional musculoskeletal pain, such as leg, hip, shoulder, neck, and nonspecific joint pain (each <10 percent).
●Associated conditions – Co-occurring pain, mood disorders, and substance abuse are common in HIV infected patients. As in the general population, chronic pain in individuals with HIV has been strongly associated with mental illness, particularly depression, and substance use [69,105,106]. Despite clinician perception that patients may be reluctant to discuss the interplay between pain, mood, and substance use, the available evidence suggests that individuals with HIV infection are very aware of this connection and are able to clearly articulate it .
●Association with outcomes – Several studies have explored the relationship between chronic pain and outcomes in individuals with HIV/AIDS:
•In one cross-sectional study, chronic pain was not associated with virologic suppression or utilization of urgent medical visits; however, individuals who had chronic pain were more likely to miss their HIV primary care visits, but only if they were not substance abusers . The presence of unrelieved pain reduced the chance of skipping a clinic visit in patients with active substance abuse.
•The relationship between chronic pain and adherence to antiretroviral therapy (ART) is less clear; some studies have suggested a strong relationship, while others have not [73,95,97,107].
•No relationship has been found between chronic pain and mortality in individuals with HIV infection .
Diagnosis — Given the high prevalence of chronic pain and the growing body of evidence linking chronic pain with outcomes in this patient population, individuals with HIV infection should be routinely and frequently asked about chronic pain. A brief chronic pain questionnaire has been tested in individuals with HIV and asks the following two questions: “How much bodily pain have you had during the last week (none, very mild, mild, moderate, severe, very severe)?” and “Do you have bodily pain that has lasted for more than three months?” [94,110]. Using these tools, chronic pain may be defined as at least mild or moderate pain for at least three months. For individuals who have chronic pain, a follow-up questionnaire to understand its functional impact, such as the Brief Pain Inventory-Short Form (BPI-SF)  or its shorter version, the PEG (average pain intensity, interference with enjoyment of life, and interference with general activity) , is appropriate. (See "Evaluation of chronic pain in adults", section on 'Pain impact'.)
As with other patients with chronic pain, an evidence-based diagnostic evaluation should be performed, if consistent with the goals of care. No guidelines to date suggest that the presence of HIV should change the diagnostic paradigm (eg, whether and when to image a patient with chronic low back pain). However, geriatric age in individuals with HIV is commonly considered to be 50 years old, and individuals with HIV have a higher prevalence of comorbid conditions, such as malignancies that may decrease the threshold for conducting additional testing . Diagnostic evaluation of chronic pain is covered elsewhere. (See "Evaluation of chronic pain in adults".)
Management — The goal of managing chronic pain is improvement of both pain and physical function (such as the ability to work or be physically active), as well as emotional function . These functional domains, as they relate to pain, can be measured with the PEG or BPI-SF, as described above. (See 'Diagnosis' above.)
In general, an approach to managing chronic pain should include initial psychoeducation about the nature of chronic pain as a chronic condition, setting expectations that the timeline for improvement is not days or weeks but rather months or years, and the importance of multimodal therapies. In our view and consistent with the Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain, opioids should not be considered first-line treatment options for chronic pain; other modalities, such as physical therapy and cognitive behavioral therapy or supportive psychotherapy, should be tried first. (See "Overview of the treatment of chronic non-cancer pain" and "Use of opioids in the management of chronic non-cancer pain".)
Few data are available to inform optimal management of chronic pain in this population. In a systematic review of pharmacologic and nonpharmacologic interventions for chronic pain in individuals with HIV infection, only 11 mostly low- or very low-quality studies were identified that met inclusion criteria . Seven were of pharmacologic interventions, five of which had significant pharmaceutical company sponsorship. Most studies were small; only three had more than 100 participants, and no study was conducted completely in the modern treatment era. The following were noted:
●Four of the seven studies of pharmacologic interventions were randomized trials. In two trials of anticonvulsants, neither gabapentin nor pregabalin was more effective than placebo for HIV associated neuropathic pain [116,117].
●Two randomized trials of a high-dose capsaicin patch versus placebo for HIV infected patients with neuropathic pain found a greater reduction in pain on a numeric pain scale with intervention (mean reduction 22.8 versus 10.7 percent in one study and 31.2 versus 25.3 percent in the second) [118,119]. However, follow-up was limited to 12 weeks, and both studies allowed premedication with topical lidocaine and opioids for capsaicin-related pain.
●Only three low- or very low-quality studies investigated opioids, none of which found that opioids improved pain or function [120-122].
●Of the four studies of nonpharmacologic intervention, the only randomized trial examined inhaled cannabis versus placebo in patients with neuropathic pain, and follow-up was limited to one week. Median pain scores decreased twice as much with cannabis (34 versus 17 percent).
Besides cannabis, three pre-post studies of cognitive behavioral therapy and hypnosis were identified. These studies also suffered from short follow-up, small effect sizes, and poor adherence.
Over the past 5 to 10 years, it has become apparent that there is very limited evidence for the efficacy of opioids in improving pain and function in individuals with chronic non-cancer pain  but good evidence for the risks of opioids, including addiction, hypogonadism, falls, fractures, depression, cardiovascular risk, and greater risk of overdose-related death, among others. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Adverse effects'.)
The risks of opioid therapy for individuals with HIV infection generally parallel those experienced in the general population; however, some studies suggest that they may be exaggerated:
●Concerning behaviors that arise among individuals on long-term opioid therapy, such as lost or stolen prescriptions, aggressive behavior towards staff, or illicit substance use (which may represent a pain self-management strategy), are especially common in individuals with HIV infection [124-126].
●Mortality may also be may be higher. One study of data from the Veterans Aging Cohort Study-Virtual Cohort (VASC-VC) for the year 2009 (which included 16,989 HIV infected and 47,613 uninfected individuals) found that the risk of mortality in individuals on long-term opioid therapy was greater for those with HIV infection than for those without (hazard ratio [HR] 1.46, 95% CI 1.15-1.87, as compared with 1.25, 95% CI 1.05-1.49) .
In addition to these risks, there is also evidence that, as in the general population, individuals with HIV experience ongoing pain, despite opioid treatment , and those prescribed opioids experience higher emergency room utilization and hospitalization rates . There is also evidence to suggest that HIV providers lack confidence in prescribing long-term opioids for chronic pain , and they worry that patients who are discontinued from long-term opioid therapy due to safety concerns (eg, ongoing substance use) may suffer worse retention in HIV primary care . Adhering to guideline-concordant care can be a challenge; in one study, as compared with HIV uninfected patients, individuals with HIV were more likely to receive long-term opioids together with sedatives and were more likely to be prescribed long-term opioids in the setting of a substance use disorder .
Providers should carefully weigh the risks and benefits of opioids prior to prescribing and, if opioids are prescribed, at every visit thereafter. Prior to prescribing, providers may consider using tools such as the Opioid Risk Tool (ORT)  to assess patients’ risk for developing opioid misuse behaviors, and they should routinely employ opioid risk mitigation strategies, such as opioid treatment agreements, urine drug screens, and checks of state Practitioner Database Monitoring Programs, where available . (See "Overview of the treatment of chronic non-cancer pain" and "Use of opioids in the management of chronic non-cancer pain", section on 'Evaluation of risk prior to initiating therapy' and "Use of opioids in the management of chronic non-cancer pain", section on 'Initiating a trial of opioid therapy'.).
Managing acute pain in a patient chronically using opioids — Patients receiving chronic opioid therapy for pain often experience episodes of acute pain, either because of a new injury or surgical procedure. Acute pain may also develop in patients who are receiving chronic opioid maintenance therapy for addiction or who are chronically using inappropriately prescribed or illegally obtained opioids. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Pharmacotherapy for opioid use disorder".)
The goals of treating acute pain in patients chronically using opioids are to prevent withdrawal, to provide adequate analgesia, and for patients with a history of a substance use disorder, to avoid triggering a relapse or worsening of the addiction disorder. A stepwise approach to managing acute pain in such patients is described in detail elsewhere. (See "Management of acute pain in the patient chronically using opioids".)
Non-pain symptoms — Even in the current treatment era, individuals with HIV infection experience a high burden of non-pain symptoms, both physical and psychological [69,100,135,136]. One illustrative study used a convenience sample of individuals with HIV infection from an urban clinic who were mostly well-controlled on ART . Non-pain physical symptoms included lack of energy (57 percent), drowsiness (37 percent), sweats (34 percent), cough (33 percent), dry mouth (33 percent), diarrhea (31 percent), “I don’t look like myself” (27 percent), feeling bloated (25 percent), dyspnea (25 percent), pruritus (24 percent), lack of appetite (23 percent), problems with sexual interest or activity (27 percent), and nausea (22 percent). Psychological symptoms were even more common and included worrying (63 percent), feeling sad (55 percent), difficulty sleeping (55 percent), feeling irritable (53 percent), feeling nervous (43 percent), and difficulty concentrating (40 percent). When pain was included, patients reported a median of eight physical and psychological symptoms; 39 percent experienced high distress from three or more physical symptoms, and 48 percent of patients reported high distress from or high frequency of at least one psychological symptom.
In the early days of the HIV epidemic, non-pain physical symptoms were often due to an opportunistic infection (OI) or an AIDS-defining malignancy. However, in the modern treatment era, the etiology of these symptoms is less clear. In some cases, they may be due to other comorbid medical or psychiatric conditions (eg, dyspnea from chronic obstructive pulmonary disease [COPD], fatigue due to depression), or they may not have an easily identifiable cause. To illustrate this shift over time, selected symptoms experienced by individuals with HIV and their etiologies in the early HIV treatment era alongside etiologies in the current ART treatment era are summarized in the table (table 8). We also include relevant management strategies for the purposes of comparison.
The following sections will focus on fatigue and anorexia/tissue wasting. Management of other common symptoms, including lipodystrophy, HIV-associated neurocognitive disorder (HAND), and neuropsychiatric issues in patients with HIV/AIDS, are covered in detail elsewhere.
Fatigue — Fatigue is defined as the decreased capacity for initiating or maintaining physical activity; it may also be described by patients as “low energy.” Fatigue is a common, often persistent symptom among individuals with HIV infection, with prevalence estimates of 30 to 80 percent in the modern treatment era [137-139]. (See "Palliative care: Overview of fatigue, weakness, and asthenia".)
Although considerable overlap occurs, fatigue is distinct from sleepiness, which is discussed elsewhere. (See "Approach to the patient with excessive daytime sleepiness".)
Fatigue in the current era of ART is likely multifactorial . Physiologic factors associated with fatigue or fatigue severity in individuals with HIV infection include liver disease, hypothyroidism, hypogonadism, anemia, and duration of HIV infection [139-141]. An association with CD4 cell count and viral load is supported by some studies but not others [139-141]. In an earlier HIV treatment era, there was an association between ART and fatigue ; it is not clear whether this is still the case. Psychological and social factors associated with fatigue include stressful life events, depression, anxiety, posttraumatic stress disorder, and low income [137,140,142].
Fatigue in individuals with HIV infection interferes with physical, social, and mental functioning ; it may also interfere with adherence to ART . An instrument to measure the severity and impact of fatigue in individuals with HIV infection has been developed (the HIV-related fatigue scale) .
Management — In individuals with HIV infection, the approach to fatigue should be the same as in the general palliative care population. This includes a search for medical or psychiatric causes (especially hypogonadism), medication review, inquiry regarding the patient’s sleep patterns, and treatment of the underlying cause, when present. Testosterone may help hypogonadal men with fatigue. Moderate exercise is a reasonable recommendation, if patients are able to tolerate it. (See "Palliative care: Overview of fatigue, weakness, and asthenia", section on 'Causes and pathophysiology' and "Palliative care: Overview of fatigue, weakness, and asthenia", section on 'Clinical assessment'.)
Several pharmacologic treatment approaches to fatigue have been investigated specifically in individuals with HIV infection, but none can be specifically recommended over another in this group . In earlier treatment eras, testosterone [147-149] and stimulants, such as dextroamphetamine  and methylphenidate , were studied with promising results. However, these studies were limited by small sample size and short duration of follow-up . Testosterone has been shown to be of benefit for hypogonadal individuals who have fatigue . (See "Hypogonadism in HIV-infected males", section on 'Indications for testosterone treatment'.)
More recently, benefit has been suggested for psychostimulants:
●In a randomized placebo-controlled trial of modafinil, a central nervous system stimulant, in a predominantly virologically suppressed group of HIV infected patients, 73 percent of individuals in the treatment arm reported improved fatigue at week 4 compared with 28 percent in the placebo arm; improvements were maintained at six months .
●A placebo-controlled trial of a closely related compound, armodafinil, yielded similar benefits in 70 patients with HIV . The fatigue response rate to armodafinil was 75 versus 26 percent in the placebo arm.
A trial of a psychostimulant may be considered. However, given the high rate of comorbid psychiatric illness and substance use disorders among individuals with HIV, we recommend that modafinil and armodafinil be used with caution.
Studies of nonpharmacologic interventions, including cognitive behavioral therapy and relaxation techniques, showed promise in an earlier treatment era  but have not been conducted in contemporary populations of individuals with HIV infection.
The benefits of exercise in terms of improving physical performance have been shown in many trials conducted in patients with advanced cancer, although benefit in terms of fatigue has been more difficult to show. (See "Palliative care: Overview of fatigue, weakness, and asthenia", section on 'Exercise'.)
There is a paucity of data on the benefits of exercise for HIV patients with fatigue. Efficacy and safety were addressed in two systematic reviews: one of progressive resistance exercise at all stages of HIV infection (seven studies, 294 participants ) and the other of aerobic exercise at all stages of HIV infection (14 studies, 454 participants ). In the first systematic review of resistance exercise, fatigue was considered as a primary outcome measure of cardiopulmonary fitness but was not reported in any of the included studies. In the second systematic review, only one of the included trials (n = 60 patients) found a significant decrease in fatigue in exercisers as compared with non-exercisers, as measured by time on the treadmill, but none of the patients were in the advanced stage of illness. Despite the paucity of data, moderate exercise is a reasonable recommendation, if patients are able to tolerate it.
Anorexia and tissue wasting — Historically, weight loss and tissue wasting were common in HIV, particularly in the later stages of the disease. The incidence of wasting has declined since the introduction of ART . Tissue wasting responds rapidly to ART, and the primary therapy for HIV wasting is initiation of ART for those who are not yet on treatment.
SUMMARY AND RECOMMENDATIONS
●The introduction of tolerable, effective antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) from a terminal disease with a uniformly poor prognosis to a serious chronic illness, at least in high-resource settings. However, even in the modern treatment era, individuals with HIV/AIDS fit well within the “serious illness” paradigm for which early integration of palliative care plays a complementary role to active treatment of the underlying disease. These patients have a substantial burden of medical and psychiatric comorbidities, as well as pain and other symptoms, throughout the course of the disease, and a wide-ranging need for psychosocial, family, and care-planning support. (See 'Introduction' above.)
●Despite advances in ART, complications of end-stage HIV disease are still seen because of undiagnosed cases and difficulties with adherence to ART and/or with retention in care. Furthermore, despite gains in life expectancy from ART, AIDS-defining illnesses still cause a sizable proportion of deaths among HIV infected individuals, and they shoulder a large burden of morbidity because of the premature age-related comorbidities. (See 'Burden of HIV' above.)
●Prognosis and disease trajectory in individuals with advanced HIV or AIDS are highly variable and depend on many factors that are both disease related and treatment related. Since many patients with advanced HIV/AIDS have not yet begun ART or have had past challenges with adherence or retention, the likelihood of long-term success of treatment of any acute condition in these patients is often uncertain. Any attempt at prognostication that does not address whether the patient has had an adequate trial of ART is ill informed and inaccurate. (See 'Prognostication and the influence of ART' above.)
●For individuals without an AIDS-defining illness who are not on ART, every attempt should be made to fully engage them in care and begin ART, with close attention to adherence. For individuals with an AIDS-defining illness who are not on effective ART, we strongly recommend a trial of ART in consultation with an HIV specialist. The optimal time to initiate ART varies by clinical situation. This trial should last for at least six months. (See 'ART management in advanced disease' above.)
●The primary goal of palliative care is to improve quality of life for the patient and their family through relief of emotional and physical symptoms. While primary care and infectious disease physicians caring for patients with advanced HIV/AIDS are able to manage most of their patients’ palliative care issues, clinicians who are specifically trained in palliative care can provide more in-depth pain and symptom management, communication regarding goals of care, and care coordination across settings and over time. (See 'Primary versus secondary (subspecialty) palliative care' above.)
●Important components of a comprehensive palliative care assessment include exploring the patient’s understanding about their illness and prognosis; assessing and managing symptoms; counseling and establishing goals of care that are consistent with the patient’s values and preferences; providing psychosocial, spiritual, and practical support, both to patients and their family caregivers; coordination across sites of care issues that are affecting access to and compliance with care; and helping with advance care planning and end of life care, including determining the need and timing of hospice care. (See 'What are the important components of palliative care?' above.)
●There is no formal guidance from expert groups regarding when to initiate advanced care planning discussions in individuals with HIV infection, and no consensus on this issue. We recommend following the guidance of the well-established “Respecting Choices” paradigm [86,87], which recommends a three-stage, prognosis-informed approach, which is outlined elsewhere. (See "Advance care planning and advance directives", section on 'Facilitating the ACP'.)
●Significant challenges to end of life care include decision-making about whether and when to stop HIV-related medications and when to refer for hospice care, given the significant prognostic uncertainty in most patients. (See 'Challenges in end of life care' above.)
●Chronic pain is common in individuals with HIV infection and includes both neuropathic and musculoskeletal pain. The goal of managing chronic pain is improvement of both pain and function (both physical and emotional). Given the paucity of evidence supporting benefit and increasing evidence about the harms of opioids in individuals with HIV infection, in our view, opioids should not be considered a first-line treatment option for chronic pain; other modalities, such as physical therapy and cognitive behavioral therapy or supportive psychotherapy, should be tried first. (See 'Chronic pain' above.)
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