Published in the Bulletin of Experimental Treatments for AIDS Summer 1999 issue, by the San Francisco AIDS Foundation.

Highlights From Recent Conferences:
-- Main Page
--Antretroviral Therapy

Related Tables to be Added at a Later Date

Summer 1999 Table of Contents

Main Page

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Research Notes

By Harvey S. Bartnof, MD

Federal HIV Treatment Guidelines Updated

The U.S. Department of Health and Human Services has indicated its commitment to keeping the federal HIV treatment guidelines current as new clinical information is presented. (For previous changes to the guidelines, see BETA, January 1999 and July 1998.) As a result of recent clinical trial results presented mainly at the 6th CROI in January, the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents were updated on May 5, 1999. The complete current document including charts is available from the HIV/AIDS Treatment Information Service's website at www.hivatis.org or by calling 800-448-0440. Additions or changes include the following:

Efavirenz combination regimens are now preferred

Even though efavirenz had previously been included as a preferred option, new language in the summary has been added to indicate that efavirenz can be substituted for a protease inhibitor when combined with two nucleoside analogs as first-line therapy for treatment-naive persons.

No different viral load threshold for women

In the section that addresses use of HIV RNA viral load measurements to help determine when to initiate therapy, the guidelines now acknowledge viral load differences between men and women (see BETA, January 1999). Recent studies suggest that viral load measurements in HIV-infected women are approximately 50% lower than those of HIV-infected men with the same rate of CD4 cell decline and HIV disease progression. However, such decreased measurements have not been consistent for all populations of women studied; the observation has been limited to non-pregnant women who became infected with HIV primarily through injection drug use. Moreover, a 50% difference in viral load is within the range of variation of the tests. Therefore, the guidelines state that "no changes in current guidelines for viral load threshold to offer treatment [for women] are recommended."

Abacavir combination regimen included as an alternative option

As a result of clinical trials of abacavir combination therapy for treatment-naive persons (see BETA, April 1999, January 1999 and October 1998), abacavir/AZT/3TC is included as an option for initial therapy. However, this combination of three nucleoside analog reverse transcriptase inhibitors (NRTIs) was listed as an alternative, not as a first-line, preferred option. This is due to a degree of uncertainty surrounding the durability of viral load suppression when using three drugs from the same class. Another consideration was the potentially life-threatening hypersensitivity reaction that can occur in 3-5% of people who take abacavir (see BETA, January 1999). On the other hand, the guidelines acknowledge that an advantage of this combination is the sparing of two other anti-HIV drug classes, the protease inhibitors and NNRTIs. The guidelines continue to state that there are no data regarding the combination of abacavir with either protease inhibitors or NNRTIs.

Hydroxyurea as an adjunct therapy

The guidelines now acknowledge that hydroxyurea may enhance the activity of certain anti-HIV drug combinations, particularly those that include ddI and/or d4T (see BETA, April 1998 and Antiretroviral Therapy, this issue). However, due to side effects and because of a relative lack of controlled trials with hydroxyurea, the guidelines indicate that more information is needed about this drug before definitive recommendations can be made. Hydroxyurea can lead to low blood cell counts, birth defects, neuropathy, hair loss, and a decreased CD4 cell count.

ddI/3TC as a nucleoside analog backbone

In the first-line preferred drug combinations, a new double nucleoside analog component-ddI plus 3TC-has been added to the existing options. However, this addition is listed with only a "moderate strength of recommendation." The other five original double nucleoside analog backbone options are categorized as "strong strength of recommendation."

Additions to nucleoside analog table

Reflecting the FDA's approval of abacavir, this drug is now listed as the sixth drug in its class. A new row has been added to table VII regarding the effects of food on absorption of each of the six nucleoside analog drugs now listed.

Addition to NNRTI table

The NNRTI table also now includes information regarding the effect of food on absorption of each of the three drugs in this class. Food has no effect on the absorption of any of the three drugs, except that high-fat meals should be avoided when taking efavirenz. If delavirdine is taken with either ddI or antacids, dosing should be separated by one hour (ddI has alkaline buffers that will decrease delavirdine absorption). In a footnote, the discontinuation rates in clinical trials due to rash for each of the three NNRTI drugs were 7% for nevirapine (Viramune), 4.3% for delavirdine, and 1.7% for efavirenz.

Additions to protease inhibitor table

The effects of food on drug absorption are now included in the protease inhibitor table. However, there is no new data that was not already known. Specific warnings regarding the combination of ddI with either indinavir or ritonavir are now listed. Indinavir should be taken one hour before or after taking ddI. Ritonavir and ddI should be taken two hours apart. Under saquinavir (Invirase), the guidelines now state that it should only be used with 400 mg of ritonavir twice daily; "Invirase not recommended otherwise." Under route of metabolism, the 3A4 liver enzyme is now listed under each drug as being inhibited. Ritonavir is listed as a "potent 3A4 inhibitor," while the other four protease inhibitors are listed as a "3A4 inhibitor (less than ritonavir)." Under storage information, it is noted that ritonavir capsules should be refrigerated, while the oral solution should not. A new footnote for ritonavir acknowledges that ritonavir capsules are currently unavailable. The newly approved protease inhibitor amprenavir (Agenerase) is not yet listed in the table.

Additional drugs not to be used with anti-HIV drugs

A new row of lipid-lowering drugs not to be used with any of the protease inhibitor drugs or delavirdine has been added to table X. The two drugs not to be used are simvastatin (Zocor) and lovastatin (Mevacor). Many persons taking HAART have developed high blood lipid levels that require therapy with a lipid-lowering agent. Alternatives listed in a footnote that "should be used with caution" include atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), and pravastatin (Pravachol).

A new column has been added for each of the three NNRTIs. Nevirapine has no drugs listed that should not be taken with it. Delavirdine should not be taken with rifampin, rifabutin, astemizole (Hismanal), terfenadine (Seldane), cisapride (Propulsid), antihistamine type 2 blockers, proton pump inhibitors, midazolam, triazolam, dihydroergotamine, or ergotamine drugs. Efavirenz should not be taken with astemizole, terfenadine, cisapride, midazolam, triazolam (Halcion), dihydroergotamine, or ergotamine drugs.

Listed alternatives to astemizole or terfenadine include loratidine (Claritin). Alternatives to midazolam or triazolam include temazepam (Restoril) or lorazepam (Ativan). Alternatives to rifabutin include azithromycin (Zithromax) or clarithromycin (Biaxin) for MAC prevention, and clarithromycin plus ethambutol (Myambutol) for MAC treatment.

Additions to drug interactions table

There are several new additions to the table of drug interactions between each of the protease inhibitor drugs and each of the NNRTIs.

New table listing HIV-related drugs with
overlapping toxicities

Not previously in the guidelines is a new table that will be helpful to both physicians and people with HIV. Eight columns include various organ systems or symptoms (bone marrow toxicity, neuropathy, pancreatitis, kidney toxicity, liver toxicity, skin rash, diarrhea, and ocular effects) and the HIV-related drugs that may be toxic to that organ or lead to the specified symptoms. The drugs include anti-HIV drugs as well as drugs used to prevent or treat HIV-related OIs.

New information about changing therapy
after viral load rebound

In the table entitled "Guidelines for changing an antiretroviral regimen for suspected drug failure," a new bullet point has been added. The new information is that due to a high level of cross-resistance in the NNRTI class of anti-HIV drugs, changing to a different drug in that class should not be done if HIV viral load rebound ("drug failure") occurs.

Use of anti-HIV drugs during pregnancy

With the FDA approval of abacavir, this drug has been added to the pregnancy data table. Abacavir is listed as pregnancy category C, with known birth defects occurring in exposed rodents. This drug reaches unborn rats through the placenta if given to pregnant rats.

New section on adherence

Given the importance of adhering to regimens of anti-HIV therapy to avoid the development of drug-resistant HIV strains, a new section plus four tables and references on adherence are now included in the guidelines.

New section on drug class adverse events

Given that all of the anti-HIV drugs were given FDA approval under an accelerated program, certain side effects were not known until the post-marketing period. These include lactic acidosis (a buildup of lactic acid in bodily tissues) and hepatic steatosis (fat buildup) for the nucleoside analogs; rash (in rare cases fatal) for the NNRTIs; and increased blood sugar with or without diabetes, fat redistribution and blood lipid abnormalities, and increased bleeding in hemophiliacs for the protease inhibitors.

NIH Proposal Could Revolutionize Access to Research Results

• E-biomed would be a new free electronic publishing Website for biomedical research results.
• The Website would allow for more rapid posting of new research results with instantaneous access from anywhere in the world.
• Traditional biomedical journal publishing could suffer due to competition.

In May, Nobel laureate Harold Varmus, MD, director of the National Institutes of Health (NIH), created a storm of controversy regarding his proposal for a new Internet Website called E-biomed that would allow for rapid electronic publishing of new biomedical research results. Publishers of traditional medical journals are shaking in their boots for fear of the potential losses they may incur-both from decreased subscription sales and from decreased advertising revenue. The proposed Website would represent a significant departure from the 300-year tradition of printed medical journals.

Varmus proposed that the NIH sponsor the new Website and assemble a governing board to oversee the project. Under the proposal, standard submission would involve authors submitting a biomedical research paper to a central E-biomed server, indicating which journal editorial board should evaluate the paper. If the paper is accepted by that journal, the paper would be posted immediately on the E-biomed Website and then published weeks to months later in the journal. If the paper is not accepted, the authors could then submit the paper to another journal's editorial board. Under a separate mechanism, authors could submit their paper to a review team of two people designated by the E-biomed governing board who have credentials for reviewing the paper. The purpose of this mechanism would be to exclude any "extraneous or outrageous material." Posting under this second mechanism would likely be a less prestigious option, according to Varmus.

Varmus outlined several benefits of the proposed system, including open access to scientific papers, assembly of personalized journals, improved formatting for the publication of modern biology research, more rapid dissemination of scientific information, reduced costs, the potential for additional signed critiques, the potential for a community site with postings of meeting notices and employment opportunities, the potential for posting of presentations from conferences, and the ability to amend reports or update cohort studies. Varmus acknowledged that the proposal raises many issues, including how to guarantee equity, how the plan should be financed and managed, and who should comprise the E-biomed governing board.

There have already been published responses to Varmus' proposal from the editors of the Lancet and the New England Journal of Medicine. Although these venerable traditional journals may be threatened, the editors welcome an open dialogue and a detailed process for determining potential options. One option would involve a two-and-a-half-year evaluation period. Varmus' full proposal can be viewed at www.thelancet.com/newlancet/reg/nochange/body.nihdiss_1.html.

Varmus, H. E-biomed: a proposal for electronic publications in the biomedical sciences. The Lancet Interactive (www.thelancet.com).

Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee of the San Francisco AIDS Foundation since 1987.

Page last updated 5 October 1999