When taken orally, only about 20% of acyclovir enters the blood. To get around this problem, the drug valaciclovir was developed. Once inside the body, valaciclovir is converted into acyclovir, resulting in levels that are 3-4 times greater than when acyclovir is taken directly. At levels such as these, the drug should have anti-CMV activity. To investigate this possibility, researchers conducted a clinical trial in which some people with AIDS received valaciclovir 8 g/day, while others received acyclovir 3.2 g/day or 800 mg/day. In analysing the data, researchers found that subjects receiving valaciclovir had a 33% reduced risk of developing CMV disease compared with subjects on acyclovir. Unfortunately, those subjects who received valaciclovir were also at increased risk of death compared to those receiving acyclovir. It is possible that the dose of valaciclovir used in this study was simply too high.
Researchers enrolled 1,227 adult subjects with AIDS, 94% of whom were male. At least half the subjects had a CD4+ count of 32 cells. About 50% had had a herpes virus infection in the past (shingles or sores in the mouth/genitals) and about 25% had had PCP before entering this study. Researchers assigned some subjects to receive 2 grams of valaciclovir 4 times each day, others to receive acyclovir 3.2 g/day or 800 mg/day.
At least half the subjects were monitored for about one year. Fifteen percent of subjects in the study developed complications due to CMV disease. These events were most likely to occur in people with fewer than 50 CD4+ cells. Twelve percent of subjects taking valaciclovir developed CMV disease, compared to 18% of subjects on acyclovir. This represented a 33% reduction in the development of CMV disease in people using valaciclovir.
Most cases (80%) of CMV disease were "CMV retinitis," followed by intestinal complications. There was no difference in the number of subjects developing cases of shingles, herpes sores or Kaposi's sarcoma between the different arms of the study (valaciclovir versus acyclovir).
Overall, 40% of subjects died during the observation period. Death rates in the study arms were:
In one analysis, "survival was significantly shorter in the valaciclovir arm [compared to the other arms]." There was no significant difference in survival rates between the 2 acyclovir arms, or between the high-dose acyclovir and valaciclovir arms.
The "most common principal causes of death" in 44 patients (9%) was non-Hodgkin's lymphoma. Other common causes of death were:"
CMV was the chief cause of death in only 3.3% of subjects.
"Gastrointestinal complaints occurred significantly more often and earlier in the valaciclovir arm [than in the acyclovir arms of the study]." People taking valaciclovir were more likely to leave the study before others who were taking acyclovir. Interestingly, 18 subjects developed one or more of the following:
According to some of the study doctors, these signs are suggestive of TMA (thrombotic microangiopathy), and were significantly more common in valaciclovir users than in people using acyclovir, though they are not sure why.
At the dose used in this study, valaciclovir has anti-CMV activity, but does not provide complete protection from complications caused by that virus. People using valaciclovir still developed CMV disease, though at a lesser rate than people not using the drug. People taking valaciclovir appeared to have reduced survival compared to others using acyclovir. A small number of valaciclovir users also appeared to be at higher risk of developing complications affecting the kidney and bone marrow. It is clear that valaciclovir carries a great deal of risk for people with AIDS when taken at the dose used in this study.
1. Feinberg JE, Hurwitz S, Cooper D, et al. A Randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced Human Immunodeficiency Virus infection. Journal of Infectious Diseases 1998;177:48-56.
2. Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced Human Immunodeficiency Virus (HIV) Disease in cytomegalovirus prophylaxis trial (ACTG 204). Medicine 1997;76(5):369-380.
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