Overcoming the False Dichotomy of Curative vs Palliative Care for Late-Stage HIV/AIDS: Title and subTitle Break"Let Me Live the Way I Want to Live, Until I Can't"

Claude is a 33-year-old African American man with advanced human immunodeficiency virus (HIV) infection (diagnosed in 1992), with a CD4 cell count of less than 200/µL (20 × 10⁹/L), an HIV viral load of higher than 750 000 copies/mL despite ongoing antiretroviral therapy, and a history of many past opportunistic infections. These have included Pneumocystis jiroveci pneumonia, cryptococcal meningitis, cytomegalovirus retinitis, and disseminated Mycobacterium avium complex infection. He has also had rectal carcinoma, scrotal carcinoma in situ, peripheral neuropathy, and chronic wasting syndrome.

Treatment-related complications have included: (1) thrombocytopenia following chemotherapy and radiation for rectal carcinoma, (2) a ruptured globe following multiple intravitreal ganciclovir implants for chronic cytomegalovirus retinitis, (3) uveitis secondary to rifabutin, and (4) chronic renal insufficiency secondary to tenofovir. Recent medications have included: didanosine, ritonavir, saquinavir, efavirenz (all recently suspended due to worsening nausea and anorexia and due to concerns about possible lactic acidosis), levofloxacin and ethambutol (also recently suspended due to gastrointestinal intolerance), fluconazole, trimethoprim-sulfamethoxazole, valacyclovir, azithromycin, long-acting morphine sulfate, dronabinol, zolpidem, sertraline, famotidine, filgrastim, and erythropoietin.

Claude has been admitted and discharged from hospice programs several times and has had conflicting feelings about advance directives concerning life-prolonging interventions. Due to his persistently high viral load, Dr K (Claude's physician at an HIV specialty clinic) wonders whether Claude has consistently adhered to antiretroviral therapy regimens. In recent months, his mobility has steadily worsened due to neuropathy and progressive loss of vision, and he has relied on a motorized scooter to move about outside his home. Ms D (Claude's aunt, who is his primary caregiver) and Dr K both noted a progressive cognitive deterioration during the preceding several months. Claude, Ms D, and Dr K were interviewed by a Perspectives editor in May and June 2002.

CLAUDE: I was diagnosed [with AIDS] in 1992 [at the age of 21]. . . . It never occurred to me that it was going to happen to me. . . . Since 1994, I've been near death 6 times, [But] there's only been a couple of times that I wished for death. . . . People say that you planned out your life before you were born. I did not plan this. I wouldn't do this to myself. It cost me an eye. It cost me my mobility, . . . [But] for me it doesn't really matter what they say. My viral load is off the scale, no T cells, low platelets, but I'm [still] walking around. . . . I've been through a lot.

DR K: Claude started coming to our clinic when he was 23, in 1994. . . . He was very unhappy about the diagnosis. That was 8 years ago. . . . Each year he developed a life-threatening illness [with] this parade of opportunistic infections, and he didn't waste away significantly, so we just continued to treat, and he seemed to hold his own. . . . We've all said good-bye to him, but he's very strong-willed. I think that this kid has survived just because he's very stubborn. . . . We had put the imminent-death conversation on hold for a couple of years because he had survived everything. This time [after a hospitalization for complications of wasting and dementia], we all sat down and said that something was different.

MS D: My sense is that part of the reason why Claude is able to survive is denial. He just says, flat out, "This ain't happening." Until it gets to the place where it's almost like a crisis, then we deal with it. . . . The last time they thought he was going to die, we worked as a team and spoke with Claude. To me, that was the best we've ever done. It was really beautiful. . . . Everybody came in, the doctor [from] the hospital, the people from hospice, his counselor, the hospital staff person. . . . We weren't there forcefully telling him what was going to happen to him. It was a caring, supportive environment. . . . I have no idea [when he is going to die], no idea. It felt like it. It really did, a couple of weeks ago. His life force was ebbing away. I said, "I guess we scared the life back into you, huh?" He will know. It's hard.

Claude, his aunt, and his physician are experiencing the myriad of medical and psychosocial difficulties that have arisen as AIDS has become a chronic disease in the United States. Following the dramatic decrease in AIDS-related mortality rates that began in 1995,¹ the rate of decline has plateaued at approximately 15 000 deaths per year since 1997.² Nevertheless, AIDS remains a leading cause of death among young adults aged 25 to 44 years, especially among African Americans and Hispanics.^{2 - 3} In addition, with no decrease in HIV incidence and the observed decline in death rates, the prevalence of HIV/AIDS has actually increased,² including the subgroup of patients requiring chronic disease management and palliative care interventions.

In a remarkably short time, AIDS has been transformed from a rapidly and uniformly fatal disease into a manageable chronic illness in the industrialized world. For HIV-infected patients in developing countries, on the other hand, access to antiretroviral therapy remains a critical goal. In the industrialized world, patient care has been both enhanced by HIV therapeutics and complicated by changing uncertainties involving therapy, adherence, prognosis, and iatrogenesis. Rather than following a grimly predictable, stereotypic, and rapidly fatal course,^{4 - 7} AIDS has now become a more prolonged illness with exacerbations and remissions, growing cumulative disease burden, significant therapy-related toxic effects, and increasing medical and psychiatric comorbidities.^{8 - 22}

Nevertheless, many of the palliative and supportive care issues that were defined in the epidemic's earlier years still remain, if less pervasively, and for many patients AIDS ultimately remains a life-threatening illness. Claude's story highlights the importance of a treatment plan that integrates curative or disease-specific interventions, such as highly active antiretroviral therapy (HAART) and treatment of opportunistic infections, and symptom palliation, to overcome the false dichotomy^{23 - 24} that limits the effectiveness of either paradigm. In this review, we use the term late-stage HIV disease to apply to patients with longstanding, symptomatic HIV disease, associated with severe immunosuppression, significant cumulative morbidity, and demonstrated failure of or inability to tolerate antiretroviral therapy.

Cumulative Disease Burden. Claude has survived 7 years from the diagnoses of disseminated M avium complex infection and cytomegalovirus retinitis. He is in the late stages of AIDS, having experienced a chronic disease trajectory, which is distinctly different from that described in the early 1980s when the median time from AIDS diagnosis to death was often less than 1 year.^{4 - 7} Yet his life-prolonging treatment has been accompanied by, and in some cases, has caused declines in physical functioning, quality of life, and appearance. His disease-specific therapy has had adverse effects (eg, nausea or vomiting, neuropathy, uveitis, renal insufficiency, hyperamylasemia, lactic acidosis) or has left him vulnerable to new hazards of longstanding HIV-associated immunosuppression (eg, rectal and scrotal carcinoma).

Comorbid Illnesses. In addition to this patient's many complications, physicians should be aware that the co-occurrence of hepatitis B, hepatitis C, or both, non–AIDS-defining cancers, psychiatric disorders, and substance abuse–related sequelae also have a major impact on morbidity and mortality in patients with AIDS and in patients infected with HIV. Some of these factors—such as malignancy and cirrhosis or liver failure—have accounted, in some studies, for a comparable or greater total burden of mortality than AIDS itself.^{9 ,25 - 30}

Pain and Other Symptoms. Several studies have documented a high prevalence of pain and other symptoms among patients with HIV disease (Table 1), especially in the later stages, that may be underrecognized, undertreated, or both.^{13 ,30 - 46} Careful and thorough attention to pain and symptom management are critical throughout the disease's progression and may in fact help improve adherence to HIV-specific therapies. In some instances—such as the possibility that the headaches that Claude experienced may have been due to cryptococcal meningitis—the best palliative intervention is a disease-specific one (eg, suppressive fluconazole); in others—such as nausea due to medications—more symptom-specific interventions are appropriate, including antidopaminergic or antiserotoninergic antiemetics, prokinetic agents, corticosteroids, or dronabinol. Table 2 lists common symptoms and their possible causes and their disease-specific and symptom-specific interventions, based on clinical experience.

Psychiatric Symptoms. Psychiatric symptoms resulting from psychotic, anxiety, or mood disorders can cause significant morbidity in HIV and AIDS and may also shorten longevity, by affecting patients' motivation and capacity to adhere to medical treatment.^{47 - 50} Cognitive disorders in late-stage HIV disease, even in the absence of overt dementia, can confound the clinical picture and may limit information processing and decision making. Psychiatrists and other mental health professionals may facilitate primary care physicians' ongoing interactions with their patients and their ability to address relevant clinical issues as the disease progresses.

Combining Disease-Specific and Palliative Approaches. Unlike certain incurable cancers, which are often treated with hospice care, AIDS care cannot readily be dichotomized into curative vs palliative approaches. No experienced clinician caring for patients with advanced HIV disease would dispute the clinical importance of chronic pain, quality-of-life, and end-of-life issues. However, at the XIV International Conference on AIDS, held in Barcelona in July 2002, of nearly 6000 abstracts presented, fewer than 20 (<1%) focused primarily on palliative care–related topics.⁵¹ Similarly, at the 14th Annual Assembly of the American Academy of Hospice and Palliative Medicine, held in Palm Springs, Calif, in January 2002, only 2 of 105 abstracts (2%) dealt primarily with HIV/AIDS.⁵² This attests to the disconnect between the paradigms of HIV care and palliative care, as well as to the opportunities for improved quality of life, HIV treatment adherence, and overall clinical outcomes if these 2 approaches were better integrated.

In recent years, the comprehensive management of HIV disease has come to routinely include assessment and treatment of HAART-related dyslipidemias, metabolic complications, and multifactorial hepatic disease.^{10 - 11 ,15 ,17 - 18 ,21} At least as important are standard treatments for pain management, symptom palliation, and common psychiatric syndromes. In addition to clinicians' needing to know palliative treatment options to provide optimal care for their patients, they also must be aware of the potential for drug interactions between palliative and HIV medications (eg, certain opioids, antidepressants, anticonvulsants, and benzodiazepines that interact with the protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and rifamycins; Table 3).^{53 - 54} Some medications—such as corticosteroids—that are not routinely used in HIV/AIDS treatment may be needed for palliative purposes (eg, for anorexia, malaise, fevers, fatigue, nausea).⁵⁵ Although steroid-related immunosuppression is a concern for patients with AIDS, short-term steroid use has not been found to be deleterious⁵⁶ and may improve quality of life for patients with late-stage disease.

DR K: [Claude] has defied things beyond my ability to predict.

Clinical Markers. Dr K describes first-hand the hazards of prognostication in the HAART era. In the early phase of the epidemic, mortality was readily and uniformly predicted by the occurrence of specific opportunistic infections and surrogate markers such as CD4 T-lymphocyte cell counts and HIV viral loads.^{57 - 61} Now, prognostic markers are much less reliable in late-stage disease, and virtually any of the traditional prognostic markers may be overridden by the potential impact of HAART on patients who may still benefit from effective antiretroviral therapy. Short-term mortality predictors promulgated by the National Hospice Organization in 1996, including CD4 cell count, viral load, and certain opportunistic infections,⁶² no longer predict 6-month mortality accurately due to the possible overriding impact of HAART. However, a recent study suggested that functional deficits (eg, impaired activities of daily living, cognitive impairments on mental status examination), and/or the existence of other life-threatening conditions (eg, cancer, end-organ failure) predicted short-term mortality in patients with advanced HIV disease who were referred to a palliative care program better than markers such as CD4 cell counts, viral loads, or past opportunistic infections. New prospective studies are needed to develop prognostic variables for late-stage HIV disease in the HAART era, particularly because the potential impact of therapy and the variable trajectory of advanced disease itself are now, at times, so uncertain.

Discontinuation of HAART. Clinicians must assess when and whether to discontinue HAART in late-stage disease ( Article ). Claude continued therapy—despite persistently high viral loads—until suspected HAART-related complications (lactic acidosis) led to discontinuation. In other cases, nonefficacious therapy may be continued as much for its symbolic meaning for patient and/or physician. As for any medical benefit, there has been ongoing debate about the viral fitness of HIV and the possible benefit of continued antiretroviral therapy despite high viral loads.^{63 - 64} Selective pressure of antiretroviral agents may favor less pathogenic viral strains than would be present in the absence of therapy, even though the quantitative viral load may be elevated. Finally, antiretrovirals may sustain cognitive functioning,⁶⁵ and because peripheral viral load does not always correlate with viral load in the central nervous system,⁶⁶ HAART may help prolong autonomous decision making. Notwithstanding these considerations, in many cases, there comes a time when continued HAART may not be warranted due to the overall clinical condition of the patient and the anticipated poor short-term prognosis. However, although detailed guidelines of indications for initiating HAART exist,⁶⁷ no such guidelines exist for cessation of HAART after treatment failure; this is an important consideration for clinical trials and for the development of best practices for advanced HIV disease.

Potential Benefits

Potential Risks

*Evidence is lacking for some of these potential benefits although they are commonly considered in clinical decision making.

CLAUDE: Don't tell me to limit myself. . . . Let me live the way I want to live, until I can't. . . . When I am not able to make decisions for myself . . . like dementia or something . . . then fine, I will hand it over to someone else, . . . and my aunt has power of attorney. . . . But as long as I can do it, I'm going to do it. I have a right to live my life the way I want to live it. . . . I'm not ready yet, I'm not willing to say, "I'm tired enough to go" yet. I like to say that I'm going to go out kicking and screaming and clawing. . . .

AIDS is an unforgiving disease and seems particularly cruel in its effect on young adults and children. Although the therapeutic era has prolonged life, this extended trajectory as a manageable long-term disease carries its own anxieties, burdens, and challenges, as Claude eloquently states. He has lived with the illness for most of his adult life and has experienced a continuing series of losses as well as the satisfaction of being able to keep going despite his physical limitations. He exhibits ongoing ambivalence about withholding life-prolonging interventions but implies that if he became demented and therefore his remaining autonomy were threatened, he would then be ready to limit such measures.

Advance care planning and goals of care should be addressed repeatedly during the course of illness not only because many events along the way may alter the patient's perspective but also because the patient may change his or her mind over time. The progression of late-stage AIDS is not linear, even though it may culminate in an eventual, unavoidable end point. Clinicians must be flexible, patient, and tolerant of the uncertainty and ambivalence that patients experience. Asking frequently and directly about how patients are handling the uncertainty of their lives provides support and indicates that the clinician is ready to hear about whatever is of concern to the patient at that moment.

Patients with AIDS are less likely to have discussed advance directives and life-limiting interventions with their physicians than other patient populations.^{68 - 70} Physicians' discomfort with discussing death and their reluctance to undermine hope may create barriers to these discussions,⁷⁰ and the availability of HAART may exacerbate these barriers. In addition, African Americans have been noted to be less likely to consider withdrawal or cessation of life-prolonging measures than certain other racial or ethnic groups.^{71 - 74} These factors, in addition to the persistent societal stigma associated with AIDS and its concentration in vulnerable populations, means that the concern that palliative care is somehow less than standard care must be addressed, within the context of patient autonomy and empowerment. This underscores the key role of the physician as someone who can accompany the patient and family through a complex process that goes far beyond medical treatment regimens. Especially in the age of HAART, it is critical not to be so narrowly invested in the therapy that the relationship with the patient is diminished.

Claude's goals for his care can be summarized as (1) maintaining autonomy and his current quality of life until it is no longer possible and (2) having his symptoms controlled in order to facilitate functioning in the short term. Thus, care for Claude includes providing enhanced mobility (eg, the electric scooter he uses); arranging services with a local agency for his impaired vision; and providing ongoing analgesic therapy for headache and peripheral neuropathy, antiemetics for nausea, and appetite stimulants and/or anabolic agents for anorexia and wasting. Disease-specific therapy might include fluconazole for suppression of cryptococcal meningitis (especially as a source of headache), and prophylactic trimethoprim-sulfamethoxazole as a simple and effective means of preventing P jiroveci pneumonia, toxoplasmosis, and possibly some bacterial infections. If M avium complex and cytomegalovirus are not currently active and if the patient is unlikely to benefit further from HAART, then these disease-specific interventions may no longer be a priority.

With the further clinical progression of the illness—or perhaps with the worsening of dementia—the range of disease-specific treatments would likely continue to narrow in an ongoing iterative process in which the potential benefits, risks, and burdens of particular therapies are repeatedly assessed. There is no rigid template for this process; it requires a specific, individualized treatment plan consistent with the patient's expressed goals of care as these may evolve over time.

MS D: In the beginning, we were told he had 6 months to live. At that time, I think that I was there as his auntie, who was preparing himself and me and the family for his imminent death. Then, when he didn't die, I became...an interpreter for him because he was in shock, so he couldn't describe what was going on with him. . . . I wake up in the morning . . . and I'm afraid to look, you know, I hold my breath. Then he walks out and I'm angry because I've been waiting. It's really challenging all of my control issues . . . My grieving never stops. Sometimes, I get tired of talking about it. Friends don't come around the way they used to. My community thing has broken off pretty bad. . . . I get emotional. And I feel like I cry wolf so much—"Claude's going to die."—[that] I don't want to say it anymore.

Families and patients together must deal with the unpredictable vagaries of this prolonged illness. The challenges for patients who have expected to die, only to find that they now need to learn how to live, have been well described.⁷⁵ Ms D poignantly describes her exhaustion, anger, guilt, isolation, and feelings of loss of control. These are all common emotions that caregivers for patients with AIDS experience. Such feelings have only intensified in the chronic disease era.^{76 - 79} Clinicians caring for patients with AIDS must anticipate the serious burden of anxiety, dread, relief, and uncertainty that now define the emotional upheaval caregivers feel when their loved one is in the late stages of the disease. Physicians should proactively address these issues with family and other caregivers. Recommending support groups and respite benefits that hospice services may provide can help caregivers who may be ambivalent about accepting help from others.⁸⁰ Helping the caregiver understand that the need for support during difficult times is normal can be a clinician's most powerful intervention for a family in distress over the burden of caring for someone with advanced HIV disease.

CLAUDE: I'm so fortunate that I even have Dr K in my life. I can't tell you. It's like she knows my body or something. I can tell her what's going on or what I'm seeing, and she'll know, and it will stop.

DR K: I don't know what to do. He still wants to live. But now the conversation is more broken. His own thought process is different. There are big gaps when he talks. It's not easy. I don't know the answer, but we've talked hospice. We've talked quality of life. He doesn't want to talk about what's on the other side. . . . When he gets up and walks out of [the hospital], he wants to live. When he feels terrible and we present his numbers and he puts that in perspective with the way he's sputtered along with untreatable HIV, he's willing . . . to let it go, but that doesn't last very long. It's pretty uncomfortable. . . . I would love to have him take a truth serum and hear from him what he's really done with his medication. . . . My sense is that he just wants to experience everything he can until the very end, and none of us have been able to say when the end is. . . .

MS D: Dr K is great. She does what she can. There's no cure, but she's always been there. . . . Presence. Show up. That's what she does for us. I have no question whatsoever about the nurse or the doctor that they are there 100% for Claude, that they do their best. And even when they're not saying anything, they are there. . . . They're not apologetic. Or they can apologize and say they don't know and still stay with you. I've never felt, from the medical standpoint, that I have been in this alone, . . . and that's all that I can ask from them.

It is notable that Claude and Ms D's appreciation for Dr K is not articulated in terms of her HIV-specific knowledge or expertise but rather on her willingness to "be there," to accompany them through the sometimes confusing and contradictory pathway of late-stage HIV disease. The physician herself wonders—with a mixture of curiosity and frustration—whether the patient has been adherent with his antiretroviral medication because despite all efforts at therapy, his HIV infection has continued unchecked. This sense of frustration—of being aware of what the therapy can provide and then being confronted with the evidence of its failure—is new to the HAART era, for unlike in the previous decade, more of the responsibility for the disease's outcome is placed in the hands of the patient and the physician.^{23 ,81} The possibility of greater hope is darkened by disappointment, regret, guilt, and second-guessing.

The failure of treatment can sometimes have negative emotional consequences for patients and their caregivers, who may feel betrayed by their own or their physicians' inability to produce a different outcome. The more physicians become frustrated with patients' difficulties in adhering to recommended HAART regimens—or their own inability to reverse the disease course—the less effective they may be in accompanying the patient through the illness. As Ms D states, the physician is there even when she doesn't have the cure. Failure to cure should not result in the emotional withdrawal of the physician because of a perceived or unconscious sense of futility; rather, it is a signal to reaffirm the commitment to the patient and to stay with him or her until the end. This responsibility to accompany patients through chronic, progressive illness is no less compelling for AIDS than for a wide range of other incurable illnesses for which therapy may be available but ultimately ineffective.

In addition to the valuable service that physicians can play in caring for patients with AIDS as they approach the end of life, the experience of caregiving can be profoundly moving and life changing for the physician as well. It is probably not an accident that the AIDS epidemic has prompted a number of physicians to write about the personally transforming experience of caring for patients with AIDS.^{82 - 86} Although each is singular, these memoirs bear striking similarities in the ways the writers describe how their own senses of values, personal history, and professional mission were fundamentally altered by the experience of working with patients with AIDS and how, in humbling ways, the experience was one of personal pain, transcendence, and growth. This great gift that our patients give us, if we are open to receive it—the link between empathy, presence, and self-knowledge—was memorably described by Walker Percy in Love in the Ruins: "If you listen carefully to your patients, they will tell you not only what is wrong with them, but also what is wrong with you."⁸⁷

Centers for Disease Control and Prevention
http://www.cdc.gov/hiv
Up-to-date information about epidemiology, prevention, and clinical/public health issues in HIV/AIDS

AIDSinfo
http://www.aidsinfo.nih.gov
General clinical and research information on HIV/AIDS, including up-to-date treatment guidelines

Health Resources and Services Administration HIV/AIDS Bureau
http://www.hab.hrsa.gov
Information on HIV and palliative care demonstration projects, resource materials, and other links related to HIV and palliative care services

International AIDS Society-USA
http://www.iasusa.org
Provides up-to-date information for clinicians actively involved in the care of people with HIV/AIDS; links to other educational, clinical, and policy resources

American Academy of Hospice and Palliative Medicine
http://www.aahpm.org
Palliative care physician membership organization that provides education, advocacy, and dissemination of palliative care-related information

UNAIDS Technical Update: AIDS Palliative Care
http://www.unaids.org/publications/documents/care/general/JC-PalliCare-TU-E.pdf
One of the United Nations Program on HIV/AIDS (UNIADS) Best Practices series, this guide defines palliative care, discusses issues relevant to HIV palliative care, and provides models and recommendations for integrating HIV and palliative care services on a global basis

Promoting Excellence in End-of-Life Care
http://www.promotingexcellence.org
Presents innovative models of end-of-life care; also features working group recommendations on palliative care for specific diseases, including HIV/AIDS

End-of-Life Physician Education Resource Center
http://www.eperc.mcw.edu
Funded by the Robert Wood Johnson Foundation, provides clinical and educational material in end-of-life and palliative care, with links to information and resources useful for clinicians

American Psychiatric Association AIDS Resource Center
http://www.psych.org/aids
Offers educational and training resources, information, policy, and clinical expertise on mental health issues and HIV/AIDS