October 2001

HRSA Care ACTION

AIDS Treatment: Where We Are Now

Five years after the wide-scale introduction of potent, but complicated, antiretroviral drug combinations in the United States, uncertainties remain about the best way to use the drugs. In the new Federal treatment guidelines, earlier advice to "hit early, hit hard" has been replaced by a more conservative approach, one suggesting that asymptomatic adults and adolescents with HIV infection start antiretroviral therapy later in the course of the disease.

The Panel on Clinical Practices for Treatment of HIV Infection, convened by the U.S. Department of Health and Human Services and the Henry J. Kaiser Family Foundation and chaired by Anthony S. Fauci of the National Institutes of Health and John G. Bartlett of the Johns Hopkins University School of Medicine, made major changes in its guidelines in January 2001, with further revisions most recently in August.  The panel’s guidelines are updated regularly and are available at www.hivatis.org and at the HRSA-supported AIDS Education and Training Center’s National Resource Center site, www.aids-ed.org.

The panel addressed the following concerns:

• Testing for plasma HIV RNA (viral load) and CD4+ T cell count (a measure of the immune system)

• Testing for antiretroviral drug resistance

• When to initiate therapy in established HIV infection

• Adherence to antiretroviral therapy

• Therapeutic considerations for patients with advanced disease

• Medication-related adverse events

• Interruption of therapy

• Considerations for changing therapy and available therapeutic options

• Treatment of acute HIV infection

• Antiretroviral therapy in adolescents

• Antiretroviral therapy in pregnant women.

The recommendations offer guidance for the "average patient" based on the best available evidence. In the past, the guidelines suggested that patients with fewer than 500 CD4+ T cells initiate therapy; the new recommendations say that patients and their doctors should consider initiating therapy for fewer than 350 T cells. The panel also recommends that treatment be considered by patients with certain levels of virus in their bloodstream—more than 30,000 viral copies using the branched chain DNA test or 55,000 copies using the reverse transcriptase polymerase chain reaction test, regardless of CD4+ count. Previous guidelines suggested 10,000 and 20,000 copies, respectively.

Although the new guidelines recommend that medications be started later, they also suggest that patients begin with powerful three- or four-drug regimens. Bartlett calls this new strategy "hit hard, but somewhat later."¹

Much of the evidence supporting the guidelines comes from observational studies, not from randomized controlled trials, the gold standard of clinical medicine. Furthermore, no one can predict with certainty the best point in an individual patient’s disease to initiate antiretroviral therapy. In discussing the panel’s new guidelines in an article in JAMA, Bartlett said, "We highlight the uncertainty, allow for flexibility, encourage an individualized approach to treatment and, at the same time, try to provide guidance."²  Individual decisions concerning treatment must be made by people with HIV in consultation with their doctors.

The sort of combination antiretroviral therapy recommended by the panel remains complicated, and often results in serious side effects. Critical challenges to adherence remain. Moreover, the drugs are expensive, and their early use may result in viral mutations. Although each patient should weigh the risks and benefits of therapy, the panel concludes that generally people with fewer than 350 CD4+ cells should be offered therapy because of their risk of disease progression and opportunistic infections. (See table 1 for a list of FDA-approved antiretroviral medications.)

The panel also recommends offering treatment to people diagnosed with HIV who are within 6 months from seroconversion. The data are not definitive, but some preliminary evidence indicates that treatment early in the course of the infection may preserve immune function and limit the replication of the virus.

In making the decision when to initiate therapy, a patient and his or her health care provider must weigh both the potential benefits and the potential risks of early versus delayed therapy (see table 1). Other important considerations include the patient’s readiness to begin treatment, his or her prospects for adhering to treatment regimens, and the speed at which the disease is progressing.

Clinical and laboratory monitoring should guide decisions concerning when to start and when to change antiretroviral therapy. In patients not taking anti-AIDS drugs, quantitative viral load and CD4+ count should be monitored several times a year. Viral load should be measured prior to starting therapy and at frequent intervals after it begins to reflect responsiveness to therapy.

The panel suggests that HIV care is best provided by clinicians with extensive experience in caring for people with HIV. If such clinicians are unavailable, it is important that experienced consultants be available to assist the primary care provider.

Often HIV develops resistance in a patient who has taken antiretroviral medications for a period of time; consequently, the drugs can become less effective. In addition, some people with HIV are infected initially with a strain of the virus that is resistant to certain medications.  Two laboratory tests can be used to evaluate viral resistance. The tests are known as genotyping and phenotyping resistance assays and, in certain circumstances, they offer important information in selecting which drugs to use for a specific patient.

• Genotyping tests uncover viral genetic mutations known to confer resistance. Viruses with certain genetic mutations have defenses against one or more drugs—sometimes against a class of drugs.

• Phenotyping tests measure the ability of a virus to replicate in the presence of different antiretroviral drugs. Viruses that are able to replicate in the presence of a drug are resistant to that drug.

According to the new guidelines, resistance testing is most useful for patients with poor suppression of viral load while taking potent antiretroviral drugs and for patients with new HIV infection. The tests have some limitations and are costly, but in combination with a patient’s history and clinical status, they can be useful in selecting drugs with the greatest chance to be effective.

Treating HIV-infected pregnant women is often significantly more complex than treating nonpregnant adults. The guidelines recommend antiretroviral therapy as initial therapy for HIV-infected pregnant women whose "clinical, immunologic or virologic status would suggest the need for treatment if nonpregnant." In addition, administering AZT according to the ACTG-076 protocol—starting at 14 weeks gestation and continuing throughout pregnancy, during labor, and to the newborn for the first 6 weeks of life—is also recommended for all pregnant women.

Guideline authors caution, however, that "recommendations regarding the choice of antiretroviral drugs for treatment of infected women are subject to unique considerations." These factors include the effect of physiologic changes associated with pregnancy on dosing requirements, potential effects of antiretrovirals on pregnant women, their effect on the risk of perinatal HIV transmission, and their effect on the fetus.  The latter consideration is problematic because the effect of certain drugs is unknown. 

Several other factors must be considered. For example, women in their first trimester of pregnancy not receiving antiretroviral therapy may wish to delay therapy until 10 to 12 weeks gestation because the embryo is most susceptible to potential effects of drugs during this period. (While evidence supporting or refuting the impact of antiretroviral therapy on the fetus during the first trimester of pregnancy is inconclusive, efavirenz and hydroxyurea should be avoided during this period.) Another issue involves when to initiate antiretroviral therapy in HIV-infected women because of its potential for reducing risk of perinatal transmission; such therapy might be delayed in nonpregnant adults. When should such therapy be discontinued?

These and other issues regarding HIV disease and pregnancy merit special attention and are outside the scope of this article. For more in-depth information, readers are invited to consult the most recent clinical guidelines, pages 29-32 and page 91; A Guide to the Clinical Care of Women with HIV, at http://hab.hrsa.gov; and Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States, at www.hivatis.org.

The new guidelines suggest that many asymptomatic people with HIV take lifelong regimens of highly active antiretroviral therapy (HAART) with all of its attendant side effects and other difficulties. Excellent adherence is associated with sustained viral control and reduced disease and death from  HIV. Conversely, poor adherence is associated with drug resistance, treatment failure, and increased complications due to HIV.

The inability of current regimens to eradicate HIV, the challenges of long-term adherence, significant drug toxicities and the potential to develop drug resistance seem to have given rise to the new recommendations, which are likely to result in initiation of antiretroviral therapy later in the course of the disease. Some AIDS treatment experts have criticized the research on which the guidelines were based. Mark Harrington, a MacArthur Foundation Fellow, said that the evidence underlying the guidelines was based primarily on observational studies and on small clinical trials. He advocates a large, well-controlled randomized trial to address the 3 question of when antiretroviral therapy should be initiated. 

Recent evidence demonstrates the economic value of drug therapy for HIV. A group of researchers in Boston using a computer model and data from clinical trials found that with a three-drug regimen, the cost effectiveness ratio was $13,000 4 to $23,000 per quality-adjusted year of life gained. Another study, by RAND Health, found that use of HAART was associated with an increase in expenditures for drugs 5 but a decline in overall health care costs. During the 3-year study, the mean monthly health care expenditure declined from $1,792 per patient to $1,410. The overall use of health care resources declined as the use of HAART became more widespread. The same study echoed other reports that some populations are not using HAART as much as others:

Women, blacks, intravenous drug users, patients with public insurance and those who had not completed high school had proportionally less outpatient care and proportionally more inpatient care. This finding suggests that unequal access to drug therapy has negative clinical consequences for patients and increases the total costs of AIDS care secondary to more hospitalizations. The authors conclude that "investments in the development and provision of new treatments for HIVinfected patients have had net economic as well as clinical returns."

New pediatric AIDS treatment guidelines were issued in August by the Working Group on Antiretroviral Therapy 6 and Medical Management of HIV-Infected Children. The guidelines indicate that when the mother's HIV serostatus has not been determined during pregnancy or following birth, the infant should be tested for HIV so that appropriate medications, if any, may be given as soon as possible after birth.  Other highlights of the new guidelines include the following recommendations:

• Antiretroviral therapy is recommended for all children with HIV who are symptomatic or who have evidence of immune-system suppression.

• Children under age 1 who are infected with HIV should be treated with antiretroviral therapy because they are at increased risk for disease progression.

• Therapy in children should be initiated with a three-drug combination because aggressive treatment is most likely to delay disease progression and preserve immune function.

• One strongly recommended initial therapy consists of two nucleoside reverse transcriptase inhibitors and one protease inhibitor. Alternative regimens are discussed in the guidelines.

• Although more research is needed into the use of genotypic and phenotypic viral resistance testing in children, these tests may be useful in guiding initial therapy decisions or in setting failed drug regimens.

Recommendations concerning health care personnel with occupational exposure to HIV-infected blood and body 7 fluids were updated in June. They now recommend counseling, testing and a medical evaluation following exposure as well as a regimen of two or three drugs if postexposure prophylaxis (PEP) is given. Specific drug regimens depend on the type of injury, the health of the source patient, and the volume of blood involved in the exposure. If initiated, PEP ideally should begin immediately after exposure.

The risk of HIV transmission to health care workers who come into contact with HIV infected blood is estimated to be 0.3 percent for percutaneous exposure and 0.09 percent for mucous membrane exposure. As of June 2000, 56 cases of HIV transmission to health care workers through occupational exposure had been documented, with an additional 138 possible cases. 

Up to one-half of all health care workers who start PEP experience side effects, and one-third discontinue therapy as a result. Because most occupational exposures to HIV do not result in transmission, it is important to balance the risk of infection against the potential side effects of the medications. Further information is available from the Centers for Disease Control and Prevention at (800) 893-0485 or www.cdc.gov and from the HRSA-sponsored National Clinicians’ Postexposure Prophylaxis Hotline (PEPline) at (888) 448-4911 or www.ucsf.edu/hivcntr.

1. Bartlett JG, "New Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents," The Hopkins HIV Report, Vol. 13, No. 2, March 2001.

2. Stephenson, J, "New HIV Therapy Guidelines," JAMA, Vol. 285, No.10, March 14, 2001, p. 1281.

3. Harrington M, "Hit Hard, Later…?," GMHC Treatment Issues, Vol. 15, No. 2/3, February/March 2001.

4. Freedberg KA, Lsina E, Weinstein MC, et al., "The Cost Effectiveness of Combination Antiretroviral Therapy for HIV Disease," The New England Journal of Medicine, Vol. 344, No. 11, March 15, 2001.

5. Bozzette SA, Geoffrey J, McCaffrey DF, et al., "Expenditures for the Care of HIV-Infected Patients in the Era of Highly Active Antiretroviral Therapy," The New England Journal of Medicine, Vol. 344, No. 11, March 15, 2001.

6. The updated guidelines are available at http://hivatis.org/trtgdlns.html#Pediatric.

7. Centers for Disease Control and Prevention, "Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis." MMWR 2001;50 (No. RR-11).

1999 AIDS Drug Assistance Program Data

According to the AIDS Pharmaceutical Assistance Annual Administrative Report, 118,462 clients were served in 1999 by the 50 AIDS Drug Assistance Programs (ADAPs) submitting data, a 15-percent increase over 1998. Of the total, 92,858 were males, 25,547 were females, and 32,614 were new clients.

AIDS Drug Assistance Programs (ADAP) are authorized under Title II of the Ryan White CARE Act. ADAP funds are used to provide medications to treat HIV disease, including measures for the prevention and treatment of opportunistic infections. ADAPs serve individuals who have neither adequate public nor private insurance, nor the means to pay for medications on their own. All 50 States, the District of Columbia, Puerto Rico, and the Virgin Islands have an ADAP, as does Guam (as of FY 2000). Fifty of the 53 ADAPs extant in 1999 submitted reports. Maine, Oklahoma, and Wyoming did not provide data.

The greatest increase in the number of clients receiving services from 1998 to 1999 occurred among African Americans, with an increase of 16 percent. Less substantial increases occurred among Asian/Pacific Islander, white, non-Hispanic, and Native American/Aleutian/Eskimo clients in 1999. The number of Hispanic clients declined 25 percent during the same period.

In 1999, 75 percent of all ADAP clients for whom age was reported (N = 95,132) were between ages 20 and 44, and clients age 45 and older comprised 23 percent. Adolescents and children represented 2 percent of all ADAP clients in 1999.

Each State and Territory establishes its own criteria for ADAP eligibility. However, all programs require documented HIV status. Programs may base eligibility on CD4+ counts, income status, or both.

Each State and Territory also determines which medications will be included in its program and how those medications will be distributed. Many programs provide medications through a pharmacy reimbursement model, whereby patients are given enrollment cards at participating pharmacies. The pharmacies then receive payment from the ADAP. Some programs use pharmacies located within public health centers. A few State ADAPs purchase drugs and mail them directly to the client.

CARE Act Funding vs. Non-CARE Act Funding

Funding has increased each year for the AIDS Drug Assistance Program. Relative to the previous year, total ADAP funding increased 87 percent in 1997, 35 percent in 1998, and 40 percent in 1999. As of FY 2001, total ADAP funding had reached approximately 3.5 times the 1996 level.

The CARE Act Title II ADAP "earmark" is the primary source of funding for the ADAP programs, but there are other sources as well. CARE Act funding expanded 265 percent, from approximately $136 million in 1996 to nearly $496 million in 1999. Other funding included CARE Act Title I allocations; Title II allocations; Medicaid; Medicare; Federal Section 329, 330, and 340 programs; private contributions; and client payments.

In 1999, approximately 96 percent of all State ADAP expenditures were for drugs; 4 percent was spent on administration and ancillary devices. Total ADAP expenditures for drugs increased by 241 percent from 1996 ($160 million) to 1999 ($545 million).

In 1999, State ADAPs spent 89 percent of $545,053,347 in total drug expenditures on antiretroviral medications (protease inhibitors, nucleoside reverse transcriptase inhibitors(NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI); see table on page 8). Because antiretrovirals are prescribed in combination, a single client may have received multiple drugs. Spending on NRTI, whose chemical structure constitutes a modified version of a natural nucleoside that suppresses replication, constituted 45 percent ($249.2 million) of antiviral drug expenditures. Protease inhibitors (PI), antiviral drugs that inhibit the viral protease enzyme, thereby preventing viral replication, comprised 34 percent ($185,677,085) of expenditures on antiviral drugs. NNRTI are drugs with structurally diverse compounds that bind to the catalytic site of HIV-1’s reverse transcriptase. The antiviral activity of these drugs is additive or synergistic with most other antiretroviral agents. In 1999, the three NNRTIs available were responsible for 10 percent of ADAP drug spending with, an allocation of $53,314,534.

Several amendments were made to the Ryan White CARE Act in October 2000, and those most significantly affecting the ADAP programs are discussed below:

1. Adherence—States may use a portion of their ADAP funds to "encourage, support, and enhance adherence to and compliance with treatment regimens, including related medical monitoring." States may normally use up to 5 percent of their award for these services, but if a State demonstrates that these services are essential and do not diminish access to medications, it may spend as much as 10 percent.

2. Health Insurance—States may likewise use a portion of their ADAP earmark to provide health insurance that covers costs of medications as long as the costs of doing so do not exceed the costs of otherwise providing medications and coverage provides full access to primary care.

Future demand on ADAP resources is expected to escalate as the standard of care evolves for people living with HIV/AIDS, a significant number of patients continue to respond positively to new drug therapies, and some patients begin to rely on salvage treatment regimens.

The reauthorized legislation reflects the increasing pressure on the ADAP program, which comes from a variety of sources:

• The standard therapy for the majority of HIV-positive individuals is HAART, which may cost more than $12,000 per year.

• Side effects and other treatment issues incur costs in addition to those involved in treating opportunistic infections.

• AIDS mortality has increased in the United States since 1995, and HIV incidence remains constant. Therefore, the number of individuals living with HIV continues to climb.

• The epidemic is growing rapidly among minorities, who historically have experienced a higher risk of poverty, lack of health insurance, co-morbidity, and disenfranchisement from the health care system. As a result, a growing number of individuals require public support.

As of October 2000, 3 percent of the ADAP earmark was allocated for supplemental grants to States with a severe need for medications. The Amendments also make way for new supplemental Title II awards that fund services to "emerging communities." Funds for these grants will become available in the first year that the total Title II appropriation, excluding the ADAP earmark, is increased by at least $20 million over the FY2000 level.

For more information, call (301) 443-7036

http://hab.hrsa.gov

HEALTH RESOURCES AND SERVICES ADMINISTRATION -  HIV/AIDS BUREAU

IN THIS ISSUE
1999 AIDS Drug Assistance Program Data
Insert: Calendar of Events

HRSA Care ACTION
is published by the HIV/AIDS Bureau,
Health Resources and Services Administration,
Department of Health and Human Services.
All information contained
herein is in the public domain.

Please forward comments, letters, and questions to:

HRSA Care ACTION
HIV/AIDS Bureau, HRSA
5600 Fishers Lane, Room 7-13
Rockville, MD 20857

Phone: 301-443-0349
Fax: 301-443-0055
rsoliz@hrsa.gov
http://hab.hrsa.gov