Being Alive - November, 1999
Walt Senterfitt

Calcium May Help Control Nelfinavir-Related Diarrhea

Most all of us who have taken the effective protease inhibitor nelfinavir (Viracept) can attest that its most bothersome side effect is frequent diarrhea that may be difficult to control. For some, standard anti-diarrhea drugs now available over the counter are sufficient to control this. Others must resign themselves to always carrying extra underwear and/or taking stronger medicines (like tincture of opium or codeine) that can cloud mental functioning and cause dependence. An ICAAC study gives some hope. A small study of 24 patients taking nelfinavir gave each participant 500 mg of calcium supplement (easily available in any drug or grocery store) twice a day and asked them to chart any changes in their bowel habits after 48 hours. Before the study, 50% of the patients reported their diarrhea as mild (grade 1, one to three loose stools per day), 42% described it as moderate (grade 2, three to seven loose stools a day), and eight percent rated it as severe (grade 3, more than seven loose stools a day). All of these participants had been taking at least one anti-diarrhea drug.

After 48 hours, all patients reported improvement, with 16 (67%) reporting all normal stools and eight (33%) reporting mild diarrhea.

This is one treatment that anyone can try at home with very minimal cost and almost no risk!

Viagra and Protease Inhibitors

"The spirit is willing but the flesh is weak." This old proverb describes the frustration that many men with HIV experience with erection problems, which can be caused b y illness, medication side effects, psychological issues or other factors. Viagra has proven a welcome partner to many over the past year in reclaiming one function many consider necessary to a joyful life. But what are the risks of interactions with anti-HIV drugs, especially protease inhibitors (pis), that can cause so many drug-drug interaction problems?

Two studies at ICAAC shed some light. Careful interaction studies were carried out on volunteer subjects who took Viagra with saquinavir, ritonavir or indinavir. All three of these pis increased the concentration of Viagra (sildenafil, generically) in the bloodstream, whereas the blood levels of the pis were not changed by Viagra.

The saquinavir and ritonavir interaction studies were done with healthy HIV-negative volunteers, who got Viagra (100 mg) each day for 8 days with escalating doses of either SAQ (1200 mg three times a day) or RIT (escalating from 300 mg twice a day to 500 mg twice a day). The investigators did not feel as though a reduction of dose in Viagra was necessary for persons taking saquinavir. However, the increase in Viagra's availability was 11 times with ritonavir, and the scientists recommended therefore that Viagra dose be reduced to no more than 25 mg, and that it be taken no more often than once every 48 hours for those who are taking ritonavir.

The other study was of HIV+ persons actually taking two nrtis together with indinavir (Crixivan). These men were given a dose of just 25 mg of Viagra together with their HIV medications. The analysis showed that Viagra's availability was increased four times, and furthermore the men all reported side effects of headaches and flushing that are frequently associated with too high doses of Viagra. In light of these findings, the investigators recommended that men taking indinavir should cut the dose of Viagra used to 12.5 mg, and should use it no more often than twice a week. Note: These more conservative recommendations were based on the experiences of HIV+ persons actually taking pis regularly. It might be smart for everyone on any pi who wants to use Viagra to start at this lower level, and increase it only if the lower level is both ineffective and free of side effects. However, because these side effects can be associated with life-threatening drops in blood pressure, no one should use Viagra without prior consultation and planning with one's HIV physician.

Grapefruit Juice May Be Okay with Crixivan After All

The package insert that comes with Crixivan warns that grapefruit juice could increase the levels of indinavir in the body. A study reported at ICAAC took 15 HIV+ patients on indinavir, but on no other medications metabolized by the same pathway that could affect indinavir's concentration, and gave them either doubly-concentrated grapefruit juice or water. The results showed that though stomach acidity was increased, there was no change in the measured values of indinavir in the bloodstream afterward other than a mild prolongation of the maximum level achieved. A fair conclusion appears to be to drink it if you want to--it will make no significant difference one way or the other.

Heart Attacks Still Rare ... But They Are Happening

A new letter to the editors of the Annals of Internal Medicine, a respected journal, describes four heart attacks that occurred in men aged 35 to 44 who had been taking protease inhibitors for two years, in a practice in Kalamazoo, Michigan. The men were all smokers. Two had developed high blood lipid levels and high cholesterol levels only after starting pis, one had elevated blood lipids before starting his pi and one had no lipid abnormality at all at the time of his heart attack. Two of the heart attacks were fatal. There was no particular pi that seemed to be implicated more than another.

Comment

The interaction of HIV, protease inhibitors and other antiretrovirals and the risk of heart disease or diabetes have been of growing concern over the past two to three years. We know enough to know that we don't understand these phenomena very well. There is more than one process going on. We don't know how to predict real problems or to distinguish which laboratory abnormalities are likely to result in actual damage to the heart and blood vessels. We can only say, at this point, to monitor things with your physician very closely. It stands to reason, though there are no data supporting this position, that reducing other cardiac risk factors like smoking or lack of exercise is a good idea.

Flush-Out Theory Flushed

No less an authority than Dr. Anthony Fauci, who oversees most clinical HIV research for the National Institutes of Health, had put forward the hope that il-2 (interleukin 2) could be used to stimulate the immune system of people whose viral loads had long been undetectable, in turn flushing out the HIV lurking in hidden, inactive reservoirs in the body. The theory also assumed that effective HAART would continue and prevent these newly flushed out viruses from infecting any other cells in the body while they were being eliminated.

The NIH tested this theory on 18 patients with viral loads that had been continuously undetectable by the most sensitive tests for at least one year. All were on triple-drug combination therapy. Twelve of the 18 were treated with il-2. Then HAART was stopped, to see if viral load would bounce back. It did, in 17 of the 18 patients, and rather rapidly and robustly at that. So this was a test not only of the flushing theory, but also of whether or not prolonged "full" suppression of the virus leads to a slowed or dampened viral rebound.

With or without il-2, the answer for now is "No."

As Dr. Fauci said this week in announcing these results, "This was extraordinarily disappointing." There was a difference between some of the rebounding HIV compared to samples taken previously, suggesting that at least part of the new virus came from unknown reservoirs in the body. "There is something about the virus that is obviously very clever," Fauci said.

However, neither Fauci nor others who believe either in flushing or in "structured treatment interruption" are anywhere near giving up. They will continue to design new experiments with various agents.

How Many Are Infected?

The CDC estimates that at the end of 1999 there will be about 750,000 people living with HIV in the United States. The United Nations estimates that there will be 33,400,000 living with HIV around the world, 95% in developing countries.

Resistant Virus Spreading

The Journal of the American Medical Association recently carried a study of 141 people (including a number from Los Angeles) who had seroconverted to HIV+ within the previous 12 months. Of this group, 36 (26%) were found to have genetic mutations consistent with resistance to one or more currently used antiretroviral drugs, at a level of a 2.5-to 10-fold reduction in sensitivity to the drugs. This is the first reported study of the prevalence of resistant virus among a significant group of newly infected individuals. Two of these 36 showed resistance to multiple drugs. The good news is that only one of these patients demonstrated resistance to both an nrti and a protease inhibitor and that only 3 of the 36 had a very-high-order resistance (greater than 10-fold reduction in sensitivity). These were all genotypic results, based on genetic analysis of the isolated virus only, so the clinical significance of these resistance patterns is not known.

Comment

The scientists believe it likely that all of the observed mutations came from infection with the mutated strain (as opposed to spontaneous mutation within the person's body). How significant it is at a clinical level is important to determine, as are geographical differences in the spreading of resistant virus. This is a very critical goal for all of us in the prevention for positive initiatives that Being Alive is supporting--development of an epidemic of resistant virus is something that will harm us all.

Please feel free to e-mail me with your comments at WSenterfit@aol.com