Draft HIV/AIDS Treatment Guidelines Available

U.S. Department of Health and Human Services, National Institute of Allergy and, Infectious DiseasesEMBARGOED FOR RELEASE, Thursday, June 19, 1997, 10:30 AM Eastern Time, Patricia Randall

All people with CDC-defined AIDS should receive combination antiretroviral therapy, preferably with three drugs including a protease inhibitor, according to comprehensive new Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, made available today for public comment. The Guidelines were developed by the Panel on Clinical Practices for Treatment of HIV Infection, which was convened jointly by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation.

"The decisions about treatments for people with HIV/AIDS should be guided by regular monitoring of the amount of HIV in the patient's blood (viral load) as well as the number of CD4+ T cells, the immune system cells that fight infection," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Dr. Fauci and John G. Bartlett, M.D., professor of medicine and chief of infectious diseases, Johns Hopkins University School of Medicine, co-chair the Panel that includes federal, private sector and academic experts in the clinical treatment and care of HIV-infected people, as well as representatives of AIDS interest groups, health policy groups and payer organizations.

The Guidelines recommend starting treatment with three drugs and changing at least two drugs when there are indications that treatment is failing, such as when HIV levels in the blood increase. Treatment with only two drugs, in general, is considered less than optimal.

Treatment with only one drug is not recommended. However, zidovudine (AZT) as monotherapy is recommended as prophylaxis to prevent HIV transmission to a baby and should be given to relatively healthy HIV-infected pregnant women who do not require antiretroviral drugs for their own treatment. These women and their newborns should receive AZT, according to the regimen recommended by the Public Health Service Task Force, to reduce the risk of HIV transmission to the babies.

HHS Secretary Donna E. Shalala praised the Panel for its efforts. "Today, we are providing much-needed guidance to patients and medical practitioners," Shalala said. "We have reason to celebrate that a diagnosis of HIV disease is no longer an automatic death sentence. At the same time, we recognize that these new medical guidelines raise important public policy issues, and we're working rapidly to address them."

DHHS Office of HIV/AIDS Policy and the Kaiser Family Foundation convened the three-year panel in December 1996. "We recognize that treatment decisions have become increasingly complex with the many new drugs available and new ways of monitoring disease progression. The Guidelines, which will be updated periodically, reflect the current state of knowledge about HIV disease and antiretroviral drugs," says Eric P. Goosby, M.D., director of the DHHS Office of HIV/AIDS Policy.

"These Guidelines will help standardize and improve the quality of care for HIV-infected persons in the United States. The Foundation is pleased to have joined with the Department of Health and Human Services in this unique public-private partnership to bring national attention to the rapid changes in HIV therapies," says Sophia Chang, M.D., director of HIV programs, Kaiser Family Foundation.

"The Guidelines relied in part on a companion document, Report of the NIH Panel to Define Principles of Therapy of HIV Infection," explains Dr. Goosby, "and together they provide the scientific rationale for therapeutic strategies as well as practical guidelines for implementing the strategies."

The NIH Panel was sponsored by the NIH Office of AIDS Research and chaired by Charles C. Carpenter, M.D., professor of medicine, Brown University School of Medicine.

Panelists included AIDS clinicians and researchers. The mission of the NIH Panel was to review the current state of knowledge of antiretroviral therapies and prepare a document outlining Principles that would guide therapeutic decisions.

Both documents, announced in the Federal Register June 19, 1997, are available for a 30-day comment period. The draft documents are available from the National AIDS Clearinghouse (1-800-458-5231) and on their Web site (http://www.cdcnac.org) and from the HIV/AIDS Treatment Information Service (1-800-448-0440) and on their Web site (http://www.hivatis.org).

After consideration of comments, both documents will be published in the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report.

Key Points in the Guidelines for the Use of Antiretroviral Agentsin HIV-Infected Adults and Adolescents

June 19, 1997

Use of Testing

Decisions on initiation of or changes in antiretroviral therapy should be guided by monitoring the amount of virus in the patient's blood (viral load) supplemented by information about the patient's CD4+ T cell count and clinical condition.

Viral load testing should generally be repeated at 3-4 month intervals to evaluate the continuous effectiveness of therapy.

Treating Established Infection

All patients with AIDS, as defined by the 1993 CDC Guidelines, or with symptomatic HIV infection should be placed on antiretroviral therapy regardless of viral load.

Asymptomatic patients with CD4+ T cell counts of less than 500 or with HIV RNA levels greater than 10,000 copies (by bDNA test) or greater than 20,000 copies (by RT-PCR test) should be offered therapy. However, other considerations, such as drug toxicity and willingness of the patient to start therapy and comply, will affect the strength of the recommendation for therapy. These factors are discussed at great length in the document. Some physicians may choose only to monitor patients with 350-500 CD4+ T cells/mm3 and low viral burdens.

Some physicians would also treat patients with low but detectable viral burdens and CD4+ T cell counts greater than 500; others would not.

A regimen of two nucleoside reverse transcriptase inhibitors and one protease inhibitor is preferred to achieve maximal viral suppression.

An alternative regimen may substitute nevirapine for the protease inhibitor, but this is not considered optimal.

If it is necessary to stop antiretroviral therapy for an extended time, clinicians and patients should be advised to stop all antiretroviral drugs simultaneously, rather than continuing one or two drugs, to minimize the potential for encouraging resistant viral strains.

Considerations for Changing a Failing Regimen

It is important to distinguish between discontinuation of combination therapy due to drug failure and discontinuation due to drug toxicity.

For drug toxicity, it is appropriate to substitute one or more alternative drugs for the agent suspected of causing the toxicity.

For drug failure, at least two drugs must be changed. Optimally, three new drugs should be used in replacement of a failing regimen.

Therapy should be changed only with the patient's full agreement and compliance and after ruling out malabsorption of drug.

Criteria for changing therapy include:

a less than ten-fold reduction in viral load level by four weeks following initiation of therapy.

failure to suppress viral load to undetectable levels within four to six months of beginning therapy.

repeated detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance.

any reproducible significant increase from the lowest viral load measurement.

persistently declining CD4+ T cell counts.

clinical deterioration.

The document contains some suggested alternative therapeutic regimens. Most suggested alternative drug regimens are still investigational in nature. While these combinations may have shown promise in smaller numbers of patients or be theoretically reasonable, no clinical trial data exist as yet to show that these regimens are broadly effective. Thus, clinicians, patients and payers should weigh advantages and consequences before choosing a regimen that is still undergoing evaluation in clinical trials.

Acute Infection

Physicians should suspect HIV infection in all patients presenting with some of the symptoms of the acute retroviral syndrome, which are easily confused with the common flu.

Patients without documented HIV infection should not be given antiretroviral therapy.

Treatment, if used, must be aggressive to achieve maximal antiretroviral effects and suppression of viral replication.

Therapeutic regimens for acute HIV infection should include the combination of two nucleoside inhibitors and one protease inhibitor. The drugs should be started simultaneously.

Once therapy is initiated, many experts recommend continuing to treat indefinitely. Research is ongoing to determine if there is a period after which therapy can be discontinued.

Considerations for Antiretroviral Therapy in the HIV-Infected Pregnant Woman

Guidelines for determining optimal antiretroviral therapy and for deciding to initiate therapy in pregnant HIV-infected women should generally be the same as those for non-pregnant adults, with the overriding consideration being for the mother's health.

Risks to the fetus from effects of antiretroviral drugs are not well understood. Some clinicians might choose to delay therapy until after the first trimester of pregnancy, or, if the mother is already on an antiretroviral drug regimen, to stop all drugs until the second trimester.

To date, the only drug that has been shown to reduce perinatal transmission by approximately 70-80 percent is zidovudine (AZT). The zidovudine must be administered beginning as early as the 14th week of pregnancy and continued throughout pregnancy. The mother must receive intravenous zidovudine during labor and delivery, and the newborn must receive zidovudine during the first 6 weeks of life. Regardless of the independent indication for antiretroviral therapy in the mother, all HIV-infected women should receive this preventive therapy during pregnancy.

Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents and Report of the NIH Panelto Define Principles of Therapy of HIV Infection

June 19, 1997

Questions and Answers

What is the Panel on Clinical Practices for HIV Treatment?

The Panel on Clinical Practices for Treatment of HIV Infection is a three-year public-private partnership convened in December 1996 by the Office of HIV/AIDS Policy, DHHS, and the Henry J. Kaiser Family Foundation at the request of DHHS Secretary Donna E. Shalala. The Panel's mission is to provide comprehensive descriptions of clinical practices in the care of HIV-infected people and to provide recommendations for treatment options to practitioners, patients, and payers. The Panel developed the document, Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents.

Anthony S. Fauci, M.D., director, National Institute of Allergy and Infectious Diseases and John G. Bartlett, M.D., professor of medicine and chief of infectious diseases at Johns Hopkins University School of Medicine co-chair the Panel. The Panel includes federal, academic and private sector experts in the clinical treatment and care of HIV- infected people, as well as representatives of AIDS interest groups, health policy groups and payer organizations.

What is the role of Kaiser Family Foundation?

The Henry J. Kaiser Family Foundation is a co-convener of the Panel on Clinical Practices for Treatment of HIV Infection. The Foundation provided funding for the meetings to develop the Guidelines and will remain a partner in the Panel throughout its three-year duration.

What is the Panel to Define Principles of Therapy?

The Office of AIDS Research at the NIH convened the Panel to Define Principles of Therapy of HIV Infection to review the current state of knowledge of antiretroviral therapies and prepare a document outlining principles that would guide therapy decisions. The expert panel developed the document, Report of the NIH Panel to Define Principles of Therapy of HIV Infection. Charles C. Carpenter, M.D., professor of medicine at Brown University School of Medicine chaired the NIH panel.

What do the Principles and Guidelines contain and how do they relate to one another?

The Report of the NIH Panel to Define Principles of Therapy of HIV Infection outlines 11 principles based on current scientific knowledge regarding HIV disease, its interaction with the immune system, and implications for decisions in treating people infected with HIV. The Report focuses specifically on such parameters as CD4+ T cell count and the amount of HIV in a person's blood (viral load).

The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents contain recommendations for practitioners to use in providing antiretroviral treatment to HIV-infected adults and adolescents, in light of the new combination therapies and new ways to monitor HIV disease progression. The Guidelines were developed, in part, based on the Principles report. Together, the two documents provide the scientific rationale for therapeutic strategies as well as practical guidelines for implementing the strategies.

Are the Guidelines different from those prepared by other organizations?

The Guidelines represent a unique collaboration between the federal and private sectors, independent of commercial interest, and reflect the current knowledge regarding treatment of retroviral infections. Such knowledge evolves rapidly with the identification of new potential treatments. Unique to the Guidelines is the accompanying Principles document, which provides the scientific rationale.

What key areas do the Guidelines cover?

Key areas include: 1) use of testing for plasma HIV RNA (ribonucleic acid) levels and CD4+ T cell count in guiding decisions for therapy; 2) testing to establish infection; 3) therapy in patients with asymptomatic infection; 4) therapy in advanced disease; 5) special considerations for treatment in patients with advanced disease; 6) interruption of therapy; 7) criteria for changing therapy and alternative treatment options; 8) therapy for acute HIV infection; and 9) considerations for antiretroviral therapy in women who are HIV-infected and pregnant.

What are the major recommendations regarding treatment?

In general, the Guidelines recommend treating patients relatively early and with an aggressive combination drug regimen including protease inhibitors. Unless a change in therapy is necessary due to drug toxicity, adding or changing just one drug at a time in treatment may allow HIV a head start in becoming resistant to the drug, and is therefore not recommended. The Guidelines recommend starting treatment with three drugs and changing at least two drugs when there is reason to consider other therapeutic strategies, such as when HIV levels in the blood increase.

Therapy with only two drugs, in general, is considered less than optimal; all monotherapy is contraindicated. The exception to this is the use of zidovudine (AZT) to prevent perinatal transmission in pregnant women who otherwise do not require antiretroviral therapy for their own treatment.

The Guidelines recommend that physicians regularly measure their patients' CD4+ T cell levels and viral loads to determine whether a change of therapy is needed, and they note that viral load determination is the most important factor to consider in monitoring patients.

Explain the treatment rating system used in the Guidelines.

Each therapeutic recommendation is accompanied by a rating that includes a letter and a Roman numeral. (See Table I. in the Guidelines.) The letter indicates the strength of the treatment recommendation (from "A: strong, should always be offered" to "E: should never be offered") and the Roman numeral reflects the evidence for the recommendation (from "I: at least one randomized trial with clinical endpoints" to "III: expert opinion").

According to the Guidelines, should everyone be on combination therapy?

Combination therapy is most effective at reducing HIV RNA load. Once the patient and physician have decided that antiretroviral therapy is indicated, treatment should be aggressive to meet the goal, consistent with the Principles, of suppressing viral load to undetectable levels. Therefore, three-drug therapy is the preferred choice, and any drug regimen that does not achieve maximal viral suppression is not optimal.

Do the Guidelines enable any physician to determine treatment for HIV-infected people?

The recommendations in the Guidelines are not intended to substitute for the judgment of a physician who is expert in the care of HIV-infected individuals. The Panel underscored that, when possible, the treatment of patients should be directed by a physician with extensive experience in the care of HIV-infected people. When this is not possible, the physician should have access to such expertise through consultations.

What role should the patient play in considering the Guidelines?

The Panel emphasized the necessity of an informed and close partnership between patient and clinician with ongoing patient counseling and education. The multidrug regimens are complicated and require close monitoring by the physician and a strong commitment on the part of the patient.

Do the Guidelines contain recommendations for treatment of pediatric HIV infection?

No. The Panel decided that the issues regarding pediatric HIV infection and treatment are extensive and should be addressed in a separate document.

Will there be updates to the Guidelines?

Once the final Guidelines are completed and issued, the DHHS/Kaiser Family Foundation Panel on Clinical Practices for Treatment of HIV Infection will update the Guidelines periodically as necessary.

Where can I get copies of the document?

The draft Guidelines for the Use of Antiretroviral Agents in HIV- Infected Adults and Adolescents and the Report of the NIH Panel to Define Principles of Therapy of HIV Infection are both announced in The Federal Register, following which there is a 30-day public-comment period. The draft documents are available from the National AIDS Clearinghouse (1-800-458-5231) and on the Clearinghouse Web site (http://www.cdcnac.org) and from the HIV/AIDS Treatment Information Service (Phone: 1-800-448-0440; FAX: 1-301-519-6616; TTY: 1-800-243-7012) and on their Web site (http://www.hivatis.org).

After consideration of the comments, both documents will be published in the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report. A second publication is planned in a peer-reviewed medical science journal.

Where do I send in comments?

Mail comments to: The HIV/AIDS Treatment Information Service, P.O. Box 6303, Rockville, MD 20849-6303.