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(CATIE) GS 840 -- just one pill a day
Sein Hosein
September 1, 1997
TreatmentUpdate81 - Vol. 9, No. 7 - pp. 1-2; September 1997

Background & Summary Unrelated to any other AIDS drug on the market, GS 840 (adefovir dipivoxil) is being tested in several studies for different reasons: as a treatment for HIV/AIDS, CMV infection and hepatitis B. One HIV/AIDS study will hopefully be taking place in Canada later this year, as will the hepatitis B study. Given at a dose of 120 mg/day, GS 840 has resulted in a small decrease in the amount of HIV in the blood. It appears that GS 840, like most other anti-HIV drugs will probably be more useful when used in combination. An attractive feature of GS 840 therapy is that PHAs will likely need to take only one pill daily.

Adefovir Created and tested in the late 1980s, adefovir (unrelated to AZT and similar drugs) gets converted into an antiviral drug once it gets inside a cell. It then acts against the essential viral enzyme RT (reverse transcriptase). Once inside a cell, the compound remains there for almost a day, which is why people need only take the drug once daily. Adefovir has broad activity against HIV, many herpes viruses and hepatitis B virus.

Increasing absorption Preliminary studies found that adefovir was not well absorbed in humans so researchers adjusted the compound and formed adefovir dipivoxil or GS 840. This is much better absorbed in HIV-infected people than adefovir, particularly when taken "after a meal." Once inside the body GS 840 is turned into adefovir.

Study Details In order to decide on the dose of GS 840 to be used in future studies, researchers first tested several doses --125, 250 and 500 mg/day for 2 weeks -- in a group of 36 HIV-infected subjects (25 male, 11 female) most of whom had more than 200 CD4+ cells. Nine of the 36 subjects received fake adefovir (placebo).

Results -- virus levels Researchers found a small but significant decrease in the amount of HIV in the blood of people receiving GS 840 while those on placebo had increased levels of HIV. In general, all doses of GS 840 had the same anti-HIV effect. Hopefully, greater decreases in viral load will occur when GS 840 is used in combination with other anti-HIV drugs.

Results -- CD4+ All groups had increased CD4+ cell counts and there were no significant differences between placebo and GS 840 groups.

Toxicity The most common side effects affected the gastrointestinal system: * loose stools * nausea * vomiting * loss of appetite * stomach discomfort * belching or farting The greater the dose of GS 840 used, the greater the side effects. Some volunteers in the higher dose groups developed temporary liver damage which cleared when they stopped taking the drug.

Losing carnitine One of the problems with using drugs such as GS 840 is that when they are broken down by the body other products are formed. One of these products joins itself to the nutrient carnitine, pulling it out of circulation and sending it to the kidneys where it goes into the urine. In the group taking 125 mg/day of GS 840, levels of carnitine fell by 12%. When higher doses of the drug were used, carnitine levels in the blood fell by as much as 66%.

A note on carnitine Carnitine is an amino acid found chiefly in red meat. This nutrient is used to help move fat to places where it can be converted into energy. Muscles are very dependent on carnitine. Although carnitine can be made at several sites in the body (brain, kidney, liver) at least one research team has found that PHAs have less than normal levels of carnitine in their blood. So supplementation with this nutrient -- 500 to 1,000 mg/day -- is probably a good idea. Exercise can also increase levels of carnitine in non-HIV-infected people. Carnitine may also be useful in protecting nerves from the potential toxicity of ddC, ddI, d4T and muscles from the toxicity of AZT. In the Canadian study of GS 840, researchers plan to provide volunteers with 500 mg of carnitine daily to compensate for any losses due to the use of GS 840.

REFERENCES: 1. Barditch-Crovo P, Toole J, Hendrix CW, et al. Anti-Human Immunodeficiency Virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis- pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-infected patients. Journal of Infectious Diseases 1997;176:406-413.