Published in the Bulletin of Experimental Treatments for AIDS January 1998 issue, by the San Francisco AIDS Foundation.

January 1998 Table of Contents

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BETA News Briefs

Liz Highleyman

In This Issue

This issue of BETA features articles on hepatitis, lymphoma and complementary and alternative medicine. For coverage of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the 35th Infectious Disease Society of America (IDSA) annual meeting held in September, see "Selected Highlights from Recent Conferences".

A common reason for anti-HIV treatment failure is the development of drug-resistant virus. An article on resistance in this issue discusses how drug resistance develops and how it can be detected. Although resistance tests may eventually become a useful tool in helping to determine the best anti-HIV drug regimens for individual patients, they cannot yet do so.

Hypersensitivity Reactions Due to Abacavir

Glaxo Wellcome has reported on an unusual side effect experienced by 2-3% of subjects in clinical trials of the experimental nucleoside analog abacavir (1592). The hypersensitivity reactions were characterized by fever, increasingly severe nausea and a generalized rash. Symptoms occurred an average of 11 days after starting the drug, and subsided after subjects were taken off abacavir. However, when subjects started taking the drug again, reactions recurred within hours and were more severe, in some cases including low blood pressure and face/throat swelling. Glaxo recommends that patients who experience a rash and systemic symptoms when taking abacavir should not be re-challenged with the drug.

Updated U.S. Government HIV Treatment Guidelines

In November the U.S. Department of Health and Human Services released updated HIV treatment guidelines. The guidelines were initially released in draft form in June. Changes include longer treatment intervals before undetectable viral load levels are reached and the inclusion of ritonavir plus saquinavir as a recommended initial therapy.

In December the government released revised guidelines for treatment of HIV disease in children and infants, and for treatment of pregnant women. Like the adult guidelines, these guidelines recommend early anti-HIV treatment using combination therapy. The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, the Revised Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection and the Revised Recommendations for Use of Antiretroviral Drugs During Pregnancy for Maternal Health and Reduction of Perinatal HIV Transmission of HIV-1 may be obtained by calling 800-448-0440 or on the web at www.hivatis.org.

News of Treatment Failure and Long-Term Success

The most widely publicized news from ICAAC concerned treatment failure. Stephen Deeks, MD, and colleagues from San Francisco General Hospital reported that virological failure (significantly increased viral load) occurred after 6 months in 53% of 136 people taking highly active antiretroviral therapy (HAART) that included a protease inhibitor.

Many of those for whom the drugs failed had advanced HIV disease, had previously taken several other anti-HIV drugs, did not start new drugs simultaneously or were unable to adhere to their drug regimen. In a second study, Deeks and colleagues showed that those for whom one protease inhibitor-containing regimen had failed tended to have limited success on subsequent regimens. The results of this study emphasize the importance of "getting it right the first time," that is, using a potent protease inhibitor-containing combination of at least 3 drugs as one's first anti-HIV treatment regimen.

Deeks said that we may be seeing the epidemic "split in two." He predicted that those who still had an undetectable viral load after 6 months of therapy would likely continue to do well.

Roy Gulick, MD, and colleagues from New York University Medical Center reported that after 2 years, 22 of 28 patients (79%) receiving a triple combination of AZT, 3TC and indinavir still had an undetectable viral load. They also suggested that HAART improves immune system function.

Double Protease Inhibitor Combinations

Other ICAAC news concerned treatment regimens that include 2 protease inhibitor drugs. Several studies indicate that such regimens -- especially ritonavir plus saquinavir -- may be a good option for people with HIV, especially those who have not previously used protease inhibitors. John Mellors, MD, of the University of Pittsburgh predicted that double protease inhibitor regimens would likely become the preferred standard of care within the next year. Other combinations under study include nelfinavir/saquinavir and nelfinavir/indinavir. See the section on double protease inhibitor combinations in "Selected Highlights from Recent Conferences."

New Saquinavir Formulation (Fortovase) Available

On November 7 the Food and Drug Administration (FDA) granted marketing approval to Hoffmann-La Roche for its new soft-gel capsule formulation of saquinavir. The new formulation will be sold under the brand name Fortovase. Researchers presented data at ICAAC showing that the new formulation is 10 times more bioavailable than the old hard-gel formulation (Invirase) and reaches higher drug levels in the body. Studies showed that the combination Fortovase/AZT/3TC reduced viral load to undetectable levels in 80% of participants, and that Fortovase is as effective as indinavir when used with AZT and 3TC.

Fortovase is now available in pharmacies. Invirase will be taken off the U.S. market by the Spring of 1998, but will remain available on a limited basis from Hoffmann-La Roche. The cost of Fortovase will be $5,700 per year, the same as Invirase.

New Combination AZT/3TC Pill

In late September Glaxo Wellcome announced that FDA had approved a new combination pill containing the nucleoside analog drugs AZT and 3TC. Sold under the brand name Combivir, the new pill contains 300 mg AZT plus 150 mg 3TC. The recommended dosing schedule is 1 pill twice daily. Combivir will reduce the number of pills that must be taken by people using anti-HIV combination regimens that include both AZT and 3TC.

Efavirenz Expanded Access

Efavirenz (brand name Sustiva, also known as DMP-266) is an experimental non-nucleoside reverse transcriptase inhibitor that can be taken just once a day. Study results released at the IDSA meeting showed that, after 48 weeks, 88% of people taking a combination of efavirenz plus indinavir achieved undetectable viral loads.

In September Dupont Merck announced an expanded access program for efavirenz. The program is for people with fewer than 400 CD4 cells/mm3 who have no other viable treatment options; entry criteria will be broadened as more of the drug becomes available. For information call 800-998-6854.

Abacavir Expanded Access Widened

Following pressure from AIDS community activists, Glaxo Wellcome has agreed to provide its experimental nucleoside analog drug abacavir (1592) to more people with HIV. The program will have no specified limits on numbers of people and no set entry requirements. The drug will first be given to people who are not otherwise able to construct a viable treatment regimen. Glaxo announced the changes following an October 13 meeting with community representatives. After the meeting, several activist groups called off their boycott of Glaxo products. The broader expanded access program is expected to be in place by the end of the first quarter of 1998. Physicians may call 800-501-4672 for more information.

Expanded Access for Adefovir

On December 4 Gilead Sciences announced an expanded access program for its experimental nucleotide analog drug adefovir dipivoxil (brand name Preveon, also known as GS 840 and bis-POM PMEA). Adefovir is taken just once a day, and should be taken along with an amino acid called L-carnitine. In early studies, adefovir produced about a 70% reduction in HIV viral load in people who had previously used other anti-HIV drugs.

The adefovir expanded access program is for people with advanced HIV disease who have experienced treatment failure and have limited treatment options. Recipients must have a CD4 T-cell count of 50 or fewer cells/mm3 and a viral load of 30,000 or more copies/mL as measured by the Roche RT-PCR test. For information or to register patients, physicians may call 800-GILEAD-5.

Long-Term Viral Suppression with Hydroxyurea

Two recent reports in scientific journals suggest that hydroxyurea (Hydrea) may be a component of a successful, long-term anti-HIV regimen. The August 30 issue of The Lancet contained a report from France on 2 patients who showed no signs of viral load rebound one year after discontinuing their treatment regimen of hydroxyurea plus ddI. The patients had no detectable HIV in their blood or lymph nodes. A similar report in the September 26 issue of Science concerned a German patient who maintained an undetectable viral load 9 months after discontinuing a regimen of hydroxyurea, ddI and indinavir. Unlike many anti-HIV drugs, hydroxyurea works in resting immune cells, which may act as reservoirs for HIV (for background on hydroxyurea, see BETA, March 1997).

HIV Remains in CD4 T-Cells Despite Treatment

Three independent research teams have found that, even with prolonged, potent anti-HIV therapy, the virus remains hidden in "reservoir" memory CD4 T-cells. Although HIV in these cells is dormant, it can reactivate and infect new cells. Such reactivation can occur when the CD4 cells are stimulated, for example, when faced with infection by a microorganism.

Researchers examined the CD4 cells of people who had been taking potent combination anti-HIV treatment for up to 30 months and who had undetectable blood viral loads. Findings were reported in the November 14 issue of Science and the November 25 issue of Proceedings of the National Academy of Sciences.

These findings call into question the possibility of complete eradication of HIV. It may be necessary for people with HIV to continue antiretroviral therapy indefinitely to keep the virus in check. Fortunately, it appears that the hidden, inactive virus did not develop resistance to anti-HIV drugs.

Natural Immunity

Jay Levy, MD, of the University of California at San Francisco reported on December 1 that specialized immune systems cells protect certain people from HIV infection. These cells, called CD8 cells, destroy HIV before it can begin to replicate in other cells. A recent study by Levy and colleagues found that about half of 56 adults and 31 children repeatedly exposed to HIV through sexual activity or needle sharing, or perinatally, remained free of HIV and anti-HIV antibodies. Levy speculates that CD8 cell activity is controlled by an unknown factor, which he has called "CD8 antiviral factor," or CAF (see BETA, June 1995). Understanding more about how such natural immunity works may help researchers develop an anti-HIV vaccine.

Immune System Recovery

Researchers at the University of California at Los Angeles published results in the October 1997 issue of Nature Medicine that suggest that the immune system can partially recover following successful anti-HIV treatment. Jerome Zack, PhD, and colleagues found that the immune system nay be able to replenish CD4 T-cells that have been depleted by HIV. In their study of mice with destroyed immune systems, new T-cells grew back in all cases. The researchers suggest that the thymus, which is known to be the site of maturation of T-cells in children, may still be intact and active in adults. It is not known whether the newly regenerated T-cells will function normally.

Engineered Virus Reduces HIV Infection of Cells

Researchers at Yale University have found a way to make a common livestock virus called vesicular stomatitis virus (VSV) target and destroy HIV in infected cells. According to the report in the September 5 issue of Cell, this strategy was used to reduce infection of T-cells in the laboratory. The researchers altered VSV by deleting some of its genes and inserting genes for the HIV co-receptors CD4 and CXCR-4 (for more on co-receptors, see "Chemokines and HIV," BETA, March 1997). This enabled the altered VSV to enter and destroy HIV-infected cells; the engineered VSV cannot infect normal human cells because it lacks the necessary surface receptors. At least a year of laboratory and animal testing will likely be necessary before human trials of the new strategy can begin.

Reduced Perinatal HIV Transmission

The Centers for Disease Control and Prevention (CDC) reported in November that perinatal HIV transmission in the U.S. had declined dramatically due to the widespread use (beginning in 1994) of the AZT regimen used in the ACTG #076 study. Between 1992 and 1996, HIV transmission from mothers to infants decreased by 43% in the U.S. See also article on perinatal HIV transmission in this issue.

First Decline in U.S. AIDS Cases

In September the CDC announced the first decline in new U.S. AIDS cases since the beginning of the epidemic. The incidence, or number of new cases, among adults and adolescents fell from 60,620 cases in 1995 to 56,730 cases in 1996, a decline of 6%. In San Francisco, there were 489 new AIDS cases in the first 9 months of 1997, compared to 3,187 new cases at the peak of the local epidemic in 1992.

Nationally, incidence declined 15% among men who have sex with men, but increased among those infected through heterosexual contact (7% increase among women and 11% among men). Among all women, there was a 2% increase in incidence last year. Between 1991 and 1995, newly diagnosed AIDS cases in women increased 63%, with the highest increases among young women and women infected through heterosexual contact. AIDS incidence declined 13% among whites and 5% among Latinos. The incidence rate for African-Americans remained the same.

Experts attributed the decline to successful prevention efforts and new treatments that prolong the period of time between when a person is infected with HIV and when they develop the symptoms of AIDS. Because death rates due to AIDS have also fallen -- a decrease of 23% from 1995 to 1996 -- there has been an 11% increase in the number of people currently living with AIDS.

Increase in Global AIDS Statistics

On December 1, World AIDS Day, the United Nations AIDS program UNAIDS announced that there were now an estimated 30 million people living with HIV/AIDS worldwide and about 16,000 new HIV infections each day. The HIV/AIDS case figure for 1996 was 22.6 million, which according to UNAIDS director Peter Piot was "grossly underestimated." The new figure reflects a change in data collection methods plus an estimated 19% true increase in HIV/AIDS cases.

UNAIDS estimates that new infections increased by 9% from last year, with 5.8 million new infections among adults and 3.1 million new infections among children worldwide. The highest number of people with HIV/AIDS live in sub-Saharan Africa; the most rapidly increasing numbers are in India and Southeast Asia.

Liz Highleyman is Assistant Editor of BETA.

Page last updated 05 February 1998