TreatmentUpdate60; Volume 7, No. 6 - June 1995
Sean Hosein

Under development for the past 5 years, cidofovir (HPMPC; Vistide(tm)) has recently been tested in humans for its toxicity and anti-CMV effects. This is the first of several reports on this drug.

* STUDY DETAILS

Researchers enrolled 31 male adults, all of whom had HIV infection. Testing of their urine revealed that they were producing CMV. Half of the subjects had a CD4+ cell count of 61 cells. No subjects had serious CMV infection in their eyes or other parts of their body. In this study subjects received various doses and schedules of cidofovir, ranging from 1/2 mg/kg twice weekly to 10 mg/kg twice weekly. Some subjects also received the drug probenecid to reduce kidney damage caused by cidofovir.

* RESULTS

In general, the higher the dose of cidofovir the more likely the production of CMV would decline. As no subjects had serious CMV infection in this study the researchers were not sure which dose was best. Preliminary results from other experiments suggest that injection of cidofovir into the eyes of subjects with CMV retinitis protects them from losing their vision.

* FOCUS ON KIDNEY DAMAGE

The most serious problem caused by cidofovir was kidney damage. Technicians detected increased levels of protein and sugar in the urine of subjects who had kidney damage. As those subjects continued to receive cidofovir, kidney damage increased; even greater amounts of protein and sugar were lost in the urine while blood levels of important ions (phosphates, bicarbonates) fell. As well, blood levels of creatinine, produced when kidney cells break down, increased to over 2 mg/dL. There seemed to be a trend in the process of kidney damage; protein appears in the urine before sugar.

Subjects receiving cidofovir 1 mg/kg did not have "significant [kidney damage]". By that statement, the researchers meant that blood levels of creatinine did not rise above 2 mg/dL. Subjects who received doses of cidofovir 3 mg/kg or more had various degrees of kidney damage. Samples of kidney cells taken from subjects receiving 3 mg/kg or 10 mg/kg revealed severe damage, similar to that seen in earlier animal experiments with cidofovir.

* REDUCING KIDNEY DAMAGE

To reduce kidney damage researchers gave subjects the drug less frequently. As well, some subjects received the drug probenecid. Thus, subjects could tolerate more cidofovir while their blood levels of creatinine did not rise above 2 mg/dL, nor did their blood levels of ions fall. Giving subjects extra saline before they received cidofovir appeared to protect some subjects from kidney damage.

* A NOTE ON PROBENECID

Probenecid is a sulpha drug that doctors sometimes use to maintain high levels of certain drugs, such as penicillin. In some studies in the late 1980s, doctors gave their patients probenecid to keep blood levels of AZT high. Some of those patients were told to reduce their dose of AZT by as much as 50%. In the experiments with cidofovir, researchers gave subjects probenecid to protect their kidneys from damage and in most cases it did.

* REDUCING THE TOXICITY OF PROBENECID

Since some people with HIV/AIDS cannot tolerate sulpha drugs, it is not surprising that some subjects in this study had allergic reactions when given probenecid including nausea, rashes and vomiting. To make subjects withstand the allergic reactions, the study doctors gave some subjects antihistamines. To others, the doctors first gave small doses of probenecid that were later increased over three weeks.

* DESENSITIZATION

For the first dose, doctors gave the subjects "10 mg, increased by 10 mg/kg on days 2 to 5, 20 mg/day on days 6 to 10, 100 mg on day 11 and 250 mg/day on days 12 to 18". To reduce 'upset stomach', subjects were eventually told to take the drug "after meals". Use of probenecid "did not appear to [weaken] the anti-CMV effect of cidofovir". Subjects receiving the 3 mg/kg dose of cidofovir and who were also taking probenecid had a delay in the time it took to suppress production of CMV (from 7 to 27 days).

* SYMPTOMS

One subject who had a herpes lesion near his rectum which did not heal despite receiving acyclovir had his lesion heal when he started to use cidofovir at 5 mg/kg week. Another subject with 'oral hairy leucoplakia' on his tongue had that infection clear after his first dose of cidofovir also at 5 mg/kg/week. Cidofovir used in this experiment was supplied by Gilead Sciences, Foster City, California.

REFERENCES

1. Lalezan JP, Drew WL, Glutzer C, et al. (S)-1-[3-hydroxy-2-phosphonlmethoxy)propyl] cytosine (cidofovir): Results of a phase I/II study of a novel antiviral nucleotide analogue. Journal of Infectious Diseases 1995;171:788-796.

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