August 2007

Innovative HIV Treatments: A look to the Future

Contributed by: Jaime L. Robenolt, Pharm. D Candidate 2008
VCU/MCV School of Pharmacy on Rotation at Alaska Native Medical Center

New Hope for Last Resort HIV Patients

On September 5, 2007 the Antiviral Drugs Advisory Committee of the FDA will meet to discuss the New Drug Application (NDA) for Isentress™ (raltegravir potassium). Manufactured by Merck & Co., Inc., the drug is in a novel antiretroviral class referred to as integrase inhibitors (2). Raltegravir is the first in its class to show extreme potential as an alternative for patients receiving salvage therapy. Salvage therapy is a last line combination of anti-retroviral agents used when a patient has failed multiple regimens or has acquired resistance to them (1).

The mechanism of action of raltegravir involves integrase which is an enzyme necessary for the HIV virus to successfully insert its viral DNA into a human host’s DNA. The virus must be able to carry out this process in order to use the host’s cellular machinery to make copies of its viral DNA in order to successfully spread the HIV infection. Integrase inhibitors, like raltegravir, block the action of integrase and prevent the HIV virus from successfully inserting its DNA into the host DNA. Raltegravir essentially blocks HIV before it can even alter human genetic material. Human cells lack the integrase enzyme, thus toxicity and side effects to human cells is expected to be low (1, 4).

Clinical trials have been successful in reducing viral loads significantly, even to undetectable levels (<50 copies/mL). CD4 counts were also increased considerably. Phase I, II, and III clinical studies have gone exceedingly well and “EARMRK” which stands for Expanded Access Research Program from Merck, will hopefully begin in September. This program will provide early access to raltegravir for patients who are resistant to antiretroviral drugs in the other classes but require continued antiretroviral treatment. For additional information on the program, please call 1-877-EARMRK1 or refer to Merck’s EARMRK website (1, 3, 6).

The most common side effects of raltegravir reported were nausea, diarrhea and headaches; however, they were reported as mild to moderate in severity in clinical trials. In addition, raltegravir has a more favorable effect on cholesterol profile than other antiretroviral drugs, specifically when compared head to head with sustiva which is known to increase total cholesterol 20-40% (1, 4).

The dose of raltegravir being evaluated is 400mg given by mouth twice daily, in combination with other drugs for best results (4). One trial discussed the incidence of virologic failure with raltegravir during clinical trials, but it is uncertain why this may have occurred or what the mechanism of possible resistance could have been. This may be one of the reasons why it is being recommended that the drug be given in combination with other antiretroviral agents. Theoretically raltegravir would be added to a patient’s current antiretroviral regimen or as an alternative if the patient has become resistant to other treatments (5).

The remaining clinical trials should provide us with some more clinically relevant data and with continued research more information will continue to emerge regarding raltegravir. If approved in September, raltegravir could open the doors to a new wave of HIV treatments for patients whose therapeutic situations once seemed very dim.

References:

1. Grinsztejn, Beatriz et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multi-drug resistant virus: a phase II randomized controlled trial. The Lancet. April 2007. 369: 1261-1269.

2. U.S. Food and Drug Administration, FDA HIV/AIDS List Serve Archive 2007: 2 August 2007.
http://www.fda.gov/oashi/aids/listserve/listserve2007.html

3. Merck & CO, Inc., Research Development and News. 7 August 2007. http://www.merck.com/newsroom/press_releases/research_and_development/2007_0724.html

4. AIDSMEDS.com 7 August 2007.
http://www.aidsmeds.com/archive/MK-0518_1639.shtml

5. AIDSMEDS.com 7 August 2007.
http://www.aidsmeds.com/articles/1667_12618.shtml

6. EARMRK HIV Investigational Studies. 8 August 2007.
http://www.benchmrk.com/secure/earmrk/earmrk.html

Predicting Hypersensitivity through Pharmacogenomics and Other Biomarkers

Abacavir hypersensitivity reactions are very serious and can even result in fatal reactions if not monitored properly in certain patients. Some of the symptoms of a severe reaction to abacavir include: fever, skin rash, malaise/fatigue/aches, respiratory symptoms, and/or GI symptoms (such as abdominal pain, diarrhea, nausea, or vomiting). If a patient is suspected to have a hypersensitivity to this drug it is imperative to not re-challenge the patient (1).

Continued research in the area may allow practitioners to predict whether or not a patient will be susceptible to the hypersensitivity reaction induced by abacavir, even before the initiation of the drug. The genotype HLA-B 5701 within the major histocompatibility complex (MHC) has been associated with an increase in these hypersensitivity reactions. However there seems to be some debate as to whether having this gene increases hypersensitivity in primary HIV infection versus chronic HIV infection and to whether it is only the gene itself that contributes to the hypersensitivity reaction or if other factors play a role in the hypersensitivity reaction (2, 3).

A recent study challenges previous studies in that it concludes that patients with HLA-B 5701 are less susceptible to hypersensitivity reactions simply due to the genetic abnormality alone during primary HIV infection as compared to chronic infection. This is because during primary HIV infection it is believed that there is a period of prolific viral replication along with an acute drop in CD4 cell counts. With that, immune response is erratic which can lead to other factors contributing to the hypersensitivity reaction to abacavir. With chronic HIV infection immune response is more stable, so the HLA-B 5701 genotype may be a dependable predictor of hypersensitivity in these patients (3).

It is this study that leads researchers to believe that genotype may not be the only influence on abacavir hypersensitivity reactions. Other factors that could play a role include immunologic status which consists of: baseline CD4 counts, CD8 counts, number of cells expressing CD38, baseline viral load, and the reduction of viral load at follow up appointments (3).

The ability to predict hypersensitivity in specific subsets of patients would be an essential tool for prescribers. Testing for every patient would be unnecessary because it is not a first line therapy so as an initial treatment, not many patients would be started on abacavir. Most patients that would begin treatment with abacavir would be patients with chronic HIV infection who have become resistant to treatment or have failed their current regimens. At that point in time if the prescriber or patient believes hypersensitivity to abacavir may be a risk, testing for the specific genotype would be indicated. As mentioned studies have shown genetic testing for the HLA-B 5701 genotype in chronic HIV infection seems to be a more reliable measure. More studies should be conducted comparing the discordance between the causes of hypersensitivity in primary HIV infection versus chronic HIV infection. In addition, studies should be carried out to evaluate any differences in the susceptibility to abacavir hypersensitivity across different cultures or ethnicities.

References:

1. Hewitt, Ross. Abacavir Hypersensitivity Reaction . Clin Infect Dis. April 2002. 34: 1137 - 1142.

2. Hetherington, Seth et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. The Lancet. March 2002. 359: 1121-1122

3. Stekler, Joanne et al. Abacavir hypersensitivity reaction in primary HIV infection. AIDS. February 2006. 20: 1269-1274.

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