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BETA News Briefs

Spring 2001

Seven-Day Drug Cycling Appears Effective

According to a study reported at the 8th Conference on Retroviruses and Opportunistic Infections (CROI) in February, "cycling" of antiretroviral drugs -- that is, starting and stopping treatment on a specified schedule -- appears to cause little or no harm in some people with HIV. The study, conducted by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), looked at ten HIV positive people who received antiretroviral treatment according to a seven days on/seven days off schedule. HIV remained fully suppressed during the nontreatment periods. However, two participants who did not restart their drugs after the seven-day off-drug period did experience viral rebound. Some of the participants continued drug cycling for ten months with "no evidence of damage to their immune systems or the development of resistant strains of the virus," according to the researchers. Anthony Fauci, M.D., of NIAID commented, "This is a big deal to people . . . [who] are positively inclined to being off-drug 50% of the time."

Results from the recent study cannot yet be considered definitive. In an earlier study of 24 people on a two months on/one month off drug cycling schedule, most experienced viral rebound during the month without treatment. Drug cycling should only be done under the care of an HIV-experienced health-care provider.


Peg-Intron Approved for Hepatitis C (HCV)

In late January the Food and Drug Administration (FDA) approved a new pegylated version of interferon alpha (Peg-Intron) for the treatment of HCV infection. The new drug is a long-acting formulation of Schering-Plough's Intron A brand of interferon alpha, an older treatment for HCV; a combination of interferon alpha and ribavirin is marketed by Schering-Plough as Rebetron. The pegylation process protects the chemical from destruction by the immune system and allows it to stay active longer in the body; Peg-Intron can therefore be injected just once per week. According to the manufacturer, weekly injections of Peg-Intron are twice as effective as the nonpegylated version taken three times per week. Bill Schwieterman, M.D., of the FDA said that people using Peg-Intron are more likely to have mild bone marrow suppression, a condition that leads to low levels of various blood cells, including immune cells; he recommended that physicians monitor persons taking the new drug. Peg-Intron is expected to sell at a wholesale cost of approximately $1,000 per month.

New OI Drug Approvals

In recent months the FDA has approved two new drugs to treat AIDS-related opportunistic infections (OIs). In January the agency gave the nod to Merck & Co.'s antifungal drug caspofungin acetate (Cancidas) for the treatment of invasive aspergillosis. The new drug is indicated for use by people who do not respond to or who cannot tolerate amphotericin B (Fungizone, AmbiSome) and/or itraconazole (Sporanox). Caspofungin is an echinocandin, or glucan synthesis inhibitor drug, that works by attacking fungal cell walls. In people with weakened immune systems, the Aspergillus fungus can attack the lungs and spread throughout the body, affecting the heart, kidneys, eyes, and brain. Caspofungin is delivered by injection; the most common side effects seen in clinical trials were fever, phlebitis (vein inflammation), nausea, and headache.

In February an FDA advisory committee voted unanimously to approve Hoffman-La Roche's valganciclovir (Valcyte) for the treatment of cytomegalovirus (CMV) retinitis. Valganciclovir is an oral version of the intravenous drug ganciclovir (Cytovene), which has long been used as a CMV treatment. Valganciclovir is a prodrug that is converted to ganciclovir in the body. Clinical trials have shown that valganciclovir is effective for early-stage CMV retinitis, but have not yet revealed long-term effectiveness.

Expanded Access for Tenofovir DF (TDF)

Gilead Sciences recently lifted restrictions that had limited enrollment in its expanded access program for TDF. Specifically, viral load and CD4 cell count requirements will no longer be considered inclusion criteria for the program. TDF, an experimental nucleotide analog (NtRTI), is taken once a day, and should be started with at least one new antiretroviral drug that the person has not previously used. The drug is currently undergoing Phase III clinical trials. On May 1, Gilead announced it had filed a new drug application with the FDA, which means TDF may be approved and available for any adult with HIV in approximately six months. For more information, contact Gilead at 800-445-3235.

Cardiovascular Disease Risk Higher in People with Lipodystrophy

A recent study by researchers at Massachusetts General Hospital in Boston showed that HIV-infected people with lipodystrophy were at significantly higher risk for developing cardiovascular disease than HIV negative people or HIV positive people who did not have body fat redistribution. The study compared 71 people with HIV and lipodystrophy with 30 HIV-infected people without lipodystrophy and 213 HIV negative healthy controls. Participants with HIV and lipodystrophy had increased waist-to-hip ratios, higher fasting insulin levels, higher diastolic blood pressure readings, and lower high-density lipoprotein (HDL, "good" cholesterol) levels; these participants were also at greater risk for impaired glucose tolerance, diabetes, and hypertriglyceridemia (high triglyceride levels). According to the researchers, "Insulin resistance, dyslipidemia [abnormal blood fat levels], truncal adiposity [abdominal fat accumulation], and increased diastolic blood pressure are known to increase cardiovascular risk in patients who are not infected with HIV and may similarly predispose HIV-infected patients with fat redistribution to accelerated cardiovascular disease." They concluded that people with fat redistribution are at high risk for metabolic abnormalities, and that their lipid levels and glucose tolerance should be monitored. Results of the study were published in the January 1, 2001 issue of Clinical Infectious Diseases.

Cancers in HIV Positive People Related to Immunosuppression

According to a study by researchers from the National Cancer Institute (NCI) and the Danish Statens Serum Institute, Hodgkin's disease (cancer of the lymphatic system), lip cancer, and seminoma (a type of testicular cancer) in people with HIV may be related to immunosuppression. Morton Frisch, M.D., and colleagues looked at 302,834 people with AIDS from 11 geographical areas. Compared with people without AIDS, people with AIDS were 11 times more likely to develop Hodgkin's disease, three times more likely to have lip cancer, and twice as likely to have seminoma. People with AIDS also had higher rates of lung cancer, penile cancer, and soft tissue malignancies, but the researchers concluded that these cancers may be associated with "lifestyle" factors such as smoking and human papillomavirus (HPV) exposure, and could not be reliably linked to AIDS-related immunosuppression alone. The researchers concluded that the risk of Hodgkin's disease increases with advancing immunosuppression, and suggested that it should be considered an AIDS-defining condition. Non-Hodgkin's lymphoma (cancer of the lymph nodes), cervical cancer, and Kaposi's sarcoma (KS) are already classified as AIDS-defining diseases. The study was reported in the April 4, 2001 issue of the Journal of the American Medical Association.

Newly Discovered Molecule Facilitates HIV Transmission

Researchers from the University of Nijmegen and New York University reported in February that they had identified a molecule that may play a role in HIV transmission. Dr. Yvette van Kooyk and colleagues found the molecule on the surface of dendritic cells, a type of CD4 cell, which are present under the skin and mucous membranes and are involved in HIV infection. Dendritic cells engulf invading pathogens and transport them to the lymph nodes, where they are recognized and neutralized by immune cells; however, in the case of HIV, the virus attacks CD4 cells, leading to immune system damage. The newly identified molecule allows dendritic cells to capture and transport HIV. The researchers said that the molecule -- dubbed dendritic-cell-specific icam-grabbing nonintegrin, or DC-SIGN -- binds to HIV and protects the virus for up to four days, long enough for it to reach immune cells and begin replicating. According to Dr. van Kooyk, the new discovery may help explain how a small amount of HIV is able to "enter, survive, and then amplify in large amounts to damage the immune system and create AIDS." The discovery suggests a possible target for microbicides that could potentially block HIV entry into dendritic cells.

New Fusion-Inhibiting Protein Found

In January, Peter Kim, M.D., and colleagues from the Massachusetts Institute of Technology (MIT) and the Howard Hughes Medical Institute reported the discovery of a new protein that blocks the fusion of HIV with cells in the body. The protein, called 5-helix, disrupts the membrane fusion process that allows the virus to enter a host cell. The 5-helix protein interferes with the hairpin-like hooks on the cell membrane that HIV uses to latch onto cells; when this mechanism is disrupted, HIV cannot come into close enough contact to fuse with the cell membrane and enter the host cell. The discovery has implications for the development of new anti-HIV drugs. Most drugs inhibit HIV replication once the virus is already inside a host cell; T-20 and related experimental fusion inhibitor drugs prevent the virus from entering cells. According to Dr. Kim, who is slated to head Merck's research division, 5-helix may be more effective than T-20 and other fusion inhibitors in development. The 5-helix protein is produced by genetically engineered bacteria, and proteins produced in this manner may be more resistant to degradation inside the body than synthetic molecules like T-20. Also, 5-helix is smaller than T-20, offering the possibility that it may be provided as a pill rather than by injection. The discovery was reported in the January 11, 2001 issue of Science.

HIV Vaccine Developments

In February, Merck announced that it would begin human trials of a new HIV vaccine candidate. David Baltimore, M.D., chair of the National Institute of Health's (NIH's) AIDS Vaccine Advisory Committee (AVAC), said committee members were "excited" about the prospect of the vaccine's success. The trial will test the vaccine's safety in a group of healthy HIV negative participants; if the results of these tests are encouraging, the vaccine will be tested in HIV positive people this summer. The vaccine candidate aims to augment the anti-HIV activity of CD8 killer T cells using an inactivated adenovirus vector carrying the HIV gag gene. Adenovirus, which causes upper respiratory or gastrointestinal infections in humans, was chosen because, like HIV, it targets dendritic cells. Merck has also used a combination strategy in which the immune system is primed with injections of naked HIV DNA, followed by the engineered adenovirus vaccine.

Results of monkey tests of the vaccine were presented in April at a meeting in Keystone, CO. In the trial, 21 monkeys were injected with a hybrid human/simian virus called SHIV. The vaccine reduced the virus to very low levels in the treated monkeys. None of the fifteen vaccinated monkeys had become ill more than a year after receiving the HIV/SIV virus, while five of the six control monkeys developed AIDS-like symptoms, and four died.

Like many vaccines, the new candidate does not prevent infection entirely, but rather provides partial protection by stimulating an immune response. Dr. Baltimore suggested that such a vaccine could extend the survival of people with HIV and could reduce transmission by reducing viral load. Merck's candidate is the first partial protection vaccine to enter human trials. John Shriver, Merck's director of vaccine research, warned that it is impossible to predict whether the vaccine will work in humans.

HIV Viral Loads Lower in Women

A study by researchers from Johns Hopkins University and NIAID revealed that HIV viral load levels are substantially lower in newly diagnosed women with HIV compared with men at the same stage of infection. The study included 156 male and 46 female injection drug users who became infected with HIV during the study period. The newly diagnosed women had a median HIV viral load of 15,103 copies/mL, versus a median of 50,766 copies/mL for men. However, as HIV disease progressed, viral load levels in women and men became more similar. Despite their initially lower viral loads, women lost CD4 cells and progressed to AIDS at the same rate as men. Women developed AIDS with a median viral load of 17,149 copies/mL, compared with a median 77,822 copies/mL for men. In fact, men who had not progressed to AIDS often had a higher viral load than women who had progressed. According to author Timothy Sterling, M.D., "This sex difference in initial viral load means that the same viral load measurement does not convey the same risk of AIDS in women and men."

The study has implications for when to begin antiretroviral treatment in women. The most recent treatment guidelines raise the threshold for initiating therapy from 20,000 copies/mL to 55,000 copies/mL (by PCR assay), which could potentially exclude many women at later stages of infection. However, guidelines based on CD4 cell counts are equally applicable to women and men. According to Thomas Quinn, M.D., of Johns Hopkins, "The results of this study suggest that greater emphasis should be placed on CD4 count than viral load when deciding when to initiate treatment." The study results were published in the March 8, 2001 issue of the New England Journal of Medicine.

Anti-HIV Therapy Increases Risk of Premature Delivery

A study reported in the December 22, 2000 issue of AIDS indicated that women taking combination antiretroviral therapy are more likely to give birth prematurely. Marie-Louise Newell, M.D., and colleagues from the Institute of Child Health in London conducted a study of 3,920 women, 896 of whom received some type of anti-HIV treatment during pregnancy; 64% received AZT (Retrovir) monotherapy, 24% received combination therapy with only NRTIs, and 12% received combination regimens that included a PI. Women taking NRTI-only combinations had an odds ratio of 1.82 for premature birth (i.e., they were almost twice as likely to deliver prematurely), while women receiving regimens that included a PI had an odds ratio of 2.6 (a more than 2.5-fold greater risk of giving birth prematurely). Monotherapy regimens were not associated with premature birth. Women who began taking combination therapy before they became pregnant were twice as likely to deliver prematurely as those who started therapy during their third trimester of pregnancy. The researchers recommended that combination antiretroviral therapy be delayed until after the first trimester in women whose "clinical or immunological status does not indicate the need for immediate combination therapy."

Protein in Placenta Blocks HIV

Bruce Patterson, M.D., and colleagues from Children's Memorial Hospital in Chicago, Northwestern University, and the Karolinska Institute reported at the 8th CROI that they had discovered a protein in the human placenta that may protect fetuses from HIV infection. The researchers analyzed 22 placentas, 14 from HIV positive women who delivered HIV negative infants, five from HIV positive women with HIV positive infants, and three from HIV negative women. The protein, known as leukemia inhibitory factor (LIF), was found in all the placentas studied, but was present at higher levels in the placentas of the HIV positive women who gave birth to HIV negative babies. The researchers then exposed placenta cultures to various strains of HIV, and found that the addition of LIF to the cultures blocked HIV replication. LIF attaches itself to placental and immune cells, leading to an unknown chemical reaction that prevents the virus from entering the cells. The researchers suggest that LIF may be the "naturally occurring protective ingredient" that protects two-thirds of infants born to HIV-infected mothers from contracting the virus themselves. (The incidence of perinatal HIV infection decreases further with antiretroviral intervention before or during delivery.)

Bush Names New AIDS Office Head

On April 9, President George W. Bush announced the appointment of Scott Evertz to head the White House Office of National AIDS Policy (ONAP). Evertz is the first gay person and the first man to hold the so-called AIDS czar post since President Bill Clinton created the ONAP in 1994, despite the fact that gay men have always been disproportionately affected by the epidemic. Evertz has worked as a fundraiser for a Catholic AIDS ministry, an antiabortion group, and a Milwaukee senior citizen's program; he is a member of the Wisconsin HIV/AIDS Care Coalition. The Bush administration also announced that the ONAP is being reorganized, and that AIDS issues would be handled jointly by members of the State Department and the Department of Health and Human Services (HHS); the change likely reflects the increasing emphasis on the global AIDS epidemic. Bush said that Secretary of State Colin Powell and HHS Secretary Tommy Thompson would jointly chair a task force dealing with AIDS.

In February, Bush's chief of staff Andrew Card provoked an outcry from AIDS advocates when he announced that the administration would discontinue the ONAP. However, the following day the White House reversed the announcement, saying that Card's statement was in error.

Correction Notice

In News Briefs in the Winter 2001 issue of BETA, a note entitled "New ddI (Videx) Formulation Approved" contained an error. Instead of reading "Videx EC is currently the only approved once-daily antiretroviral drug," the statement should have said, "Videx EC is currently one of only two approved once-daily antiretroviral drugs." Efavirenz (Sustiva) is also a once-daily drug.

Also in the last issue, near the end of the "Anal Neoplasia" article, a Web site was listed as The correct, updated link is:

BETA regrets the errors and any confusion they may have caused.

Liz Highleyman is a freelance medical writer and editor based in San Francisco.

Back to the SFAF BETA Spring 2001 contents page.

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
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