Highlights from the Institute of Human Virology Meeting
Several interesting presentations were discussed at the recent Laboratory of Human Virology meeting in Baltimore. Of particular interest were a few presentations of laboratory studies of drugs that inhibit cellular factors of HIV. These drugs can be used in combination with the current nucleoside analogue therapies resulting in increased potency, which may overcome HIV already resistant to the nucleoside analogues [such as AZT (zidovudine Retrovir®), ddI (didanosine Videx®), ddC (zalcitabine Hivid®), d4T (stavudine Zerit®), 3TC (lamivudine Epivir®) and abacavir (Ziagen®)].
One such drug, mycophenolate(CellCept®) which is used as an immune suppressant for transplant patients, made abacavir six times more potent in blocking HIV replication based on lab studies. It works in a similar fashion as hydroxyurea, but mycophenolate specifically reduces white blood cells of the amino acid building block, guanosine. Since abacavir is a guanosine nucleoside analogue (it mimics guanosine to block HIV from reproducing), the combination works especially well.
In lab studies, the combination of mycophenolate and abacavir was effective against multi-nucleoside drug resistant viruses, so these drugs may be potentially useful for people on third line regimens. It is believed that lower doses of mycophenolate than those used in the transplant studies will be effective against HIV. Small safety studies are ongoing using 250mg of mycophenolate twice a day with standard doses of abacavir. Larger studies to confirm the laboratory studies are expected to begin soon.
Mycophenolate also has activity against hepatitis C virus (HCV) based on laboratory studies. The proposed mechanism of HCV activity is by blocking inosine monophosphate dehydrogenase (IMPDH) enzyme. This enzyme regulates the production of building blocks (nucleotides) that HCV needs to reproduce. Additionally, as an immunosuppressive drug, mycophenolate may block the activity of certain cells (lymphocytes) which can cause inflammation in the liver of people with HCV. Studies are planned to use mycophenolate in combination with pegylated interferon-alpha to treat HCV.
Another drug, resveratrol, also shows similar activity when used in combination with the nucleoside analogues. Resveratrol is a natural product which can be found in the skin of grapes and other plants. Resveratrol blocks some of the cellular enzymes which HIV uses to reproduce as well as increases the production of other enzymes which activate some of the nucleoside analogue drugs. Lab studies show that resveratrol enhances the anti-HIV activity of ddI by 200-times. This combination is also able to overcome viruses that had previously become resistant to ddI. Similar effects have been shown when resveratrol is used in combination with AZT.
White Blood Cell Studies
An interesting observation from a group in the United Kingdom show that women who received white blood cells from their partners had enhanced laboratory markers which may result in resistance to HIV infection. They followed a groups of women who had habitual spontaneous abortions and, as a result, required white blood cells from their partners which were given intravenously (injection in to the vein), subcutaneously (injection under the skin) and intradermally (in to the skin). This process is also sometimes called allogeneic immunization.
They found that the women had significant increases in MIP-1a, MIP-1ß and Rantes levels. These substances, known as chemokines, have been shown to suppress HIV replication in laboratory studies. They also found that after the allogeneic immunization, the women had fewer cells with CCR5 and CXCR4 receptors, which have been identified as the "doorway" through which HIV infects CD4+ cells. Additionally, they found that the CD4+ cells were much harder to infect with HIV after the allogeneic immunization. These are intriguing findings and suggest that allogeneic immunization may be protective of HIV infection. For more information on chemokines and co-receptors, please read the Co-receptors Discussion Paper from Project Inform.
TAT Gene Therapy
Another approach to protect against HIV infection with a tat toxoid is now rapidly moving ahead in studies. The tat gene is required for HIV replication, and so can be considered toxic to the body (a toxin). A toxoid is a toxin that has been treated so that the toxic property is destroyed, but it is still able to generate an immune response (like a vaccine). This approach has been studied in Europe for the past couple of years and preliminary results are quite encouraging.
In one small study eight people with HIV received the tat toxoid. Volunteers had slight increases in CD4+ cell counts and slight decreases in viral load. Additionally, half of the participants developed delayed type hypersensitivity responses (a measure of immune response) to the tat toxoid.
In a study with people who were HIV negative who received the tat toxoid, almost all of the participants had very high antibody titers (measure of an immune response to the toxoid) which lasted for more than 20 months. Additionally, four out of the five participants had delayed type hypersensitivity responses and increases in cell mediated immunity responses (another indicator of immune response).
Drug Interaction and the Anti-HIV Drug Emivirine (Coactinon®)
A recent study showed significant interaction between the two anti-HIV drugs, nelfinavir (Viracept®) and emivirine (Coactinon®, formerly known as MKC-442). An earlier small study suggested that emivirine decreased nelfinavir levels by about 30% in blood. A new study suggests that the interaction is far greater.
A study evaluating the addition of emivirine to a regimen of d4T (stavudine, Zerit®), 3TC (lamivudine, Epivir®) and nelfinavir looked to see if adding the drug resulted in better and longer suppression of HIV. The exact degree of the interaction is still not known, but it's thought that emivirine reduced nelfinavir levels by over 50%. As a result, it's highly unlikely that nelfinavir contributed any anti-HIV activity as part of the combination studied. It's known that emivirine decreases indinavir (Crixivan®) levels by about 80% in blood.
The study employed a higher dose of nelfinavir than what is traditionally recommended (1,000mg three times a day for a total daily dose of 3,000mg) to compensate for the drug interaction observed in the earlier study. As a result of this greater than anticipated interaction, no difference in anti-HIV activity was seen between the two groups. Triangle Pharmaceuticals, the developers of emivirine, had originally hoped to file for approval of this drug by the end of 1999. However, it's now likely that the filing will be delayed.
Have You Ever Thought About Attending an AIDS Conference?
The International AIDS Conference will be held in Durban, South Africa, from July 9-14, 2000. Information on conference registration, the community scholarship program and submitting abstracts for poster and oral presentations are available through the conference website (www.aids2000.com) or by writing the conference organizers. Contact information is provided below:
XIII International AIDS Conference
P.O. Box 1620
Conference coordinator (International): Karen Bennet
Conference coordinator (Africa): Fakazile Myeza
Information is available in English, French and Spanish
If you or someone you know is interested in attending the International AIDS Conference, register early and seek information about scholarship programs. Often, conferences and forums on specific topic areas take place in conjunction with the International AIDS Conference. You should keep your eyes open for events of interest as you get closer to making your travel arrangements for the meeting if you've decided to go.
For example, each year the International Community of Women living with AIDS typically holds meetings or events prior to and during the International AIDS Conference. There has been talk about a Women and AIDS meeting to coincide with the Durban meeting, though nothing formal has yet been proposed. Also, sometimes there's an international conference on alternative and complementary therapy for HIV disease which proceeds the main conference. Last year, a two day forum to get people living with HIV and their advocates and educators up-to-speed on treatment information took place prior to the meeting. These events are not endorsed by the International AIDS Conference per se, but for those who are interested, keep your eyes open for posting of these types of events to maximize your time in Durban.
Scholarship Application Forms must be received by the Congrex in Sweden by February 1, 2000. They must be mailed and will NOT be accepted through fax.