Comprehensive Clinical Care: Managing HIV as a Chronic Illness

Comprehensive Clinical Care: Managing HIV as a Chronic Illness

It is increasingly clear that HIV/AIDS care is best provided by health care providers with a specialized knowledge of the disease. However, the fact that many of our patients will live for decades means that routine health maintenance must become an integral part of treatment.

Potent combination antiretroviral therapy has led to steep declines in AIDS-related deaths and opportunistic diseases. AIDS health care professionals have begun to openly share a perception that they have held privately for some time: HIV infection has been transformed from a uniformly fatal disease into a long-term illness. As the disease trajectory changes, so do the necessary elements of comprehensive HIV clinical care. It is increasingly clear that HIV/AIDS care is best provided by health care providers with a specialized knowledge of the disease. However, the fact that many of our patients will live for decades means that routine health maintenance must become an integral part of treatment. This article focuses on the elements of comprehensive HIV/AIDS care, including general health maintenance, HIV-specific health maintenance, and clinical strategies to maximize the benefits of antiretroviral therapy.

Routine Health Maintenance

Until recently, AIDS care was characterized by either urgent or routine office visits to assess the degree of disease progression or of viral suppression and immune reconstitution. This model of care evolved in response to the very real demands of HIV infection acting as an acute or subacute illness. In the past 3 or 4 years, as HIV has evolved into a chronic illness, a typical office visit has come to involve reviewing laboratory data, medication schedules, and adherence strategies, and performing a directed physical examination. Even for individuals with less than perfect viral suppression, opportunistic diseases and other stigmata of disease progression have become much less common.

The current model of HIV/AIDS care often lacks a periodic, comprehensive physical examination and the routine laboratory and radiographic studies that are recommended as part of primary- and secondary-disease prevention for all adults. In addition to routine "HIV-directed" physical examinations every 3 to 4 months, patients over the age of 40 should undergo a yearly comprehensive physical examination and a detailed review of systems. Patients should be evaluated both for evidence of the complications of HIV infection and the normal health problems that affect adults. (See attached Periodic Health Screening Chart for recommended physical, laboratory, radiographic, and health-maintenance interventions.) It may be necessary to schedule dedicated health-maintenance visits or collaborate closely with a primary care provider to address patients' health maintenance needs.

Causes of Mortality in Antiretroviral-Treated Patients

Two abstracts presented at the 39th ICAAC meeting demonstrated that in patients treated with combination antiretroviral therapy, AIDS deaths are rare. In 252 patients followed for 2 years by Reiter and colleagues, there were no AIDS deaths among the 154 on combination therapy, compared with 12 AIDS deaths among 98 patients who received no antiretroviral therapy. Three secondary deaths occurred in the treatment group: 1 from advanced diabetes and coronary disease, 1 from hepatitis C-associated cirrhosis, and 1 from pancreatitis secondary to ddI treatment. Justice and colleagues reported that in the CHOROUS cohort of more than 4500 patients, less than half the 140 deaths were attributable to progression of HIV disease. Common causes of death in this cohort were liver failure, myocardial infarction/sudden death, suicide, non-Hodgkin's lymphoma, pancreatitis, lung cancer, and stroke. These studies indicate that mortality in antiretroviral-treated patients is now largely secondary to progression of underlying comorbid illnesses and side effects of therapy, findings that powerfully underscore the need to anticipate, prevent, and treat the side effects of such illnesses.

HIV-Specific Health Maintenance

Hyperlipidemia

Screening for and treatment of hyperlipidemia has emerged as an essential part of HIV care. Hypertriglyceridemia has long been recognized as part of the sequelae of uncontrolled HIV infection. Elevations in total cholesterol, LDL, and triglycerides are now widely seen in individuals on antiretroviral therapy and may be most prevalent in individuals on PIs and NNRTIs. The use of anabolic steroids is also associated with elevations in serum lipids. The degree of atherosclerotic risk posed by these elevations is related to the magnitude of the elevations and the number of other atherosclerosis risk factors present (e.g., hypertension, diabetes mellitus, tobacco use, obesity, age, sedentary lifestyle, and a family history of atherosclerotic cardiovascular disease). Each additional risk factor significantly increases the risk of atherosclerosis posed by any given elevation in serum lipids. Thus, any attempt to treat a patient's lipid levels should be accompanied by vigorously addressing the other modifiable risk factors.

A detailed discussion of the treatment of hyperlipidemia is beyond the scope of this article. Treating a patient for hyperlipidemia typically begins with behavior modification. The National Cholesterol Education Program (NCEP) recommends instituting a low-fat diet (saturated fat less than 7% to10% of total calories, total fat less than 30% of total calories, and cholesterol less than 300 mg/day), increasing exercise, and quitting smoking. However, some clinicians consider these dietary recommendations to be too lenient; they recommend reducing total dietary fat to less than 15% to 20% of total calories and reducing total cholesterol to less than 100 mg/day. Very often dietary modifications and exercise alone will decrease lipid levels by 10% to 30%. The NCEP recommends a 6- to 12-month trial of behavioral therapy before beginning antihyperlipidemic agents in persons without a known history of atherosclerotic cardiovascular disease; for patients with known coronary artery disease, a shorter trial of behavioral therapy before adding antihyperlipidemic agents may be appropriate. Many cardiologists and internists recommend immediate initiation of antihyperlipidemic agents for all patients with hyperlipidemia and known cardiovascular disease. Regardless of timing, antihyperlipidemic agents should be added to behavioral therapy, not substituted for it. (See Table 1 for a list of commonly available medications to treat hyperlipidemia.)

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Table 1. Antihyperlipidemic and Hypoglycemic Agents

Hyperglycemia

The association of hyperglycemia and glucose intolerance with antiretroviral therapy was first reported in 1996. Whether antiretrovirals cause glucose intolerance or unmask underlying glucose intolerance is not clear. At this time, it is prudent to screen periodically for glucose intolerance with either a fasting blood glucose or a serum hemoglobin A1c. As with hyperlipidemia, behavioral therapy is essential in the treatment of hyperglycemia: aerobic exercise, a diet low in fat and concentrated sugars, and appropriate medication are critical first steps. Because the hyperglycemia associated with antiretroviral therapy may be related to underlying insulin resistance, many clinicians use so-called "insulin sensitizers" when initiating pharmacologic therapy. These agents can have significant side effects and should be used with caution. (See Table 1.)

Abnormalities of Liver Function

Because HIV-positive people have multiple risks for perturbed liver function, liver-function tests should be performed on a regular basis. Many medications used to treat HIV and its comorbidities can affect the liver. Co-infection with hepatitis C virus (HCV) and HIV are common. Although the prevalence of HCV in the United States is estimated at 1.8%, the prevalence in HIV-infected persons has been reported to be between 12% and 90%. HCV infection is strongly correlated with the use of illegal (especially injectable) drugs and unsafe sexual practices. Approximately 9% of HIV-positive persons are coinfected with hepatitis B. Hepatic dysfunction and cirrhosis secondary to HCV and HBV often limit a patient's ability to tolerate antiretroviral medications. As effective and tolerable treatments for HCV and HBV become more available, they will become a standard part of HIV clinical care.

Hypogonadism

Men and women with HIV infection often have low levels of endogenous androgens. Some studies show a 30% rate of hypogonadism for men. Because endogenous androgens are partially responsible for maintaining lean body mass, hypogonadism is one of the many factors that contribute to wasting in HIV. Serum testosterone levels should be checked periodically. In men, testosterone can be replaced with injections of testosterone enanthate 100 mg/week or with a transdermal testosterone patch. Less is known about the prevalence of hypogonadism in women. Currently, replacement of testosterone in women is not common, but it is the focus of several ongoing studies.

Other Laboratory Tests Specific to Treatment

Many HIV drugs can adversely affect organ systems, which therefore require regular laboratory monitoring. AZT, hydroxyurea, TMP-SMX, pentamidine, and ganciclovir are among the drugs associated with cytopenias (see Table 2). Although it is well known that ddI causes pancreatic toxicity and requires regular monitoring of serum amylase, all the NRTIs and all the PIs except amprenavir and saquinavir have been associated with pancreatitis. Dapsone is associated with both hyperglycemia and anemia.

Treatment with NRTIs is associated with a syndrome of lactic acidosis, which is characterized by fatigue, dyspnea, tachycardia, weight loss, nausea, vomiting, and abdominal pain. At the 39th ICAAC, Boxwell and colleagues described a series of 60 cases of NRTI-associated lactic acidosis (reported to the FDA as of June 1998), most of which (83%) occurred in women. Twenty of these individuals (85% of whom were women) died. Sixty-four percent of the women who died were obese, 71% had hepatic steatosis, and 29% had pancreatitis. Stavudine was involved in 76% of the cases of lactic acidosis; AZT was involved in 25%. The mechanism of lactic acidosis is unclear, but it may involve mitochondrial toxicity: the NRTIs may poison polymerase gamma, the enzyme involved in replication of mitochondrial DNA. Although serum lactic acid and pyruvic acid are elevated in lactic acidosis, there are, as of yet, no common and easily obtained laboratory tests that detect or predict the early development of lactic acidosis.

HIV-Specific Periodic Physical Exam Screening

Most clinicians examine the mouth, eyes, lymph nodes, liver, and spleen at each office visit. A few "HIV-specific" elements of the physical examination should also be performed once or twice a year. All women with HIV should have 2 Pap smears a year because of the increased incidence of cervical cancer in this population. One recent report shows no decline in invasive cervical carcinoma with combination antiretroviral therapy. Men who have sex with men (MSM) and engage in anal intercourse are often infected with human papillomavirus (HPV), which can lead to anal squamous intraepithelial neoplasia (ASIL) and squamous cell carcinoma. Two recent reports, one from Seattle and one from San Francisco, showed rates of anal HPV of more than 90% in HIV-positive MSMs, compared with HPV-positive rates of 60% to 65% in HIV-negative MSMs. Palefsky noted in J AIDS 1999 that the risk of HPV progressing to ASIL was about 15% over 21 months. Goldie and colleagues, in an abstract presented at the 12th World AIDS Conference, showed that annual anal pap screening for ASIL in MSMs costs approximately $12,600 per year-of-life saved, as compared with $13,000 for PCP prophylaxis, $31,000 for MAC prophylaxis, and $180,000 for cervical cancer screening in HIV-negative women. Although the treatment of anal carcinoma carries significant morbidity and mortality, ASIL often responds to treatment with imiquimod 5% cream and close follow-up. For male patients who have taken anabolic steroids, there may be an increased risk of prostate cancer. Although prostate specific antigen (PSA) screening in the general male population has been the subject of intense debate, it is prudent to perform yearly digital rectal prostate examinations and PSA screening in all men who have taken anabolic steroids. Yearly prostate examinations are also recommended for all men over age 40.

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Table 2. Hematologic Complications of Common HIV Medications

Population-based studies have shown that HIV-positive people are at increased risk for numerous cancers, including non-Hodgkin's lymphoma, Kaposi's sarcoma, Hodgkin's lymphoma, multiple myeloma, and tumors of the brain, testes, mouth, and anus. Despite the fact that AIDS-related mortality and most opportunistic diseases have decreased dramatically since 1996, the incidence of several cancers, especially non-Hodgkin's lymphoma, Hodgkin's lymphoma, immunoblastic lymphoma, and Burkett's lymphoma, have risen or remained steady. Patients with lymphomas most often present with focal or generalized lymphadenopathy. A careful examination of the cervical, axillary, and inguinal lymph nodes -- as well as the spleen and liver -- should be performed at every visit to detect these treatable cancers.

Other Routine Screening

People with HIV infection should be tested for infection with hepatitis A, B, and C. Yearly PPD screening is still recommended, as is screening for exposure to toxoplasmosis. Virtually all patients should be screened at least once -- and subsequently as indicated by their risk category -- for syphilis, gonorrhea, and chlamydia. Patients should be screened for tobacco, alcohol, and other types of substance abuse and referred for appropriate treatment. Substance abuse is a common cause of medication nonadherence and subsequent treatment failure.

Health Maintenance Interventions

A person with hepatitis C is at risk for more rapid development of cirrhosis if he or she subsequently becomes infected with hepatitis A or B. Hepatitis A and B vaccines are effective health-maintenance interventions. Prevention of subsequent hepatitis A and B in patients who are hepatitis C positive should be a priority. The CDC and expert panels recommend yearly influenza vaccine and routine pneumococcal and tetanus vaccines for HIV-positive patients. Data on the global effectiveness and safety of these vaccines, especially influenza, vary widely. Although several studies show adequate immunogenicity of pneumococcal vaccine in individuals with both high and low CD4-cell counts, the same is not true of influenza and tetanus vaccines. Several studies show very poor immunogenicity of influenza vaccine in people with CD4 counts under 100 cells/mm³, and minimal responses in patients with between 100 and 300 cells/mm³. Tetanus vaccine has also been reported to have decreased immunogenicity in those with low CD4-cell counts. These discrepancies may be due to the fact that pneumococcal vaccine is not T-cell dependent, while influenza and tetanus vaccines are. Many, but not all, studies show a reversible rise in HIV viral load with vaccination. Tasker, in a study performed in 1995, found excellent immune response to the influenza vaccine without a rise in HIV viral load in a cohort of 102 patients, half of whom received the vaccine. Ninety percent of the patients had CD4 counts over 200 cells/mm³, and none of them received combination antiretroviral therapy.

Currently, assessment of the usefulness of influenza vaccine is hampered by the timing of virtually all published reports: They were carried out before the availability of potent combination antiretroviral therapy. We don't know if influenza vaccine is slightly, somewhat, or very effective in individuals on potent regimens with suppressed viral loads and CD4 counts under 100 or 200 cells/mm³. The vaccine's risk seems low, and its benefit may be significant. HIV viral loads should not be measured within 30 to 60 days of vaccination, especially if an individual is being monitored closely for viral escape.

Prevention Counseling

The recent great successes of antiretroviral therapy have led some people to the foolish and dangerous impression that precautions against the transmission and contraction of HIV can be relaxed or disregarded. At its best, HIV infection remains a life-long illness requiring multiple, regular medical interventions. The long-term side effects of antiretroviral therapy are simply not known. It remains incumbent on all health care professionals to strongly counsel all HIV-positive patients regarding the essentials of preventing transmission of the virus to others. Frank, open, and nonjudgmental discussions with patients regarding drug use and sexual practices are an essential part of prevention counseling. If the patient has a sexual partner who is not infected, the partner should be included in at least some of the counseling sessions. The USDHHS published a guide to HIV Partner Counseling and Referral Services in December of 1998. This monograph provides useful information on helping HIV-positive persons notify people they may have exposed to HIV who are unaware of their possible exposure.

Many people who are HIV positive and on therapy have unprotected sex with other positive individuals who are also on therapy. This behavior incurs multiple risks, including becoming infected with a resistant or more virulent strain of HIV, as well as becoming infected with agents that cause opportunistic diseases, such as CMV or HHV8.

Many individuals with a history of substance abuse continue this behavior while in treatment for HIV. As noted above, substance abuse is an important risk factor for nonadherence and treatment failure. All patients should be screened for the abuse of drugs and alcohol. Those who are still using should be advised of the risks of their drug use and referred for substance-abuse treatment. Substance abuse is an illness characterized by remission and relapse. Patients may need to be counseled and referred for treatment multiple times. The U.S. Preventive Services Task Force recommends that persons who continue to inject drugs be counseled on measures to reduce the risk of blood-borne infections: practicing safer sex, using a new, sterile syringe each time one injects, never sharing injection equipment, proper cleaning of injection equipment with bleach, and proper cleaning of injection sites. These patients should be referred to clean-syringe programs if they exist.

Maximizing Success

Several studies have shown that the more experienced a health care professional is in treating HIV, the better the clinical outcomes. Studies dating as far back as 1994 show improved outcomes in terms of patient survival, hospital days, time to recovery from OIs, emergency room use, and cost of care when patients are cared for by health care professionals with expertise in HIV. In an abstract presented at the 39th ICAAC meeting, Becker and colleagues compared patients treated by HIV specialists and nonspecialists. The specialist's patients spent 71% fewer days in hospital, 46% less money on inpatient care, and had fewer specialty referrals and better HIV-related outcomes than those treated by nonspecialists in the same practice.

In the past 5 years, much of the discussion of HIV care has focused on which antiretroviral drugs to use. Very little has been written -- and no consensus guidelines have been published -- on how best to provide these medications so that people can reliably take them. After the correct medications are chosen, adherence is the single most important aspect of clinical success with antiretroviral therapy. Paterson and colleagues, presenting at the 6th Conference on Retroviruses and Opportunistic Infections, emphasized this point. Using electronic MEMS caps to assess adherence, these researchers demonstrated that when adherence was less than 80%, viral suppression was less than 50%. Even patients with 95% to 100% adherence had only 81% suppression, indicating that 100% adherence is probably necessary with the current medications.

No single adherence strategy will work for all patients and clinics. However, some of the key elements of a treatment program that fosters adherence can be identified: interdisciplinary teams of HIV-knowledgeable physicians, nurse practitioners, nurse specialists, pharmacists, and case managers who are consistently present for all patient visits; multiple educational contacts with patients before beginning antiretroviral therapy and in the first month or two of therapy; systematic review of medications with patients at every visit; a warm and caring environment where patients and families will feel safe to share problems with adherence and other personal issues; bilingual health care professionals or the use of medically trained translators; and the availability of support groups, psychological counseling, and substance-abuse treatment.

Conclusion

Advances in antiretroviral therapy appear to have transformed HIV infection into a long-term, treatable illness. It is incumbent on all AIDS health care professionals to optimize therapeutic outcomes by practicing in a setting that recognizes the social and psychological needs of our patients, while providing expert HIV-specific care and consistent attention to routine health maintenance.

— Gary S. Reiter, MD

Dr. Reiter is Assistant Professor at the University of Massachusetts Medical School, Worcester, and Medical Director of the River Valley HIV Clinic, Holyoke, MA.

Published in AIDS Clinical Care February 1, 2000

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