ICAAC Round-up

CCR5 update

Patrick K. Dorr, of Pfizer, presented a complex report on interactions between the company’s CCR5 antagonist drug, maraviroc, and the CCR5 receptor on T-cells. CCR5s are from the entry inhibitor class of drugs. They help stop HIV from entering the cell, in this case, by preventing binding of the virus to the CCR5 receptor sitting on T-cells.

Basically, Dorr reported that, “You should be able to start with a CCR5 and if resistance occurs, shift to another CCR5.” In other words, this class of drug may not cause the cross-resistance seen in other drugs (where if your virus develops resistance to one drug, it also has resistance to other drugs in that class). Remember: this has yet to be shown in patients. (See also News Briefs)

Maturation inhibitor

There was also exciting news on a new class of drugs, maturation inhibitors, a late breaker (not scheduled, but deemed important) report. This was the first time that the results of multiple doses of PA-457 were reported. Previously, only single-dose results had been presented. (A single dose provides a good pharmacokinetic portrait of a drug, and helps development proceed to multiple dosing.)

Maturation inhibitors block the last step in gag processing, explained presenter George Beatty, M.D., M.P.H., of the University of California, San Francisco Positive Health Program. Briefly, gag processing occurs as HIV matures and leaves a cell to infect new ones.

As usual in early drug development, this was a very small study. Four doses were studied for 10 days, with six persons on each dose. The highest dose, 200 mg, saw the best results, a 1 log decrease in viral load. Beatty said that viral decay was still on its way down at the end of the 10 days.

One person achieved good levels of the drug in blood, but did not respond (see a decrease in viral load). There was one serious adverse event, cerebrovascular (related to the blood vessels of the brain) complication in a person with a history of hypertension, but PA-457 could not be ruled out. There were no significant (grade 3 or 4) laboratory abnormalities.

Beatty said there is little chance of drug interaction problems with PA-457 because it does not get processed the way most of the HIV drugs do, through the CYP-450 system of liver enzymes. Steady state blood levels were not achieved until Day 7, so results are based on three days of steady state. Longer studies will need to be done in order to validate these statements.

TMC-125: for Sustiva and Viramune failure

TMC-125 is the first non-nucleoside drug in development to show effectiveness against HIV that is resistant to other non-nukes (like Sustiva and Viramune), reported Dr. Howard Grossman of New York City. He presented another late breaker on 24-week results from a study called C223.

The results are especially important because when HIV develops resistance to the current non-nukes, it does so easily, with only one mutation. This makes this powerful and convenient class of drugs useless for many patients.

C223 was a large study, with 200 participants. They started out with more than 1,000 viral load and drug resistance to both the non-nuke class of drugs as well as the protease inhibitors (PIs). Their HIV had three or more primary mutations against the PIs.

Participants were put into three arms: a 400 mg dose, an 800 mg dose, or a standard of care HIV drug combination that did not include TMC-125. TMC-125 was given twice a day with other HIV drugs, as the study doctor saw fit for that patient.

People in the 800 mg arm did the best. They saw a 1.8 log reduction in viral load—an excellent decrease. Those on the 400 mg dose also did better than the people in the control group—they had a 1.04 reduction (also an excellent result) in their viral load compared to 0.19 (a poor result) for people on a standard of care regimen.

Rash is the primary side effect of non-nukes. This can become serious. Almost one in eight people taking TMC-125 experienced rash, and some had to stop taking it for this reason.

In a Medscape report (www.medscape.com), Mark A. Wainberg, Ph.D., wrote that, “These findings provide evidence that TMC-125 will probably be an important drug to rescue individuals who have failed currently approved [non-nucleoside] drugs. Because TMC-125 does not require boosting with ritonavir, the potential also exists that this compound will be useful in first-line therapy.”

In a previous report, on Study C203, presented at the 10th European AIDS Conference last year, about one in three people stopped taking TMC-125 or the comparator dummy pill because of side effects. About one in 15 people taking TMC-125 discontinued due to adverse events (vs. one in 30 for those taking the dummy pill). Diarrhea was the most frequent adverse event in both groups (one out of four for drug vs. one in three for the dummy pill). Rash occurred in one of six people on TMC-125 (vs. one of 10 people on the dummy pill). Pancreatitis has also been seen with TMC-125.

Brecanavir

Results from 24 weeks on a protease inhibitor in development were presented. Like almost all the PIs, brecanavir (640385/r) has its blood levels boosted by a small dose of Norvir, another PI (hence the small “r” in the chemical name, for the generic name of Norvir, ritonavir).

Of 31 persons enrolled, four discontinued the drug, two because of adverse events (one with nausea and vomiting and another with liver enzyme elevations) and two withdrew their consent. There were six women in the study.

At the end of 24 weeks, about 75% of the participants who started the study had undetectable viral loads. Half of these patients started out with a median of about 55,000. This is a really good response.

Persons with drug resistance to PIs had a very large drop in viral load, a median 2.2 log. Those whose virus was still sensitive to PIs saw an even greater reduction of 3.3 log. This is from on-treatment analysis, a less strict analysis that only looks at the people who stayed on treatment.

The most common side effects were fatigue (13%), nausea (10%), and indigestion (10%). Lipid increases were “modest.”

TMC-114

Like TMC-125, this drug is being developed by Tibotec. TMC-114 is a protease inhibitor, boosted with a small amount of Norvir (ritonavir). In the Power 2 study, participants on TMC-114/r did better at 24 weeks than the people taking a different PI. All participants had a treatment history with three HIV drug classes. The dose going into further development is 600 mg TMC-114 with 100 mg of Norvir, twice a day. ClinicalOptions.com reported one death from lung cancer that was possibly related to TMC-114.

Viramune in pregnancy

For a few dollars and a few doses, Viramune can dramatically cut transmission from a woman to her newborn. Used this way, however, it causes a high incidence of drug resistance.

In this report, researchers found that adding Retrovir (AZT) to the Viramune dose does not lead to a greater decrease in transmission. Further analysis will look to see whether adding Retrovir decreased the rate of drug resistance.

The study took place at the Salvation Army Howard Hospital in rural Zimbabwe. Of 7,467 pregnant women screened for the study (most of them subsistence farmers), 1,610 were found to be HIV-positive, for a prevalence rate of 21.6%. The presenter said that some women couldn’t deliver in the hospital because of food and gas shortages in the country. He said the results of this study confirm the finding of a previous one.

Mixed results for Sustiva

In yet another late breaker, final 144-week data was presented for A5095, from the Adult AIDS Clinical Trials Group (AACTG). Sustiva with Combivir (two drugs in one) was compared to Sustiva with Trizivir (three drugs in one). Drug substitutions—Viramune for Sustiva and Zerit for the Retrovir contained in Combivir—were allowed.

It was already established from previous reports that using the triple-drug Trizivir did not improve effectiveness over the dual-drug Combivir as a background to Sustiva. Both regimens packed a wallop—80% or more of all individuals saw their viral load stay below 50 at 144 weeks. This was using strict intent-to-treat analysis. They also sustained an average increase of 300 T-cells.

There was also no difference between the people who started out with a very high viral load—more than 100,000—and those who had less. The average starting viral load was about 70,000, and 43% of participants had more than 100,000. The average T-cell count was 240. These individuals had never been on HIV medication before.

But concerns over Sustiva’s side effects and effectiveness in African Americans have been raised, and A5095 confirmed those problems—to a degree.

There was a statistically significant shorter time to virologic failure (detectable viral load; in this study failure was defined as two measures above 200 twice in a row at 16 weeks or later) for African Americans compared to Whites. There was no greater risk for Latinos compared to Whites.

There was also a statistically significant shorter time to a Grade 3 or 4 adverse event and to discontinuation plus greater resistance at time of virologic failure for African Americans compared to Whites.

Looking further, one factor fell out as associated with virologic failure in African Americans: self-reported non-adherence—that is, missing doses or not taking medications correctly. (Perhaps this could have occurred due to greater side effects).

Those African Americans who reported being adherent did not experience more virologic failure than did Whites. There was also no difference in adherence between the two groups.

For everyone overall, people reporting non-adherence at 12 weeks had a shorter time to virologic failure. Also, people co-infected with hepatitis C had a greater risk of virologic failure (and African Americans may possibly have had a greater incidence of co-infection). There was a rate of any virologic failure of 25% for both arms (with some individuals going to undetectable later on).

Patrick Clay, a Pharm.D. who has specialized in HIV clinical pharmacy care since 1996, cautions patients not to be overly worried about the findings.

“The drug [Sustiva] is working for many people, including Black patients, and has also failed White patients. Basically, not all the drugs will work for everyone the same way. Some people will do better than others, some will not take the medicines as well as others,” said Clay. “We need to counsel, educate, and continue the course. This post-hoc analysis is just that—preliminary data that needs more information before we can act on it. People should not be afraid of going on this once-a-day, highly effective medicine.”

Of the 765 individuals in this study, the majority (56%) were people of color, an outstanding accomplishment in study enrollment. Whites made up 41%, African Americans made up 35%, and Latinos made up 21%. Almost one in five participants was a woman.

At 144 weeks, 80% of African Americans, 89% of Whites, and 91% of Latinos had less than 50 viral load.

“This is the real message of the study,” said Clay. “It works in at least 80% of people.”

A5095 originally had three arms, including one with Trizivir by itself that was dropped due to inferior effectiveness. (People who are doing well on Trizivir only need not panic.) As reported earlier, Trizivir had one hand tied behind its back due to the scientific blinding of the study—people had to take four pills twice a day (with three dummy pills for the Sustiva, as the dose was back then) instead of the normal dose, one pill twice a day. e

Special thanks to Patrick Clay, Pharm.D., for reviewing this article.