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NIH Panel Identifies 11 Principles for HIV Therapy

Sharon Scott Morey

The National Institutes of Health (NIH) Panel to Define Principles of Therapy of HIV Infection, under the auspices of the NIH Office of AIDS Research and the Department of Health and Human Services (DHHS), has formulated 11 principles for the treatment of human immunodeficiency virus (HIV) infection. The principles for treatment form the basis for treatment recommendations from a DHHS panel charged with developing recommendations for the use of antiretroviral drugs. This panel was sponsored by the DHHS and the Henry J. Kaiser Foundation. (A summary of the treatment recommendations developed by the DHHS panel will be published in an upcoming "Special Medical Reports.")

Both documents--titled "Report of the NIH Panel to Define Principles of Therapy of HIV Infection" and "Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents"--are published in the April 24, 1998, issue of Morbidity and Mortality Weekly Report. Copies of both reports are available from the Centers for Disease Control and Prevention National AIDS Clearinghouse (800-458-5231) and on the National AIDS Clearinghouse Web site (http://www.cdcnpin.org). The documents are also published in the June 15, 1998, issue of Annals of Internal Medicine.

The following text, excerpted from MMWR, summarizes the 11 principles of treatment developed by the NIH panel:

• Principle 1. Ongoing HIV replication leads to immune system damage and progression to acquired immunodeficiency syndrome (AIDS).

The report states that HIV infection is always harmful, and true long-term survival free of clinically significant immune system dysfunction is unusual. In developed countries, 10 to 11 years is the average interval between HIV infection and progression to AIDS in persons not receiving antiretroviral therapy.

Treatment goals include maintaining immune function in as near a normal state as possible, preventing disease progression, prolonging survival and preserving the patient's quality of life. To achieve these goals, therapy should be initiated before extensive immune system damage has occurred.

• Principle 2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4⁺ T cell destruction, whereas CD4⁺ T cell counts indicate the extent of HIV-induced immune damage already suffered. Regular, periodic measurement of plasma HIV RNA levels and CD4⁺ T cell counts is necessary to determine the risk for disease progression in an HIV-infected person and to determine when to initiate or modify antiretroviral treatment regimens.

According to the report, plasma HIV RNA levels should fall to approximately 1 percent of their initial levels within two weeks of initiating therapy and should reach a nadir (ideally below the level of detection) within approximately eight weeks.

Plasma HIV RNA levels can vary by threefold (0.5 log₁₀) in either direction. With current plasma HIV RNA assays, variability is greater toward the lower limits of sensitivity. Thus, with very low plasma HIV RNA, differences of greater than 0.5 log₁₀ may not reflect a biologic or clinical change.

CD4⁺ counts should be checked regularly in patients not receiving antiretroviral therapy as well as in those receiving such therapy. It is not yet known whether the CD4⁺ level during antiretroviral therapy provides an assessment of immune system function or risk of opportunistic infection equivalent to that of the CD4⁺ level in the absence of antiretroviral therapy.

• Principle 3. Because rates of disease progression differ among HIV-infected persons, treatment decisions should be individualized by the level of risk indicated by plasma HIV RNA levels and CD4⁺ T cell counts.

Data are not yet available to define the degree of therapeutic benefit when CD4⁺ T cell counts are relatively high and plasma HIV RNA levels are relatively low. In late-stage disease, antiretroviral therapy can be of benefit even when CD4⁺ T cell levels do not increase.

• Principle 4. The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection by sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy.

The report explains that when more sensitive HIV RNA assays become available, the goal of antiretroviral therapy should be suppression of HIV RNA levels to below detection by these more sensitive assays. Less profound suppression of HIV replication is associated with a greater likelihood of the development of drug resistance. Continued monitoring of HIV RNA levels is necessary during antiretroviral therapy, because suppression to undetectable levels may be transient.

• Principle 5. The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents with which the patient has been previously treated.

The combination of antiretroviral drugs used when therapy is initiated or changed needs to be carefully chosen because it will influence subsequent options for effective antiretroviral therapy if the chosen regimen fails to result in satisfactory suppression of HIV replication. No currently available antiretroviral drug ensures sufficient and durable suppression of HIV replication when it is used as a single agent. Currently, durable suppression of detectable levels of HIV replication is best accomplished with the use of two nucleoside analog reverse transcriptase inhibitors and a potent protease inhibitor. While the use of two nucleoside analog reverse transcriptase inhibitors may be considered, no combination of two currently available agents of this class has been demonstrated to consistently provide sufficient and durable suppression of HIV replication. Certain combinations of two protease inhibitors have been reported to provide suppression, but experience with this approach is limited.

When a failing regimen is changed, it is important to change more than one component of the regimen. The addition of single antiretroviral agents, even very potent ones, is likely to lead to viral resistance to the new agent.

• Principle 6. Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimal schedules and dosages.

The report states that combination therapy should be initiated with all drugs simultaneously, ideally within one or two days of each other. Recommended doses should be maintained; underdosage with any one agent in a combination or the administration of fewer than all drugs should be avoided. Drug resistance is less likely if all antiretroviral therapy is temporarily stopped than if the dosage of one or more drugs is reduced or one drug of an effective regimen is withheld.

• Principle 7. The available effective drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases future therapeutic constraints.

Before the decision is made to alter antiretroviral therapy because of an increase in HIV RNA, the plasma HIV RNA measurement should be repeated to avoid unnecessary changes based on misleading HIV RNA values. Antiretroviral therapy should be changed when plasma HIV RNA again becomes detectable. When it is necessary to change therapy because of toxicity or tolerance, alternative antiretroviral drugs should be chosen based on their anticipated efficacy and lack of similar toxicities.

• Principle 8. Women should receive optimal antiretroviral therapy regardless of their pregnancy status.

Because the first trimester of pregnancy is the most vulnerable time for teratogenicity, it may be advisable to delay initiation of therapy, if feasible, until 14 weeks of gestation. Women who are receiving antiretroviral therapy at the time pregnancy is diagnosed should continue therapy. The report states that data are insufficient to refute or to support concerns about potential teratogenicity.

Transmission of HIV to the fetus can occur at all levels of maternal viral load. Therefore, use of the recommended regimen of zidovudine alone or in combination with other antiretroviral drugs should be discussed and offered to HIV-infected women who are pregnant.

• Principle 9. The same principles of antiretroviral therapy apply to HIV-infected children, adolescents and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic and immunologic considerations.

Not all antiretroviral drugs that have demonstrated efficacy in combination therapy in adults are available in pediatric formulations. According to the report, antiretroviral drugs selected to treat HIV-infected children should be used only if their pharmacologic properties have been defined in the relevant age group of the patient.

The specific HIV RNA and CD4⁺ T cell criteria for initiating therapy in adults do not apply directly to newborns, infants and young children. Absolute levels of plasma HIV RNA during the first years of life in children are frequently higher than those in adults infected for similar durations. The increased susceptibility to opportunistic infections in children with CD4⁺ counts higher than those in adults indicates that the CD4⁺ T cell criteria suggested as guides for initiation of therapy in adults are not appropriate to guide therapeutic decisions in children.

• Principle 10. Persons identified during acute primary HIV infection should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection by sensitive plasma HIV RNA assays.

Studies suggest that antiretroviral therapy during primary infection may preserve immune function by blunting the high levels of HIV replication and immune system damage. The NIH panel believed that suppressive antiretroviral therapy for acute primary HIV infection should be continued indefinitely until clinical trials provide data to establish the appropriate duration of therapy.

• Principle 11. HIV-infected persons, even those whose viral loads are below detectable limits, should be considered infectious. Therefore, they should be counseled to avoid sexual and drug use behaviors that are associated with either transmission or acquisition of HIV and other infectious pathogens.

No data are available concerning transmission of HIV to others when HIV replication is suppressed by antiretroviral therapy. Similarly, the ability to acquire a multiply resistant HIV variant from another person remains a possibility during suppressive therapy. Persons infected with HIV, including those receiving antiretroviral therapy, should be counseled to avoid behaviors associated with transmission of HIV and other infectious agents.

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NIH Consensus Panel Advocates Increased Access to Treatment for Opiate Addiction

Sharon Scott Morey

Panelists for the National Institutes of Health (NIH) have issued a report recommending a reduction in U.S. Food and Drug Administration (FDA) regulations for methadone maintenance programs. The report, which was prepared at the Consensus Development Conference on treatment for opiate addiction, states that current federal regulations make it difficult, if not impossible, to tailor treatment to the needs of the individual patient. The FDA's treatment regulations for methadone were written in 1972.

In a call to loosen the regulatory reins, the report states, "By prescribing MMT (methadone maintenance treatment) procedures in minute detail, FDA's regulations limit the flexibility and responsiveness of the programs, require unproductive paperwork, and impose administrative and oversight costs greater than what are necessary for many patients. We know of no other area where the Federal government intrudes so deeply and coercively into the practice of medicine." The report notes that therapeutic doses of methadone are now known to be higher than previously thought, but FDA regulations discourage the use of such higher doses.

The panelists of the consensus conference recommend elimination of the federal regulations and establishment of alternative means of oversight, such as accreditation, for improving methadone maintenance treatment programs. The report states that the Department of Health and Human Services "can more effectively, less coercively, and much more inexpensively discharge its statutory obligation to provide treatment guidance. . . by means of publications, seminars, Web sites, continuing medical education and the like."

The panelists also recommend that current laws and regulations be revised to eliminate the extra level of regulation of methadone as compared with other schedule II narcotics. Under the current law, methadone can be dispensed only from facilities that obtain an extra license and comply with regulatory requirements. According to the consensus statement, "These extra requirements are unnecessary for a medication that, when diverted at all, is not often diverted for recreational or casual use but to individuals with opiate addiction who lack access to clinically administered methadone." The panelists believe that by eliminating the extra levels of regulation, more physicians could prescribe methadone, making such treatment available in many more locations.

The two-and-one-half day conference focused on five key questions regarding the treatment of opiate addiction: What is the scientific evidence to support the concept that opiate addiction is a medical disorder? What are the consequences of untreated opiate addiction to individuals as well as society? What is the efficacy of current treatment modalities? What are barriers to effective use of opiate agonists in the treatment of opiate addiction? And, finally, what are the future research areas and recommendations for improving opiate agonist treatment and access to such treatment?

The report states that opiate addiction has been proved to be a medical disorder characterized by predictable signs and symptoms and by a strong tendency to relapse after long periods of abstinence. The opiate addict's craving for opiates induces continued use despite a strong motivation to stop. In addition, research has shown that pathophysiologic changes in the brain occur with continuous exposure to opiates.

According to the report, the consequences of untreated opiate addiction exact a great cost to society. The financial costs of untreated opiate addiction to individuals, families and society are estimated to be approximately $20 billion a year. Health care costs related to opiate addiction are estimated to be $1.2 billion a year. From 1991 to 1995, in major metropolitan areas, the annual number of emergency department visits for opiate-related problems increased from 36,000 to 76,000. During this four-year interval, the annual death rate from opiate-related problems increased from 2,300 to 4,000. Multiple studies have shown that effective treatment of persons addicted to opiates markedly reduces the crime rate. According to the consensus statement, data from 1993 indicate that more than one fourth of inmates in state and federal prisons were incarcerated because of drug offenses. More than 95 percent of opiate addicts report committing crimes during an 11-year at-risk interval.

While methadone is the most commonly used agent for the treatment of opiate withdrawal and maintenance of abstinence, other agents available for detoxification and maintenance include LAAM (levo-alpha acetyl-methadol), buprenorphine and naltrexone. The consensus statement points to evidence that access to treatment of opiate addiction is limited and that large numbers of patients have no access to treatment. Of the 600,000 opiate addicts in the United States, only 115,000 are known to be in methadone maintenance programs. To increase the availability of effective treatment, the consensus panel recommends wider participation by physicians trained in substance abuse and additional funding for the treatment of opiate addiction. "All primary care medical specialties (including general practice, internal medicine, family practice, obstetrics and gynecology, geriatrics, pediatrics and adolescent medicine) should be taught the principles of diagnosing and treating patients with opiate addiction."

The NIH consensus statement on opiate addiction concludes with 11 recommendations for improving the treatment of opiate addiction, as follows:

1. Leadership is needed within the Office of National Drug Control Policy (ONDCP) and related federal and state agencies to inform the public that addiction is a medical disorder that can be treated, resulting in significant benefits to patients and society.
2. Our society must make a commitment to offer effective treatment of opiate addiction to everyone who needs it.
3. Opiate-addicted persons under legal supervision should have access to methadone maintenance treatment. The ONDCP and the Department of Justice should implement this recommendation.
4. Training in the diagnosis and treatment of opiate addiction should be improved for physicians and other health care professionals.
5. Regulations should be reduced for methadone maintenance programs as well as other treatment programs.
6. Funding of methadone maintenance treatment programs should be increased.
7. Methadone maintenance treatment should be required as a benefit in public and private insurance programs.
8. Pregnant women with opiate addiction should be a target population for involvement in methadone maintenance treatment.
9. Methadone maintenance treatment must be culturally sensitive to enhance a favorable outcome for African-American and Hispanic persons.
10. Patients, underrepresented minorities and consumers should be included in bodies charged with policy development.
11. The availability of opiate agonist treatment should be expanded in those states and programs where this treatment option is currently not available.

Copyright © 1998 by the American Academy of Family Physicians.
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