New Standard of Care for HIV Disease

Four documents released in the last two weeks have formalized a U.S. standard of care for HIV disease. These guidelines outline treatment approaches which are already in use by leading HIV physicians. Their official publication will greatly support efforts to improve the quality of HIV treatment for thousands of patients elsewhere in the medical system who have quietly been receiving seriously inadequate care.

While not every physician will agree with every recommendation, these documents, and their reception so far, seem to reflect an unusually high degree of expert consensus on HIV treatment at this time.

Three of the documents are from government agencies, and are therefore expected to have the most impact on decisions about what treatments will be reimbursed by third-party payers. The fourth, the result of an independent effort, organized by the International AIDS Society, USA, to develop recommendations for HIV care, is consistent with the government reports. The IAS document may have more distribution initially, because it has been published in JAMA (JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION), June 25, 1997.

The four documents are:

(1) REPORT OF THE NIH PANEL TO DEFINE PRINCIPLES OF THERAPY OF HIV INFECTION, released by the U.S. Department of Health and Human Services. It was prepared by a panel of 23 experts chaired by Charles Carpenter, M.D., of Brown University.

(2) A companion document, GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS OF HIV-INFECTED ADULTS AND ADOLESCENTS also released by the U.S. Department of Health and Human Services. These guidelines were developed by a panel of 24 experts chaired by Anthony S. Fauci, M.D., of the U.S. National Institutes of Health, and John G. Bartlett, M.D., of Johns Hopkins University. (Dr. Carpenter and one other panelist, Robert T. Schooley, M.D., of the University of Colorado, were also on the Principles panel.)

Both of these reports were released as drafts for public comment; after the comment period ends on July 21, they may be revised before becoming final. It is unlikely that major changes will occur.

(3) 1997 USPHS/IDSA GUIDELINES FOR THE PREVENTION OF OPPORTUNISTIC INFECTIONS IN PERSONS INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS, published in the MMWR (the MORTALITY AND MORBIDITY MONTHLY REPORT, of the U.S. Centers for Disease Control and Prevention), June 27, 1997. This is the final version of these recommendations, which have already gone through a comment period. The recommendations were developed by a working group of more than 40 experts.

(4) ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN 1997: UPDATED RECOMMENDATIONS OF THE INTERNATIONAL AIDS SOCIETY-USA PANEL, published June 25 in JAMA. These recommendations were prepared by a panel of 13 expert physicians, seven of whom were also on the NIH Panel to Define Principles of Therapy in HIV Infection.

It would be impossible to meaningfully summarize these reports in a short article. But we can indicate what kinds of information they contain. REPORT OF THE NIH PANEL TO DEFINE PRINCIPLES OF THERAPY OF HIV INFECTION outlines current scientific knowledge about HIV disease, and 11 principles on which treatment should be based. Each of the 11 is discussed in detail. Overall there are 28 pages of text, eight pages of illustrations and tables, over a hundred references, and a list of the names and affiliations of the panelists. Because specific guidelines such as particular drugs are not included, it is believed that this document will not need to be updated very often.

The 11 principles are:

1. Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual.

2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4+ T cell destruction, while 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 of disease progression in an HIV-infected individual and to determine when to initiate or modify antiretroviral treatment regimens.

3. As rates of disease progression differ among individuals, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4+ T-cell counts.

4. The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of 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.

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 treated previously.

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

7. The available effective antiretroviral 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.

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

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

10. Persons with acute primary HIV infections should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays.

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

(2) GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS OF HIV-INFECTED ADULTS AND ADOLESCENTS have more specific treatment and testing recommendations. We cannot summarize the report here, but the headings and subheadings outline its scope:

* Introduction

* Use of Testing for Plasma HIV RNA Levels and CD4+ T Cell Count in Guiding Decisions for Therapy

* Established Infection

-Considerations for Initiating Therapy in Patients with Asymptomatic HIV Infection

-Initiating Therapy in the Patient with Asymptomatic HIV Infection

-Initiating Therapy in Advanced HIV Disease

-Special Considerations in the Patient with Advanced Stage Disease

* Interruption of Antiretroviral Therapy

* Considerations for Changing a Failing Regimen

-Criteria for Changing Therapy

-Therapeutic Options When Changing Antiretroviral Therapy

* Acute HIV Infection

-Whom to Treat During Acute HIV Infection

-Treatment Regimen for Primary HIV Infection

-Patient Followup

-Duration of Therapy for Primary HIV Infection

* Considerations for Antiretroviral Therapy in the HIV-Infected Pregnant Woman

* Conclusion

Unfortunately these draft antiretroviral guidelines do not discuss treatment of children, leaving that for later.

This report has 16 pages of text, 18 pages of illustrations and tables, and 34 references.

(3) 1997 USPHS/IDSA GUIDELINES FOR THE PREVENTION OF OPPORTUNISTIC INFECTIONS IN PERSONS INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS is full of useful information, not only about preventive drug treatments, but also about food safety, pets, travel, childhood immunization schedules, and the cost of drugs and vaccines. Seventeen different infections and classes of infections are discussed in separate sections. Tables include: CD4 cell counts for children up to 12 years (which are different from CD4 cell counts for adults); drugs and doses for adults and adolescents, and for children; immunization schedules for HIV-infected children, noting where they are the same as for HIV-negative children and where they are different; and a summary of recommendations for preventing exposure (sexual, environmental and occupational, pet-related, food- and water-related, and travel-related). There are 27 pages of text, 18 pages of tables, and 24 references.

(4) ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN 1997: UPDATED RECOMMENDATIONS OF THE INTERNATIONAL AIDS SOCIETY-USA PANEL is a shorter document, 8 pages in JAMA, including 61 references, and tables. The headings and subheadings are:

* Scientific Rationale for Updated Recommendations

* Initiating Antiretroviral Therapy

-When to Initiate Therapy

-Initial Antiretroviral Regimens

* Changing Antiretroviral Therapy

-Considerations for Changing Therapy

-What To Change To

* Special Considerations

-Primary Infection

-Postexposure Prophylaxis

-Perinatal Transmission

* Summary

There are no major inconsistencies between these RECOMMENDATIONS, and the Federal antiretroviral GUIDELINES. There are minor differences; for example, note the following discussions from the respective sections on when to start therapy. From the IAS RECOMMENDATIONS:

"Therapy is now recommended for all patients with plasma HIV RNA concentrations greater than 5000 to 10,000 copies/ml regardless of CD4+ cell count... Therapy should be considered for all subjects with HIV infection and detectable plasma HIV RNA who request it and are committed to lifelong adherence to the necessary treatment. For patients with low plasma HIV RNA levels and high CD4+ cell counts, therapy might be safely deferred in the short term with reevaluation of plasma HIV RNA level every 3 to 6 months. A small minority of subjects who may be true long-term nonprogressors or slow progressors might be identified with this approach... Therapy continues to be recommended for patients with symptomatic HIV disease or with CD4+ cell counts below [500], particularly below [350]. The latter recommendation is especially important in situations in which HIV RNA assays are not available."

From the (Federal) GUIDELINES:

"In general, any patient with less than 500 CD4+ T cells/mm(3) or greater than 10,000 (bDNA) or 20,000 (RT-PCR) copies of HIV RNA/ml of plasma should be offered therapy. However, the strength of the recommendation for therapy should be based on the readiness of the patient for treatment as well as a consideration of the prognosis for disease-free survival as determined by viral load, CD4+ T cell count (Table IV and Figure 1), and the slope of the CD4+ T cell count decline."

[Notes: (1) Figure 1 from the GUIDELINES is reproduced here (page 5); it shows how the risk of disease progression depends on viral load and CD4 cell count. (2) Two viral load tests are now in common use in the U.S.: bDNA and RT-PCR. The tests are different; the values reported by the current PCR test tend to be about twice as high on the average as those reported by the bDNA test currently in use. That is why the GUIDELINES gives two numbers for starting therapy -- greater than 10,000 copies if the bDNA test is being used, and 20,000 if the result is from PCR. Each patient should use one kind of test consistently, to show changes in viral load; the two-fold correction factor is for averages, and would not be reliable for an individual, since the tests may respond differently to different strains of HIV.]

Why are there two slightly different treatment standards, instead of one? Much of the reason is historical. The IAS panel started first, and released a draft of its guidelines a year ago, at the XI International Conference on AIDS, July 1996 in Vancouver. But that draft had been delayed for months by a publication embargo, and when it became public it was already widely considered obsolete, because its recommendations for treatment were not aggressive enough in light of new knowledge about HIV disease. The panel continued its work, and produced the current draft, which does reflect the new knowledge.

Meanwhile, the U.S. Public Health Service, which often takes the lead on such matters, needed to establish its own guidelines process -- partly in order to develop consensus within the government on what treatment should be reimbursed.

How To Get Copies of These Reports

You can obtain copies of the three government reports by mail, from the HIV/AIDS Treatment Information Service, 800/448-0440 (the opportunistic infection guidelines need to be ordered separately), or from the CDC National AIDS Clearinghouse, 800/458-5231. In case you need the National AIDS Clearinghouse document numbers, they are D936 (the PRINCIPLES, and the GUIDELINES, in one package), and D938 (the final opportunistic infection guidelines, which are published by the CDC in its weekly journal, the MMWR, June 27, 1997).

Note that the PRINCIPLES, and the antiretroviral GUIDELINES, are currently drafts, which will be superseded when the final versions are published in MMWR, probably later this year.

The IAS RECOMMENDATIONS were published in JAMA on July 1, 1997, and could be found in a medical library.

If you have access to the World Wide Web, you can get all four documents immediately. The PRINCIPLES and the antiretroviral GUIDELINES were announced in the FEDERAL REGISTER on June 19, and at that time they were released on the Web site of the National AIDS Clearinghouse, http://www.cdcnpin.org/, and also on the Web site of the HIV/AIDS Treatment Information Service, http://aidsinfo.nih.gov/. On these sites the documents are published as "PDF" files to be read by the Adobe Acrobat(TM) reader -- a program which can be downloaded free for all common computers. Some Web browsers can open PDF files automatically.

[Note: Some people have had difficulty using the PDF files, because of unfamiliarity with the computer procedures involved. To make these reports more conveniently available online, they have been converted unofficially so that they can be read directly on the World Wide Web; these versions are posted at the site of Healthcare Communications Group, (website no longer available). Here they can be read like anything else on the Web, with no need to download the PDF files or the Acrobat reader.]

The opportunistic infection guidelines can be found at http://www.cdc.gov/mmwr/mmwrsrch.htm;  this site has current and back issues of the MMWR, in the PDF format. The opportunistic infection guidelines are in the June 27, 1997 issue (volume 46, number RR-12).

The IAS guidelines are currently online at the JAMA HIV/AIDS Information Center, http://jama.ama-assn.org/.

Public Comment Period

Two of the Federal documents (PRINCIPLES, and antiretroviral GUIDELINES) were released in draft form for a 30-day public comment period. Written comments must be postmarked by July 21, and mailed to: The HIV/AIDS Treatment Information Service, P.O. Box 6363, Rockville, MD 20849-6303.

Illustration -- Likelihood of AIDS

In our print edition we reproduced a graph, "Likelihood of Developing AIDS Within 3 Years," which is Figure 1 in the antiretroviral GUIDELINES. This illustration would make an excellent poster or postcard to show the importance of getting medical care for HIV infection. It can be found through (website no longer available) (we have not published the direct link, because the site is now being reorganized, and the link will change).