U.S. Patients and Doctors Find HAART Poses Challenges
Debilitating side effects, demanding drug regimens and high costs are some of the barriers that limit the benefits of highly active antiretroviral therapy in the United States.
The benefits of highly active antiretroviral therapy (HAART), the three- and four-drug combinations against HIV, have been widely publicized. In many industrialized countries, these potent drug regimens have reduced deaths from AIDS and prolonged the lives of thousands of people.
Less well-known are the formidable challenges HAART presents, including its side effects and the potential for rapid spread of drug resistance. Antiretroviral drug combinations have been available in the United States for less than three years, yet there is a rapidly growing body of knowledge about their disadvantages as well as their benefits. This knowledge may be instructive for other countries searching for ways to make antiretroviral therapy available to their HIV-positive citizens.
Limited Options
In the countries where it is available, HAART generally includes three or four drugs in two distinct categories: nucleoside analogs and protease inhibitors. They are commonly prescribed as part of the same regimen in the United States because one or two protease inhibitors strengthen the effect of one or two nucleoside analogs. Unfortunately, protease inhibitors do not work as well with a third category of HIV drugs, non-nucleoside analogs, and they should not be taken alone.
By the end of August 1998, the U.S. Food and Drug Administration had approved four protease inhibitors--indinavir, nelfinavir, ritonavir and saquinavir--and five nucleoside analogs--didanosine (ddI), lamivudine (3TC), stavudine (D4T), zalcitabine (ddC) and zidovudine (AZT). Only two non-nucleoside analogs--nevirapine and felavirdine--had been approved for prescription use.
If one of the drugs involved in the triple or quadruple therapy is not well tolerated or if a patient's HIV infection becomes resistant to it, a whole new set of drugs must be prescribed for the regimen to be effective. Thus, with a limited number of HAART medications available on the U.S. market so far, only a few different drug combinations are possible. HAART regimens can also fail because of lack of viral load response or poor treatment adherence.
Resistance and Adherence
Because of its "highly active" nature, HAART can provide a symphonic response to HIV infection. If doses are missed or taken improperly, however, the crescendo falls flat. Not only does the treatment lose its potency, but also the patient's HIV infection can rapidly become resistant to the drugs involved, meaning that their HIV infection changes its chemical or genetic form to resist the effects of these drugs. Even more ominously, sexual transmission of HIV strains resistant to HAART medications has been documented and may be a growing problem.
Missing a single dose of HAART medication even twice a week can cause the development of drug-resistant HIV--a real danger because adherence to the drug regimens is difficult. Once HAART is initiated, a patient must be willing and able to take as many as 40 pills (12 is the minimum daily dosage in any currently recommended HAART regimen) and drink as many as eight glasses of water a day. The pills must be taken at several times during the day, some with food and others on an empty stomach.
A patient's ability to adhere to these complicated regimens is one of several important considerations for clinicians in determining when to begin HAART, according to Dr. Frederick Hecht, a clinician at San Francisco General Hospital Medical Center who has been treating HIV-positive patients since 1986. He noted that U.S. physicians generally prescribe HAART based on the current recommendations provided in the Journal of the American Medical Association by the International AIDS Society,1 but they may follow these recommendations to different degrees.
"I'm slightly more conservative than the guidelines because of the long-term side effects," said Dr. Hecht, an assistant clinical professor of medicine at the University of California, San Francisco, Medical School. "I want to be clear that someone will not be at risk of developing resistance because of non-adherence."
Side Effects
The side effects experienced by many people on HAART can readily provoke a patient to miss a dose or take a "drug holiday" from the regimented existence the treatment necessitates. Sometimes side effects are so severe that a physician must prescribe a different drug combination, involving a totally new regimen.
Most of the information available about HAART side effects is self-reported by patients because of the lack of placebo-controlled clinical research trials, according to Dr. Hecht. One study he is involved in, the Options Project, is looking at the most appropriate time for HIV-infected individuals to begin HAART, taking into account the potential side effects of this treatment. The side effects from individual drugs as well as the deleterious drug interactions reported so far are many, and vary from one individual to the next. The most common ones, however, are becoming better documented and recognized by health care professionals.
According to Dr. Hecht, who currently treats about 100 HIV-positive patients, long-term side effects include lipodystrophy, which is a nearly complete lack of fat below the skin (or sometimes a redistribution of it to the pelvic area), and, less commonly, diabetes. After two years of HAART availability in the United States, coronary heart disease also emerged as a side effect in some patients who had lived long enough to develop it. "This makes me concerned," he said, "especially for those who would be on treatment five to ten years."
Common short-term side effects that Dr. Hecht has seen in his patients include medication-related nausea, fatigue, kidney stones (from indinavir) and diarrhea (from nefinavir). Patients taking ritonavir have experienced mouth numbness, loss of taste, nausea and, occasionally, vomiting.
More than Drugs
HAART is not always readily available to or feasible for everyone infected with HIV, no matter where they live. This powerful therapy demands commitment from patients, physicians and health care systems.
Since HAART became available in the United States in early 1996, it has become increasingly clear that it must be prescribed and monitored by highly trained physicians and nurses who maintain the most current knowledge of all the potential side effects, drug interactions and resistance variables. Counselors who can provide emotional and psychosocial support and case managers who can identify financial assistance options are also a critical part of the HAART team wherever this form of care is attempted. In addition, such highly complex pharmaceutical treatment demands a sophisticated health care infrastructure and delivery system to support the necessary laboratory tests, drug supplies and outpatient clinic visits.
For industrialized nations, another lesson of the experience with HAART to date might be the realization that HIV care involves much more than a technological fix. With viral strains already developing drug resistance, prevention may indeed be the best medicine against HIV. In the end, however, care is not only a basic human right, but a crucial part of the HIV prevention cycle, and it involves much more than simply dispensing medications.
Study Reveals Gaps in HIV Care in the United States
Preliminary results from the first nationally representative sample of adults living with HIV/AIDS in the United States show that less than half of them--43 percent--receive regular health care, defined as one visit to a health care provider every six months.
These results, presented at the 12th World AIDS Conference in Geneva, Switzerland, in June 1998, also indicate that slightly more than half of HIV-positive Americans have tried highly active antiretroviral therapy (HAART).
Access to the newer HIV/AIDS therapies mirrored the overall deficiencies in health care for HIV-positive adults revealed by this national HIV Cost and Services Utilization Study (HCSUS). Nevertheless, the proportion of HIV-infected adults who had tried HAART rose from 16 percent to 55 percent during 1996.
Conducted from January 1996 through July 1997, the HCSUS used two rounds of client interviews to learn about five types of care accessed during the previous six months: doctor or clinic visits, emergency room visits, hospitalizations, use of antiretroviral medications and use of prophylactic therapies.
Nearly 3,000 HIV/AIDS patients were sampled at 148 urban and 51 rural sites, chosen based on caseloads, in the 48 states in of the continental United States. Fifty-four percent of the study group consisted of individuals aged 35 to 50, with 34 percent younger than 35.
More than three out of four participants were male and almost half were men who have sex with men. Twenty-four percent were drug users, and 18 percent were heterosexuals. Nearly half the study participants were white, one-third African-American, and 15 percent Hispanic. Most were unemployed.
Study participants reflected the following categories of disease stages defined by the Centers for Disease Control and Prevention: 38 percent had clinical AIDS, 52 percent had symptomatic HIV infection and 10 percent had asymptomatic HIV infection.
Study results released in Geneva by the HCSUS Consortium, representing the National Opinion Research Center at the University of Chicago, Harvard University, Project Hope, the University of California at San Diego, and seven other research organizations, show that the cost of HIV/AIDS treatment in the United States is $6.7 billion a year. Forty-six percent of the total is spent on hospital costs, and 39 percent covers pharmaceuticals. The remaining 14 percent (some $938 million) funds outpatient treatment, emergency room visits, lab costs, and other care services.
The average annual per patient cost is $20,000, double the average annual income of nearly half of those infected with HIV in the United States.
The researchers estimate that HIV is responsible for 8 percent of the total potential years of life lost in the mainland United States. Expenditures for care of those living with HIV, however, account for less than 1 percent of total personal health costs.
The study also found that one out of five people living with HIV in the United States has no insurance to cover the cost of health care. Only thirty-two percent have private health insurance, while 48 percent are covered by the government programs Medicare or Medicaid.
HIV-positive women, African-Americans, Hispanics, drug users, and others with low socioeconomic status, no health insurance or only Medicaid have lower levels of health care.
The researchers concluded that until new strategies are identified and utilized and additional funding is allocated to provide adequate and equitable health care for all HIV-positive adults in the country, the United States will not be able to optimize health outcomes for this disease.
The HCSUS was funded by the U.S. Agency for Health Care Policy and Research, the Health Resources and Services Administration, the National Institute of Mental Health and the National Institute on Drug Abuse, among others.
CCJ Carpenter, MA Fischl, SM Hammer, et al. Antiretroviral therapy for HIV infection in 1998: recommendations of the IAS-USA Panel. Journal of the American Medical Association. 1998;280:78-86.
