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

April 1999 Table of Contents

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News Briefs

By Liz Highleyman

In This Issue

This issue of BETA features articles on metabolic side effects associated with anti-HIV therapy. This issue also presents two articles concerned with the current, somewhat tenuous state of HIV/AIDS clinical research today: "Volunteering for Clinical Trials," outlines issues particularly relevant to a person with HIV considering becoming involved with a clinical study, while "Current Challenges to HIV Research," delineates researchers' concerns. The issue also includes news summaries specific to women and HIV.

Amprenavir (Agenerase) Receives FDA Approval

On April 15 the Food and Drug Administration (FDA) approved amprenavir (Agenerase, formerly known as 141W94 and VX-478), a second-generation protease inhibitor. The drug was discovered by Vertex Pharmaceuticals and is being marketed by Glaxo Wellcome. Amprenavir is taken as eight 150 mg capsules twice daily with or without food, although it should not be taken with high-fat foods or vitamin E supplements. A liquid formulation is available for children.

In clinical studies amprenavir appears to be a potent inhibitor of HIV, and early data indicate that the drug can penetrate the blood-brain barrier. The most commonly reported side effects are nausea, vomiting, diarrhea, fatigue, headache, skin rash, and tingling around the mouth. Persons taking hormonal contraceptives or rifabutin will need to make special dose adjustments and those with sulfa allergies may have difficulty taking the drug; such persons should carefully discuss using amprenavir with their doctor.

Amprenavir cannot be taken with astemizole (Hismanal), bepridil (Vascor), cisapride (Propulsid), midazolam (Versed), triazolam (Halcion), rifampin, or ergotamine medications. Amprenavir's resistance profile appears different from those of the other approved protease inhibitors, and preliminary studies suggest that the use of amprenavir in a combination regimen will not rule out the later use of another drug in its class. For more information, see page 44 in this issue.

The expanded access program will continue to supply the drug to participants enrolled before approval until it is available on local formularies. In California, amprenavir was approved for the ADAP formulary on April 17.

CROI 1999: A Few New Insights

The 6th Conference on Retroviruses and Opportunistic Infections (CROI) was held January 31-February 4 in Chicago. The conference did not produce news of any major treatment breakthroughs, but did provide some promising evidence that certain anti-HIV drug combinations continue to be effective for longer periods of time.

New options with different combinations were also reported. Along with these positive reports, however, came more disturbing news about late treatment failures in persons who had been responding favorably to the drugs, and the recognition that body fat redistribution may also be associated with certain non-protease anti-HIV therapies. In light of these results, many researchers are increasingly focused on new strategies, such as intermittent treatment (for those newly infected with HIV) and therapies intended to strengthen the immune response.

Some researchers have suggested that stopping and restarting anti-HIV therapy among newly infected persons may allow the immune system to better fight the virus, and may provide clues to the development of an effective anti-HIV vaccine. In addition, new information regarding very short treatment courses for pregnant HIV positive women appears quite promising. Detailed coverage of CROI begins on page 33.

Protease Inhibitors and Sildenafil (Viagra) Should Not Be Combined

On April 28 the European Agency for the Evaluation of Medicinal Products (EMEA) issued a warning about potential adverse effects resulting from taking the impotence drug sildenafil (Viagra) while also taking protease inhibitors. In particular the combination of ritonavir and sildenafil was noted to result in signficantly increased plasma levels of sildenafil for up to 24 hours after sildenafil was taken.

The root of the problem lies in the fact that ritonavir inhibits the P450 metabolic pathway. Other potent inhibitors of the metabolic pathway include saquinavir (Invirase), erythromycin, and the antifungal drugs ketoconazole and itraconazole. While the EMEA essentially recommends that persons using protease inhibitors refrain from using sildenafil altogether, the agency statement adds that if sildenafil is "absolutely necessary" for a person taking protease inhibitors, that person should not exceed 25 mg of sildenafil per 48-hour period. The statement also contains a reminder that the current recommended starting dose is 25 mg.

Some African-Americans Carry Gene that Increases HIV Susceptibility

Researchers reported at CROI that one-fifth of African-Americans carry a genetic mutation that may make them more susceptible to HIV infection. This population is six times more likely than whites to become infected with HIV if exposed to the virus. Leon Kostrikis, MD, and John Moore, MD, of the Aaron Diamond AIDS Research Center in New York reported that the mutation occurs in the gene that encodes the CCR5 co-receptor, which allows certain strains of HIV to enter human host cells.

The researchers studied 1,500 babies born to women with HIV and found that the majority of HIV-infected babies that were black carried the newly discovered mutation. Unlike CCR5 mutations discovered previously, this new mutation--dubbed CCR5-59356-C/T-- appears to increase rather than decrease susceptibility to HIV infection. The findings may help explain why a greater proportion of African-Americans is affected by HIV/AIDS compared to other racial/ethnic groups.

In related news researchers from the National Cancer Institute reported in the December 4, 1998 issue of Science that another variation of the gene encoding CCR5 can promote the rapid progression of HIV disease, perhaps by increasing the number of co-receptors on host cells, thus allowing more virus to enter.

A study of 2,400 participants found that 43% of blacks and 50% of whites carried the CCR5-P1 variant. The average time to disease progression was three and a half years in people who carried two copies of the genetic mutation, compared to an average of ten years among the HIV-infected population as a whole.

Two New HIV Blood Tests

In early March the FDA approved a more sensitive version of a commonly used polymerase chain reaction (PCR) HIV viral load blood test. The new test, Roche Molecular Systems' Amplicor HIV-1 Monitor Ultrasensitive, can detect viral loads as low as 50 copies/mL of blood plasma. The test has been used by researchers in clinical trials since 1997, but has not been available commercially.

The new test is ten times more sensitive that the previous Amplicor test, which can measure viral loads as low as 500 copies/mL. The approval should allow for coverage of the ultrasensitive test under government assistance programs, and Roche has expanded its patient assistance program to include the new test (call 1-888-TEST-PCR for information about the program).

In related news the FDA is examining a new procedure for testing the supply of donated blood. Currently, blood is typically screened using an HIV antibody test that shows a positive result 22 days after infection. The new test, which detects nucleic acids, can reveal viruses such as HIV and hepatitis C before antibodies develop. The test can identify HIV 11 days after infection, reducing the detection time by half.

The new test is already used by some blood centers, and on April 12 was adopted for use by the American Red Cross. The new test costs $6-8 more per pint than the current standard test. Although the risk of acquiring HIV through a blood transfusion is very low, the new test could make the procedure even safer; the FDA estimates that the nucleic acid test could prevent 12 HIV infections and 84 hepatitis C infections per year in the U.S.

Researchers Trace HIV to Chimpanzees

On the opening day of CROI, Beatrice Hahn, PhD, made headlines with news that HIV originated in chimpanzees in western equatorial Africa. The report also appeared in the February 4, 1999 issue of Nature. A subspecies of chimpanzees carries a variant of the simian immunodeficiency virus (SIV) called SIVcpz, which is very similar genetically to the HIV-1 strains known to infect humans (HIV-2 is believed to have originated with an SIV strain than infects sooty mangabey monkeys).

Hahn and colleagues believe that the chimpanzee virus "jumped" from chimpanzees to humans on at least three occasions, perhaps due to the butchering and eating of chimpanzee meat. The habitat of Pan troglodytes troglodytes, the chimpanzee subspecies that carries SIVcpz, coincides with the area where the human HIV epidemic originated. HIV probably first infected humans in the late 1940s or early 1950s.

The three distinct cross-species transfers are believed to have been responsible for the three major subgroups of HIV (M, N, and O). The chimpanzees do not suffer immune system decline despite SIV infection, leading researchers to hope that the discovery will lead to clues about controlling HIV disease in humans. However, the chimpanzee species is endangered due to poaching and habitat destruction, making such research a challenge.

Abbott Seeks Approval of New Ritonavir Capsule

In March, Abbott Laboratories submitted an application to the FDA and the European Agency for the Evaluation of Medicinal Products seeking approval to produce and market a new capsule formulation of its protease inhibitor drug ritonavir (Norvir). Abbott announced last June that it had discovered manufacturing difficulties with the previous capsule formulation which involved crystal formation that affected the way the capsules dissolve. Since existing supplies ran out last fall, only the liquid formulation of ritonavir has been available; that formulation is unpopular due to its notoriously bad taste.

The new formulation is a soft-gel capsule that was in development prior to the manufacturing problem. Liquid ritonavir will remain available to all who need it until the new capsule is approved.

FDA Approves KS Treatment

In early February the FDA approved Ligand Pharmaceuticals-- Panretin gel for the treatment of Kaposi's sarcoma (KS). The vitamin A-based gel, a form of retinoic acid, is self-administered to KS lesions on the skin. According to clinical trial results presented by Ligand, the gel reduced or eliminated lesions in one-third of participants. Side effects of Panretin gel include a rash, which may be painful.

In related news, scientists confirmed in December that Kaposi s sarcoma-associated herpesvirus (KSHV, also known as HHV-8) plays a role in causing KS. Researchers from the Amsterdam Cohort Studies on HIV Infection and AIDS studied over 1,400 gay men and over 1,100 injection drug users (IDUs). They reported in the December 24 issue of AIDS that the prevalence of KSHV was low among IDUs, but high among gay men, similar to the distribution of KS in these populations.

Evidence indicates that KSHV is sexually transmitted; one report at CROI indicates that KSHV is transmitted primarily by receptive oral sex (see Conference Coverage in this issue of BETA).

3TC Approved for Children

In late March the FDA approved the use of 3TC (Epivir, also known as lamivudine) for HIV positive infants, children, and adolescents age three months to 16 years. 3TC, a nucleoside analog manufactured by Glaxo Wellcome, is approved for use in combination regimens with other antiretroviral drugs. An estimated 75% of adults receiving combination anti-HIV therapy include 3TC as part of their regimen.

Updated Pediatric Guidelines for Anti-HIV Therapy

On April 15 the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children released updated Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. As with the recently updated adult guidelines, the new pediatric guidelines include information about the use of efavirenz (Sustiva) as part of a first-line combination anti-HIV regimen. The guidelines are available on the Internet at www.hivatis.org or by calling 1-800-448-0440.

AZT in Children: Short- and Long-Term Effects

A study released in January indicates that use of AZT to prevent vertical transmission from mother to baby appears to have no long-term adverse effects thus far on children. The study was published in the January 13 issue of the Journal of the American Medical Association. See "Recent News about Women and HIV" in this issue of BETA.

A related study presented at a meeting of the Society for Maternal and Fetal Medicine, also in January, appears to indicate that use of protease inhibitors during pregnancy is safe. Researchers from the University of Southern California School of Medicine examined 32 infants born to HIV positive women taking combination antiretroviral therapy. So far all are HIV negative. There was a low rate of premature births, and no birth defects were seen.

In less optimistic news researchers from France reported at CROI that two infants whose mothers had taken AZT plus 3TC during pregnancy had died of a rare neurological disease that affects mitochondrial (cellular energy) function. The women were part of a study investigating AZT/3TC's ability to prevent vertical transmission.

The women took AZT starting in the third week of pregnancy and received 3TC during the last eight weeks; in addition, the infants received the drug during the first five weeks after birth. The two babies who died were not infected with HIV. Further research is ongoing to determine whether 3TC is safe for use during pregnancy and by newborns.

New HIV-Protective Protein Found in Tears and Saliva

In March researchers reported that proteins found in tears, saliva, breast milk, and the urine of pregnant women appear to neutralize HIV. The report appeared in the March 16 issue of the Proceedings of the National Academy of Sciences. Sylvia Lee Huang and colleagues showed that the proteins, known as lysozyme and ribonuclease, can kill HIV in test tube experiments. The presence of lysozyme may help explain why HIV is not known to be transmitted through saliva (although it is transmitted through breast milk).

The proteins were discovered during experiments involving human chorionic gonadotropin, a hormone produced during pregnancy that inhibits HIV replication and is associated with a reduction of KS lesions (see BETA, July 1998). The researchers suggested that lysozyme destroys viral membranes and ribonuclease interferes with viral genetic material.

The discovery of the anti-HIV activity of these proteins could lead to the development of a vaccine and new treatments that work against the virus by a different mechanism than existing drugs; such agents, because they occur naturally in the body, are unlikely to produce serious side effects.

In related news Samuel Baron and colleagues at the University of Texas Medical Branch in Galveston presented results indicating that saliva can kill 90% of HIV-infected white blood cells. This occurs because saliva is hypotonic; that is, it lacks the salts found in most body fluids (including blood, semen, and breast milk). The HIV-infected cells, which have a high salt content, absorb water until they burst.

The finding helps explain why HIV is not known to be transmitted through kissing and other types of contact with saliva. Researchers hope the discovery may lead to the development of a microbicide that could deactivate HIV. The report appeared in the February 8 issue of the Archives of Internal Medicine.

HIV Lives in Syringes for Weeks

Researchers reported in January that HIV can survive for four weeks or longer in syringes that have been used to inject drugs. Whether or not viable HIV can be recovered depends on how much blood has been left in the syringe and how much virus the blood contains. Nadia Abdala and colleagues from Yale University reported the findings in the January 1 issue of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. The findings emphasize the benefits and importance of needle exchange programs that can help remove potentially infectious syringes from circulation.

Annual Colposcopies and Pap Smears Recommended for Women with HIV

According to a study presented by Annekathryn Goodman of Massachusetts General Hospital at the annual meeting of the Society of Gynecologic Oncologists in March, most HIV positive women should receive colposcopy examinations annually, in addition to Pap smears, to reduce their risk of cervical cancer. A colposcopic examination involves using a lighted microscope to view the cervix.

Colposcopies and Pap smears can detect abnormal cell growth that may indicate the early stages of cancer. Goodman recommended colposcopies for women with HIV because they are more likely than HIV negative women to have false-negative Pap smears.

In related news, the FDA in March approved a new DNA-based blood test to detect human papillomavirus (HPV), several strains of which are associated with cervical and anal cancer. The Hybrid Capture II test can detect all 13 strains of HPV. A five-year trial of the new test is currently underway. Although the new test can detect HPV, it cannot determine whether cervical cells are abnormal, and Pap smears are still recommended for this purpose.

Finally, the National Cancer Institute (NCI) recently sent a letter to U.S. physicians informing them of changes in recommendations regarding cervical cancer treatment. The NCI now advises that women with metastasized cervical cancer (cancer that has spread) should receive both chemotherapy and radiation therapy.

The new recommendations are based on the results of five studies that have not yet been published; the studies indicate that women who receive both forms of therapy have a 30-50% lower death rate than women who receive only one type of treatment.

Major Vaccine Trials Begin

On March 8 the first HIV vaccine effectiveness trial in the San Francisco Bay Area began enrolling participants. The trial is being conducted by the San Francisco Department of Public Health and the University of California at San Francisco.

The phase III trial is part of a four-year, multisite research effort that will include over 50 locations and 5,000 participants in North America; a similar study will enroll 2,500 injection drug users in Thailand. Researchers hope to enroll 300 at-risk participants in the Bay Area. The study will test a recombinant vaccine known as AIDSVAX B/B, developed by VaxGen.

The vaccine contains two different synthetic versions of the gp120 protein found in the envelope of HIV. The genetically engineered vaccine does not contain whole virus and is not believed to cause HIV infection. Researchers hope that the vaccine will "prime" the immune system to respond to whole virus.

While other vaccine trials have examined the safety and feasibility of candidate vaccines, this study is the first to focus on a vaccine's effectiveness in preventing HIV infection. The trial is a double-blind design in which some participants will receive the candidate vaccine while others receive a placebo; because it is not known whether the vaccine is effective, participants are strongly urged to practice protected sex and safer needle "works" usage. For more information or to enroll, call 415-514-4822.

In related news the National Institute of Allergy and Infectious Diseases (NIAID) in February launched the first AIDS vaccine trial in Africa. The phase I trial will enroll 40 HIV negative participants in Uganda. This trial will test Alvac, a genetically altered canarypox-based vaccine that contains three HIV genes; the product is produced by Pasteur Merieux Connaught.

No serious side effects have been seen in preliminary studies in nearly 1,000 American and French volunteers. The phase I trial is designed to further study the vaccine's safety and tolerability; effectiveness studies will follow if early results appear promising. Although most people with HIV in Africa are infected with HIV subtypes A and D, the vaccine is based on subtype B virus, the type most common in the U.S. and Europe.

Nabel to Head Vaccine Effort

In March, President Clinton appointed Gary Nabel, MD, to head the federal government's AIDS Vaccine Research Center, part of the National Institutes of Health (NIH). Nabel, who assumed the new position in mid-April, is a Professor of Internal Medicine and Biological Chemistry at the University of Michigan at Ann Arbor and an investigator with the Howard Hughes Medical Institute; his previous work includes research on DNA-based vaccines for cancer and the Ebola virus.

The announcement came after an 18-month search; HIV/AIDS activists had criticized the amount of time the position went unfilled after the president announced in May 1997 his goal of developing an AIDS vaccine in ten years. According to Nabel, "The development of an AIDS vaccine remains a formidable challenge and an urgent need, and the [Vaccine Research Center] hopes to drive the development of effective vaccines with our partners in academia, industry, and the general public."

Many PWAs Missing Out on Treatment

According to a study conducted by RAND and presented at CROI in February, half of all persons with HIV in the U.S. are not receiving treatment. Of those who are receiving treatment, one-third are not receiving the type of combination therapy recommended by the federal guidelines for anti-HIV treatment.

The study, known as the HIV Cost and Services Utilization Study, surveyed 160 physicians and 2,200 HIV positive persons throughout the U.S. The study estimated that 335,000 people in the U.S. are receiving anti-HIV treatment; the CDC estimates that 600,000-900,000 people in the U.S. are living with HIV. Among people with HIV, 65% reported receiving no treatment at all, or fewer drugs and lower doses than recommended.

Lead researcher Samuel Bozzette said that underserved populations--including people of color, poor people, and those who rely on government health coverage--were less likely to have access to standard-of-care treatment. In addition to economic barriers, some people choose not to take anti-HIV drugs because they do not believe the drugs are effective or believe their side effects outweigh their benefits. In addition, many people with HIV are unaware that they are infected.

New Federal AIDS Funding Announced

On April 6, Health and Human Services Secretary Donna Shalala announced that the department had awarded $710 million in new grant money to increase access to primary care services for people with HIV/AIDS. The Title II Ryan White Comprehensive AIDS Resource Emergency (CARE) Act grants were awarded to the individual states, the District of Columbia, and U.S. territories.

The grants are calculated based on the number of people with AIDS in a given area. New York City received the largest grant, over $127 million. California received nearly $96 million. State AIDS Drug Assistance Programs (ADAPs), which provide drugs to people with HIV who cannot otherwise afford them, will receive $461 million of the new money.

The grants will be administered by the Health Resources and Services Administration (HRSA). Shalala said, "These grants reaffirm the Clinton administration's commitment to providing vital HIV/AIDS health care to communities most in need."

Liz Highleyman is a freelance writer based in San Francisco and a former member of BETA's editorial staff.

Page last updated 1 June 1999