Innovations in End-of-Life Care
an international journal of leaders in end-of-life care
Palliative Care for AIDS: Challenges and Opportunities in the Era of Highly Active Anti-retroviral Therapy
Peter A. Selwyn, MD, MPH and Mimi Rivard, MS, NP
[Citation: Selwyn PA, Rivard M. Palliative care for AIDS: Challenges and opportunities in the era of highly active anti-retroviral therapy. Innovations in End-of-Life Care. 2002;4(3), www.edc.org/lastacts]
The past two decades have seen both the emergence of AIDS as a new, life-threatening illness and its conversion from a rapidly fatal to a manageable chronic disease. This pattern has been most marked in industrialized countries where the promise of HIV-specific therapies has been realized for many individuals living with HIV. However, even in the era of "highly active anti-retroviral therapy" (HAART), AIDS remains an important cause of morbidity and mortality in many young adult populations, and attention to palliative and end-of-life issues is an essential aspect of clinical care. This review will outline the major clinical themes and challenges now involved in the provision of palliative care for patients with AIDS, including pain and symptom management, advance care planning, and psychosocial issues. (The Featured Innovation in this issue of Innovations discusses the programmatic experience and outcomes of a demonstration project that has attempted to integrate HIV and palliative care at a large urban teaching hospital.)
In the early 1980s, AIDS quickly became the leading cause of death for young adults in the United States.1 With advances in AIDS care and HIV-specific therapy, mortality rates began to decline in the mid-1990s, and accelerated with the introduction of the protease inhibitors in 1996.2-7 However, the decline in death rates has since plateaued, and there remain approximately 15,000 deaths per year from HIV/AIDS.8 Moreover, the declines in death rates have not been uniform across all populations affected by HIV/AIDS, and decreasing mortality has not been as pronounced among African Americans and Latinos as it has been among whites.9,10 Moreover, recent surveillance data and clinical studies have indicated that mortality among patients with HIV has been steadily increasing from common co-morbidities such as hepatitis B and C, co-occurring malignancies (both AIDS-defining and non-AIDS-defining cancers), and substance abuse-related deaths.11-16 In addition, for certain patients, even the benefit of HAART is not always attainable, due to lack of access to care, inability to adhere to effective treatment regimens, active substance use or other psychiatric illness, progressive viral resistance despite therapy, serious other co-morbidities, or unmanageable drug toxicities. In addition, the incidence of new HIV infections in the United States is not believed to have decreased, and has remained stable at approximately 40,000 new cases per year.17 As a result of these trends, AIDS-related mortality continues to be an important phenomenon, even while the number of patients living with AIDS (i.e., the prevalence) has actually increased. (Figure 1).18,19
In the pre-HAART era, AIDS was a uniformly fatal, relentlessly progressive illness, characterized by multiple opportunistic infections, swift decline, and death within months of diagnosis. The impact of disease-specific treatment on the natural history of HIV infection has now resulted in a much more variable trajectory of illness for many patients. For some, HAART has meant the possibility of full return of function and health, while for others, treatment has meant the "conversion of death to disability," with the emergence of a chronic disease phase characterized by exacerbations, remissions, and eventual death20 as the survival time from diagnosis to death has lengthened.21 Over a remarkably short period of time, the historical evolution of HIV disease—for which the stereotypic disease course from diagnosis to death first resembled that of certain untreatable fatal cancers (e.g., pancreas, lung)—has shifted to a trajectory more typical of chronic, progressive illnesses (e.g., congestive heart failure, chronic obstructive pulmonary disease, hepatic cirrhosis), with much more variability in outcomes. (Figure 2)22 Clinical assessment of prognosis and outcomes is thus much more complex than was previously the case, and the need for palliative care may co-exist with disease-specific therapy over an extended period of time.
Notwithstanding the dramatic therapeutic advances in HAART, it is important to recognize that the curative vs. palliative dichotomy in HIV care is a false one. Even though HIV care has evolved over a short period of time with the rapid development of disease-specific therapy, the tension between palliative and curative approaches has always been present. As shown schematically in Figure 3, since the early 1980s there have been several mini-paradigm shifts in which the hope of cure for AIDS or the reality of the limitations of HIV therapy have led prematurely to extreme optimism or pessimism, respectively. The overall direction has been toward more curative or disease-modifying therapy, but the curve has oscillated back and forth, and even after the heady optimism of the late 1990s following the introduction of the protease inhibitors, few if any researchers are currently speculating about the likelihood of viral eradication or "cure" for HIV infection. In fact, a more sober assessment would suggest that AIDS is a chronic, progressive disease that may still cause considerable morbidity and mortality, and that the need to integrate palliative and curative approaches may be even more important than it was in the pre-HAART era.23
In addition, the psychosocial context of AIDS only adds further complexity to the role of palliative care in HIV treatment. AIDS has always presented unique psychosocial problems for patients, families, and care providers: a life-threatening illness affecting young adults, often with multiple infected family members, raising difficult issues of premature death, unfinished business, legacy, and survivorship. Guilt, shame, anger, and despair may compound the emotional challenges of coming to terms with this progressive, incurable infectious disease. Some of the behaviors linked to HIV infection remain socially unacceptable in certain contexts, and the association between AIDS, poverty, and racial-ethnic minority populations in the United States further compounds the vulnerability of many patients living with HIV/AIDS. Despite some advances in public education and awareness about AIDS, there remains a significant degree of stigma, fear, and prejudice regarding AIDS within the society as a whole. Given this context, it is critical for decisions regarding palliative care to address important issues concerning perceived withdrawal of care (or perceived "second-class" or less-than-aggressive care), cultural differences regarding advance care preferences, and the marginalization of vulnerable populations.24,25
Pain and Symptom Management
Existing data suggest a considerable symptomatic burden of illness in late-stage HIV disease, suggesting an ongoing important role for palliative medicine interventions. Since early in the epidemic, clinical studies have documented a high prevalence of pain and other symptoms in patients with AIDS.26-29 Pain in AIDS has been attributed variously to (1) the effects of specific opportunistic infections (e.g., headache with cryptococcal meningitis, visceral abdominal pain with disseminated mycobacterium avium complex [MAC] infection), (2) the effects of HIV itself or the body's immune response to it (e.g., distal sensory polyneuropathy, HIV-related myopathy), (3) the effects of medications used to treat HIV disease (e.g., dideoxynucleoside-related peripheral neuropathy, zidovudine-related headache, protease inhibitor-related gastrointestinal distress), or (4) non-specific effects of chronic debilitating illness, along with other miscellaneous causes.
Some of these findings are from the pre-HAART era, and certainly the contribution of specific opportunistic infections to pain syndromes and other symptoms in AIDS has diminished over time with the declining incidence of such infections more generally. However, it should be noted that in some instances the incidence and/or prevalence of pain may have actually increased over time. As is often the case with AIDS, the irony of decreased mortality rates is that by surviving longer some patients may thus be vulnerable to new complications, as in the observed increasing prevalence of HIV-related peripheral neuropathy that occurred with longer survival in the Multi-Center AIDS Cohort study.30 (Further, in a recent example of the potential overlap of palliative and disease-specific therapies in AIDS, analysis of data from an ongoing observational cohort study found that the severity of HIV-related neuropathy was associated with plasma viral load levels—suggesting that anti-retroviral therapy itself might in fact be useful for treating or preventing this painful syndrome.)31 In addition, while pain due to opportunistic infections may have diminished with the advent of HAART and more effective prophylactic regimens, some of the medications used in HIV treatment themselves may cause pain and other symptoms, compromising effective treatment unless the symptoms are also effectively palliated.
Notwithstanding the high prevalence of pain in AIDS, several studies have also demonstrated that pain in patients with AIDS is likely to be under-diagnosed and under-treated.32,33 This may reflect both the general under-recognition of pain by most physicians and/or the additional reluctance to consider seriously any self-report of pain in patients with a history of substance use problems. Moreover, recent reports have documented that non-white race/ethnicity may be a risk factor for inadequate analgesia in general in medical settings, and that even the physical availability of narcotic pain medication may be limited in pharmacies serving poor urban neighborhoods where HIV infection may also be concentrated.34,35 Regardless of the possible explanations for under-treatment of pain, the result is that patients with AIDS are at risk for significant pain and resulting diminished quality of life, an outcome that in most cases could be prevented with adequate pain assessment and management.
In addition to pain, patients with AIDS have been found to have a high prevalence of other symptoms, particularly but not exclusively in the advanced stages of the disease.36-44 Moreover, one recent study suggested that physicians frequently fail to identify and often under-treat common symptoms reported by patients with AIDS.45 Symptoms have included a mixture of physical and psychological conditions, such as, fatigue, anorexia, weight loss, depression, agitation and anxiety, nausea and vomiting, diarrhea, cough, dyspnea, fever, sweats, pruritus, etc. Table 1 summarizes the findings of several key studies that have examined the symptom burden in patients with AIDS in different populations. It is striking that these studies,46-50 conducted in the United Kingdom, Canada, France, and Italy, showed a remarkable consistency of symptoms across populations even with different selection criteria, different time periods, and varying methods for determining the prevalence of symptoms.
In addition to these studies, which were conducted mostly in late-stage patients admitted to hospice or hospital with symptomatic disease, a symptom prevalence study was conducted using a large national probability sample of more than 3,000 patients with HIV infection in the United States receiving care in 1996.51 For this sample, the prevalence of the most common ten symptoms for the preceding six months was as follows: fever, sweats, or chills (51%); diarrhea (51%); nausea or anorexia (50%); numbness, tingling, or pain in hands/feet (49%); headache (39%); weight loss (37%); vaginal discharge, pain, or irritation (36%); sinus infection or pain (35%); visual problems (32%); and cough or dyspnea (30%). Another study of AIDS outpatients receiving care in New York in the early 1990s found a mean of 16.7 current symptoms (using the Memorial Symptom Assessment Scale), of which the most common were worrying (86%), fatigue (85%), sadness (82%), and pain (76%).52 With these populations as well, the concordance of symptom types with those in the previously published studies is noteworthy, as is the high prevalence of symptoms in relatively non-selected populations of patients with HIV.
As with the findings related to pain, symptoms in AIDS may result from the specific effects of opportunistic infections (e.g., sweats, fever, in disseminated MAC infection, dyspnea in pneumocystis carinii pneumonia), from the apparent effects of the progression of HIV infection itself (e.g., weight loss, fatigue), from medications (e.g., anti-retroviral-induced nausea and vomiting), or from the non-specific manifestations of late-stage illness (e.g., depression, fatigue, malaise). As with studies of the prevalence of pain, it must be noted that much of the observational knowledge regarding symptom prevalence in AIDS was generated in the pre- or early HAART era, and that the specific effects of certain opportunistic infections may have diminished as these entities have become less common.53,54,55 Nevertheless, the challenges of symptom management have also grown with several factors: (1) the prolongation of the chronic disease phase in some patients, with the resulting more protracted late-stage course (described above) requiring more sustained attention to complex symptom management in chronically ill patients; (2) the recognition of the wide cumulative range of drug toxicities and symptomatic sequelae that occur in patients on long-term anti-retroviral therapy; (3) assessment of the contribution of drug toxicities vs. the underlying effects of disease progression, thus raising important clinical issues regarding the competing effectiveness and toxicity of different therapeutic options (e.g., balancing short-term quality of life vs. long-term prolongation of life in a patient contemplating a potentially toxic anti-retroviral regimen, deciding whether disease-specific therapy may also in fact have a palliative impact on symptoms in a given situation, etc.); (4) the emergence of co-existing co-morbid conditions that have complicated the management of patients with AIDS, including chronic viral hepatitis (especially but not limited to hepatitis C); and (5) chronic co-morbid psychiatric illness and substance abuse in patients with AIDS.56-58
The Changing Philosophy of HIV Care
Palliative medicine seeks to provide the best quality of life for patients and families, within a model in which the goals of care are collaboratively developed with care providers according to the wishes of patients and families. This model emphasizes communication, collaboration, and the willingness to accept patient-focused outcomes as paramount (e.g., quality of life, or wishes regarding cessation of therapy). It is of interest that this collaborative approach—one in which uncertainty is shared, patients and their care providers work through difficult decisions, unable to control the ultimate outcome, and in which there are many nuances and no clear "right answer"— was one that defined much of AIDS care in the pre-HAART era. This was an environment in which clinicians learned to work together with patients and families to clarify goals of care, to determine the important issues related to quality of life and the end of life, and to be comfortable helping patients and families negotiate the complexities of progressive, incurable illness.
With the arrival of more effective disease-specific therapy for HIV/AIDS, much of the focus has shifted to more curative or quasi-curative therapies (e.g., anti-retroviral therapy and adherence), for which the goals of treatment are more clear-cut, uniform, and physician-generated. Focusing on the patient- and family-centered goals of care ensures that decisions will be made that do not violate important concerns of the patient and family; curative, palliative, or both types of interventions can be offered, not unilaterally and driven solely by diagnostic or treatment algorithms but rather collaboratively and driven by the priorities and values of the patient and family. Some of this work takes time, and may be more open-ended than the narrow focus on test results and medication adherence that has lately come to dominate routine HIV care.
Specific examples of some common clinical scenarios involving decisions about palliative and/or disease-specific care (and the context for decision making based on goals of care rather than on simple diagnosis-treatment algorithms) might include:
- The use of blood transfusion and/or psychostimulants (e.g., methylphenidate) and/or corticosteroids to treat fatigue in late-stage patients, with or without HAART.
- Aggressive anti-emetic therapy for protease inhibitor-induced nausea and vomiting, or alternatively, revision or even discontinuation of anti-retroviral therapy if such side effects are unable to be managed successfully.
- Continued suppressive therapy with intravenous foscarnet or ganciclovir for CMV retinitis (to preserve vision and prevent blindness), or intravenous amphotericin B for azole-resistant candidiasis (to permit continued oral intake in a patient who desires this), even after the discontinuation of anti-retroviral therapy and other prophylactic regimens in a dying patient.
- Palliative treatment of disseminated MAC (e.g., with anti-pyretics, narcotic analgesics, and corticosteroids) in patients with advanced disease unwilling or unable to take anti-infectives.
- Withdrawal of MAC or PCP prophylaxis in patients expected to die soon.
- Withdrawal of HAART after evident treatment "failure," with assessment of medical risk-benefit as well as the symbolic and emotional value.
- Use of HAART to provide short term palliative benefit (e.g., reducing the burden of constitutional symptoms which may be related to high viral loads), separate from long-term therapeutic intent.
- Decisions to initiate or not initiate HAART in newly diagnosed, late-stage patients (e.g., the possibility for disease-reversing therapy, vs. the possibility that the patient may not respond, preparation for death vs. hope for "cure," addressing therapeutic confusion, distinguishing realistic from false hopes, etc.).
All of these scenarios involve decisions that cannot be made solely within the conceptual framework of infectious disease-specific treatment, and must to be informed both by medical evidence and risk-benefit analysis as well as by the priorities, values, and preferences of patients and families. (There also may be particular challenges posed for palliative care providers in some instances, e.g., the use of HAART for palliative intent in hospice settings, where capitated payments may limit the ability to continue expensive pharmaceuticals and force difficult programmatic decisions about appropriate treatment standards.) In all the above-referenced examples, it should be clear that decisions need to be based on the specific goals of care, i.e., the relative values of quality of life or prolongation of life; the use of aggressive palliative care interventions to help mitigate side effects of other medication; the use of certain disease-specific therapies primarily for palliative or quality-of-life intent; the decision not to prolong life "no matter what," once a certain important threshold had been reached (e.g., progressive dementia or the inability to manage oral feedings or medications). This type of decision making is clearly in much more ambiguous and nuanced territory than the simple assessment of anti-retroviral efficacy by measuring surrogate laboratory markers, but it is no less important and in many ways more challenging.
Table 2 lists common symptoms in AIDS, along with their varied possible etiologies, and examples of both disease-specific therapies and palliative interventions. Either one or both types of approaches might be appropriate in a given situation, depending on the patient's disease stage, functional status, symptom burden, risk and potential benefit of therapy, and expressed care preferences and goals.
Prognostic Uncertainty and Palliative Care for HIV/AIDS
Even as one attempts to focus on the goals of care in informing treatment decisions, it must also be recognized that prognostication concerning the course of HIV disease is much less certain and predictable than it was in the pre-HAART era. While CD4+ counts and viral load assays are excellent measures of response to therapy and indeed of prognosis in general, the possibility of effective anti-retroviral therapy—or alternatively the lack of this possibility when there are no viable treatment options—can completely alter prognosis for people with AIDS.
The National Hospice Organization's 1996 Guidelines for determining prognosis in certain non-cancer diagnoses attempted to generate criteria indicative of likely less-than-six months' prognosis for patients with AIDS (Table 3).59 While some of these clinical conditions may be useful prognostic markers, none of them would likely override the potential positive impact of effective anti-retroviral therapy if this were still an option. Indeed, some patients have been referred to hospice and expected to die, only to surprise themselves and their care providers with their miraculous recoveries (the Lazarus Syndrome) from effective HAART while also receiving palliative care. In these cases, forcing patients to choose an either-or approach would clearly be unconscionable; this reality only makes the integration of palliative and curative approaches both more difficult and more necessary than ever before.
One issue that frequently arises, related to the complexities of prognostication and clinical decision making in the HAART era, involves the discontinuation of anti-retroviral therapy in a patient who is either not responding or felt to be unlikely to respond to treatment. Even though there is controversy about whether to stop therapy even in the face of apparent treatment failure (i.e., the concept of viral fitness and possible benefit of anti-retroviral selective pressure on viral replication dynamics even in the setting of high viral loads and low CD4+ counts,)60,61 it must be recognized that the survival benefits of anti-retroviral therapy even when effective are usually not immediate, and rather, they must be evaluated in light of potential favorable impact to prevent future decline. Thus it is reasonable to question whether it makes therapeutic sense to continue anti-retroviral therapy in a patient dying of lung cancer, or with end-stage liver failure—whether or not the medications could even be tolerated in this setting—or in the obvious end stages of progressive symptomatic HIV disease. It is of interest, however, that existing recommendations and guidelines for anti-retroviral therapy and prophylaxis in AIDS do not address the question of withdrawal of therapy, only initiation of therapy, reflecting the predominant treatment focus that now defines HIV care; there is an important need, however, to develop appropriate guidelines for consideration of treatment withdrawal in late-stage and dying patients.
In the instances noted above, anti-retroviral therapy will not be likely to have any meaningful benefit and will probably only add to the therapeutic confusion, i.e., in a patient who is clearly dying yet for whom aggressive therapy is being continued. (One exception, as mentioned above, might be a patient with a significant constitutional symptom burden, which may be associated with a high HIV viral load.) In other cases, the patient may have such a strong emotional investment in continuing therapy that it is completely reasonable to continue it. However, it should be stressed that this is as much a psychosocial as a medical decision, if not more so. This example again underscores the importance of clarifying the goals of therapy, assessing the potential impact and likely risks and benefits, and working collaboratively with patients to determine priorities and treatment plans—all aspects of a good patient-provider relationship, but which can also become obscured if too much of the focus is on the treatment instead of on the patient.
Given the complex interweaving of disease-specific and palliative care needs for people with HIV/AIDS, any successful response must address and integrate these two treatment paradigms in an integrated way. Over-riding attention to HIV-specific or palliative care interventions, without consideration of what both approaches can offer in a given instance, will predictably result in poor treatment outcomes for patients with advanced disease. The challenge for program implementation, as discussed in the accompanying program description article, is to develop both the individual and institutional opportunities to provide comprehensive clinical expertise in both these areas. For clinicians in palliative care settings, it should be evident that even as therapies for AIDS have become more specialized and potentially effective, the need for palliative care has not been eliminated and in many ways has only become more challenging. The solutions for integrating these clinical paradigms will differ in different care settings, and will need to be based on the realities and possibilities of specific clinical environments.
In recent years, a distance has developed between palliative care and AIDS care, and opportunities to create a more unifying paradigm have been lost. Hospices have been faced with fewer AIDS patients, and may even face ethical conflicts and/or financial disincentives in providing comprehensive HIV care (e.g., continuing HAART or other HIV-specific therapies that may have palliative benefit but be prohibitively costly). In addition, HIV care providers have become increasingly specialized, and may be less attuned to the end-of-life issues that so clearly defined the earlier phase of the epidemic. As we have outlined in the preceding discussion, the need for palliative care for AIDS continues alongside the new therapeutics, and the disciplines of palliative care and HIV care still have much to learn from each other. We hope that these issues can be actively addressed by both palliative and HIV care providers, so that the clinical benefits of both paradigms can become more fully realized for patients with AIDS in the current therapeutic era.
Supported in part by a grant from the Health Resources and Services Administration (HIV SPNS #5 H97 HA 00150-02)
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61. Frenkel L, Mullins J. Should patients with drug-resistant HIV-1 continue to receive antiretroviral therapy? New England Journal of Medicine. 2001;344:520-522.[Return to Overview Essay]
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