Published in the Bulletin of Experimental Treatments for AIDS June 1997 issue, by the San Francisco AIDS Foundation.

June 1997 Table of Contents

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News Briefs

by Liz Highleyman and Mark Bowers

In This Issue

On June 19, the Department of Health and Human Services and the National Institutes of Health released new guidelines for the treatment of HIV infection; the guidelines are reprinted in this issue of BETA. The issue also contains the executive summary of a report on primary HIV infection by the University of California's Universitywide AIDS Research Program and a consensus statement from the San Francisco AIDS Foundation's Scientific Advisory Committee on the new soft-gel capsule formulation of saquinavir (Invirase).

Features include articles on nausea and on diarrhea, two of the most common and distressing symptoms related to HIV infection and anti-HIV therapy. The issue also includes a 2-part report on the National Conference on Women and HIV, held May 4-7 in Pasadena, CA.

Combination Therapy and HIV Eradication Studied

Two articles in the May 8 issue of Nature magazine show that relatively few infected cells can sustain HIV infection. Tae-Wook Chun and other researchers looked at the effect of treatment on HIV levels in the lymph nodes of patients receiving potent combination antiretroviral therapy, and determined that a very small number of HIV-infected cells can produce from 10² to 10⁶ virions (viral particles) per cell. A type of long-lived T-cell called a memory cell can harbor HIV genetic material, which may begin to replicate when the T-cell is activated.

David Ho, MD, and other researchers at the Aaron Diamond AIDS Research Institute established mathematical models of HIV infection that project the time to possible eradication of HIV from the plasma of an individual receiving potent combination antiretroviral therapy. The researchers reported an initial rapid drop in viral load, following by a second slower decline. They estimated that it would take 2.3-3.1 years to eliminate HIV from the blood. Longer treatment may be needed to eliminate HIV from probable sanctuary sites such as the brain and gonads.

CCR5 Mutation Not Always Protective

Three recent case reports indicate that people with a double CCR5 mutation are not completely protected from HIV infection. Reports in the past year had seemed to indicate that people who possessed 2 mutant copies of the gene coding for the CCR5 chemokine receptor could not be infected with HIV, because the virus uses the co-receptor along with CD4 to enter macrophages, typically the first cells infected by HIV (see Chemokines and HIV in the March 1997 issue of BETA). It has now been shown that HIV can still infect such persons by entering T-cells (which are typically infected later in the disease process). A team of Australian researchers reported on one such case in the February 28 issue of Nature Medicine; other cases have been described in the U.S. and France. For more information, see Research Notes in this issue.

Traditional Approval for 3TC

The Food and Drug Administration (FDA) recently granted traditional approval to Glaxo Wellcome's 3TC (Epivir). The drug had previously been granted accelerated approval in November 1995. The wider approval follows the newly released results of the international CAESAR study, which showed that the combination of 3TC and AZT (Retrovir) decreases disease progression and death in people with AIDS. Accelerated approval for 3TC was based on data showing a positive effect on surrogate markers for disease progression, while full approval is granted when studies show a positive clinical effect (a decrease in morbidity or mortality).

Expanded Availability for Indinavir

Merck and Company announced May 14 that its protease inhibitor drug indivanir (Crixivan) will be sold at pharmacies nationwide. Due to supply limitations, the drug had previously been available only through Stadtlander's Pharmacy, a Pittsburgh mail-order company. Merck has completed a new production plant and plans further expansion to meet increasing demand for the drug. A steady supply of the drug is necessary because sporadic use can lead to the development of drug-resistant HIV. Merck will continue to track the number of patients receiving the drug.

Oral Sporanox Approved

Janssen Pharmaceuticals announced marketing approval for the oral formulation of their antifungal drug itraconazole (Sporanox) for the treatment of oral candidiasis (thrush). Studies have shown that the drug is well tolerated and may be an effective treatment for fluconazole-resistant candidiasis. Call 1-800-544-2987 for reimbursement assistance.

Generic Acyclovir Approved for Sale in U.S.

IVAX Pharmaceuticals announced that marketing approval has been received for a generic version of acyclovir. Glaxo Wellcome's 7-year exclusive patent to market acyclovir in the U.S. under the brand-name of Zovirax expired in April 1997.

Bristol-Myers Squibb Acquires Rights to 2 New Protease Inhibitor Drugs

Bristol-Myers Squibb Company announced on May 29 that it has acquired the development and marketing rights to 2 new protease inhibitor drugs. The compounds -- known as BMS-234475 (CGP-61755) and BMS-232623 (CGP-73547) -- were discovered by Novatis Pharma AG. Squibb plans to initiate Phase II clinical trials of the first agent; the other is in the early stages of preclinical development.

Nelfinavir Added to California ADAP

The newest protease inhibitor drug was recently added to the California AIDS Drug Assistance Program (ADAP) formulary. Nelfinavir (Viracept), which was approved in March, was added to the formulary on May 9, the quickest addition to date. ADAP provides drugs for free or at reduced cost to patients who meet certain eligibility requirements. Two other new drugs -- nevirapine (Viramune), a non-nucleoside reverse transcriptase inhibitor, and cidofovir (Vistide), a treatment for cytomegalovirus (CMV) disease -- were added to the formulary on April 24. For information about ADAP in San Francisco, call 415-863-AIDS.

Expanded Medicaid Coverage for HIV Proposed

The Clinton administration plans to expand the federal Medicaid program to cover low income people with HIV who do not have disabling symptoms. Current Social Security Administration regulations require that a person with HIV have symptomatic disease that renders them "unable to engage in any substantial gainful activity."

Vice President Al Gore said that he believes the move will be cost-effective. Early treatment with promising new drug combinations has been shown to reduce the incidence of symptomatic illness, leading to decreased hospital costs. Department of Health and Human Services officials believe that persons receiving antiretroviral therapy may be less infectious (less likely to transmit the virus), and that there is a "strong public health rationale" for expanded eligibility.

The administration plans to implement the change through state demonstration projects rather than by attempting to change the Medicaid laws. It is estimated that 50% of people with AIDS rely on Medicaid coverage at some point in their illness.

DMP 266 Shows Promising Results

New data from a Phase II study of DuPont Merck's non-nucleoside reverse transcriptase inhibitor DMP 266 showed that the drug reduces viral load levels. Thirty persons participated in the study and received a combination of indinavir and DMP 266; 9 of the participants also received d4T (Zerit). At 42 weeks, 83% of participants receiving the combination achieved undetectable HIV RNA viral loads (limit of detection 400 copies/mL). The average viral load reduction was 2.5 logs and the average increase in CD4 count was 140 cells/mm³. The new drug appeared to be well-tolerated; no difference in adverse events was reported in those taking the combination compared to those taking indinavir alone.

PMPA Reduces Viral Load

Data from a Phase I/II trial has shown that PMPA reduces participants' viral load by 1.1 log (90%). Twenty participants each received 8 intravenous doses of the drug. This was the first human study of PMPA, a nucleotide analog drug developed by Gilead Sciences of Foster City, CA. At the 2 dose levels studied, HIV RNA levels decreased continuously throughout the study period; no significant side effects were reported. Gilead stopped the trial earlier than expected in order to focus on the development of an oral formulation of the drug.

CMV Retinitis May Develop Following Antiretroviral Therapy

A University of California at San Francisco (UCSF) study has shown that people with HIV may develop cytomegalovirus (CMV) retinitis after receiving antiretroviral therapy including protease inhibitor drugs. Five people developed retinitis after successful antiretroviral therapy that raised their CD4 counts to approximately 200 cells/mm³ (typically CMV retinitis develops in persons with CD4 counts under 50 cells/mm³). Study author Mark Jacobson, MD, suggested that retinitis might develop as a result of an inflammatory response that comes into play as CD4 cell numbers increase.

Resistance Testing Available

Specialty Laboratories in Santa Monica, CA, announced in May the development of a test to measure HIV resistance to antiretroviral drugs. The HIV-1 GenotypR PLUS blood test is available to physicians who want to pinpoint HIV mutations present in their HIV positive patients. The DNA sequencing test can measure resistance to AZT, ddI, ddC, d4T, 3TC and the 4 approved protease inhibitor drugs. Many health insurance plans will cover the $400 polymerase chain reaction (PCR) test.

Another genotypic test was launched May 29 by International Murex Technologies Corporation and Innogenetics NV. The LiPA HIV-1 RT test simultaneously identifies mutations associated with resistance to the nucleoside analog drugs AZT, ddI, ddC, 3TC and abacavir 1592; a Murex protease inhibitor resistance test is under development.

Genotypic testing looks for changes in the genetic structure of HIV that are associated with resistance to antiretroviral drugs. Physicians must then know which mutations correspond with resistance to which drugs -- an area in which expertise is currently sorely lacking -- in order to tailor combination therapies to suit individual patient needs, eliminating those drugs to which resistance has already developed. Some drugs remain clinically useful despite the development of characteristic resistance mutations.

Protease Inhibitors Approved for Children

In March, FDA approved 2 protease inhibitor drugs for use in children with HIV. Abbott Laboratories' ritonavir (Norvir) had previously been approved for use in adults. Agouron's nelfinavir (Viracept) was approved simultaneously for use in adults and children. Ritonavir is available in a liquid formulation for children, and nelfinavir is available in a vanilla-flavored powder.

Triple Combination Therapy in Children

In an article in the May 8 issue of The New England Journal of Medicine, Katherine Luzuriaga, MD, and colleagues reported that triple combination therapy with AZT, ddI (Videx) and nevirapine reduced viral load by 1.5 log in HIV-infected infants. The regimen was well tolerated and no serious adverse side effects were reported. Suppression of HIV replication was sustained over 6 months of treatment. The researchers concluded that combination antiretroviral therapy is most effective when started early in HIV infection.

HIV in Infants

Another article in the May 8 New England Journal of Medicine reported on a study of the pathogenesis of HIV infection in perinatally infected infants. The study looked at 106 HIV positive infants at several medical centers in the U.S. William Shearer, MD, Thomas Quinn, MD, and colleagues found that HIV replicates quickly in infants. By 1 month of age, the infants had a median viral load of 150,000 copies/mL (80% of babies in this study were born to women who did not take AZT during pregnancy or delivery). The researchers concluded that infants with high viral loads in the first months of life are at risk for rapid HIV disease progression, and suggested early antiretroviral treatment.

AZT Prevents PHT in Women with Advanced AIDS

AZT is effective in reducing the rate of perinatal HIV transmission (PHT) even in women at relatively advanced stages of AIDS, according to a recent report from the National Institutes of Health. The earlier ACTG 076 study showed that AZT reduced the rate of perinatal transmission by two-thirds, but the women in that study had relatively intact immune systems, with CD4 cell counts above 200 cells/mm³.

HIV and Cancer

The first National AIDS Malignancy Conference sponsored by the National Cancer Institute (NCI) was held in April. Valerie Beral, MD, of Oxford University reported that HIV infection increases the risk of developing Kaposi's sarcoma, non-Hodgkins lymphoma, cancer of the eye, and in situ carcinoma of the cervix and anus. While the risk of cervical neoplasia is increased in women with HIV, invasive cervical cancer is not. Leiomyosarcoma, a previously rare cancer, is now the second most common cancer in HIV-infected children. Studies suggest that people with HIV/AIDS have a higher incidence of lung, testicular and certain other types of cancer, but not of breast or liver cancer (although some unusual cases of breast cancer have been reported in HIV positive women; see the report from the National Conference on Women and HIV ). Richard Klausner, MD, of the NCI said that 30% or more of people with AIDS also develop cancer. Many cancers in people with HIV are believed to be linked to infection with other viruses. For further information on anal cancer in people with HIV, see our next issue (September 1997).

AIDS Rates in U.S. Cities

The Centers for Disease Control and Prevention (CDC) recently released new figures on the number of AIDS cases in various U.S. cities. The data was presented in the April 18 issue of Morbidity and Mortality Weekly Report. The cities with the 10 highest rates of AIDS cases per 100,000 people are New York City (120.1), Miami, FL (99.4), Jersey City, NJ (97.7), San Francisco (95.0), West Palm Beach, FL (85.4), Ft. Lauderdale, FL (83.6), Newark, NJ (73.9), San Juan, Puerto Rico (70.4), Baltimore, MD (61.6) and Baton Rouge, LA (58.2). The numbers include all existing cases in 1996, not only newly reported AIDS diagnoses. The figures reflect a shift in the epidemic toward the South. Although the New York City AIDS case rate is well above the rate of the next highest city, it held steady over the past year, while the rate for Baton Rouge tripled. Several cities (including Miami, Jersey City, Dallas, TX and New Haven, CT) saw a decline in absolute case numbers from 1995 to 1996.

U.S. Tuberculosis Rates Decline

In 1996, for the fourth year in a row, tuberculosis rates in the U.S. declined. The total number of cases reported was down by 1,533, a decrease of 7%. Tuberculosis has been associated in some studies with worsening HIV disease progression, and is the major cause of death of people with AIDS worldwide.

Liz Highleyman is on the editorial staff of BETA. Mark Bowers is Managing Editor of Treatment Publications at the San Francisco AIDS Foundation.

Page last updated 2 July 1997