SEPTEMBER 1998

NUMBER ONE

Wanted: Fewer Pills, Simpler Regimens
By Richard Jefferys

It's well known that the more complicated a drug combination is, the harder it is to stick to a drug schedule. Drug manufacturers are now working to simplify dosing regimens and to help overcome poor adherence, side effects, and drug resistance linked to HIV combination therapy (see below). New reports show once-daily dosing of ddI, 3TC, and nevirapine look promising. But it's important to realize that not all drugs can simply be switched from two times a day down to one, for example, because they don't stay in the body long enough to be effective at reduced doses.

Sustiva (efavirenz, formerly DMP266): At the recent World AIDS Conference, the biggest splash was made by a new once-daily drug called Sustiva (DuPont Pharma), a non-nucleoside reverse transcriptase analog. A study in drug-naive patients compared AZT/3TC/Sustiva to the most widely used "standard of care" regimens-AZT/3TC/Crixivan-and to a Sustiva/Crixivan combination. After six months, 74.5 percent of the AZT/3TC/Sustiva group had viral-load counts below 400 copies ("undetectable" by a standard viral-load test) compared with 56.2 percent in the AZT/3TC/Crixivan group. People who began the study with viral loads over 100,000 copies also had very positive results: Ninety percent of those taking AZT/3TC/Sustiva had "undetectable" viral loads below 400 copies.

Safety/Side Effects: The major side effects from Sustiva are on the central nervous system, although in this study they didn't cause many people to stop taking the drug. Mild side effects, such as dizziness, sleeplessness, feeling "out of it," and anxiety, get better after a couple of weeks, say researchers. There were also more cases of rash in people in the group taking Sustiva than Crixivan. Using Sustiva at lower doses (200 mg a day or 400 mg a day) produces fewer side effects, while 600 mg a day may be too high a dose for some people, particularly those with lower weight. Pregnant women shouldn't use the drug, which caused birth defects in fetal monkeys.

Sustiva can cause a false positive THC (marijuana) reading on one type of urine test (Cediadau multilevel THC assay), but DuPont Pharma officials say that a confirmatory test for THC will show it is a negative result. The problem alarms AIDS advocates since drug testing of employees and inmates in prison is common. There's no evidence Sustiva induces the THC brain receptor.

Hydrea (hydroxyurea or HU) is a 35-year-old cancer drug that targets cell enzymes, not viral enzymes like most HIV drugs, and blocks T-cell activation. It appears to work against resting T-cells that can harbor HIV and helps NRTI drugs like ddI work better, even if HIV has developed resistance to ddI. Studies at Geneva compared four different ddI-based combinations (ddI/d4T/HU; ddI/HU; ddI/AZT; ddI/d4T) and found the three-drug combination with hydroxyurea worked best. In that group, 75 percent of people had viral loads below the detectable level (under 400 copies), compared with 50 percent of those taking only ddI/d4T. But there were smaller T-cell increases in the hydroxyurea arm (30 T-cell increase with HU compared with 90 T-cells on ddI/d4T).

Safety/Side Effects: So far, hydroxyurea has produced few side effects in the vast majority of patients, but those with advanced HIV disease may be vulnerable to bone-marrow suppression. Side effects may include nausea, anemia, neutropenia (low white-blood cells), bone-marrow suppression, and, very rarely, dry mouth. If side effects don't appear within the first weeks, says researchers, they aren't likely to develop. Since long-term use of hydroxyurea can cause bone-marrow suppression, the drug should be used with caution in those with low T-cell counts and those taking AZT, which also causes anemia.

Ziagen (abacavir) is Glaxo Well-come's new AZT-like nucleoside analog drug. Unlike with the above study, the company is testing a three-drug combination using abacavir with a two-drug combination of AZT and 3TC. (Two-drug combinations have not been generally recommended for HIV treatment for some time now, particularly those with 3TC, since HIV can develop resistance to 3TC within two weeks in a two-drug combination.)

After three months, 75 percent of people taking the three-drug regimen had viral loads below the limit of detection (under 400 copies) compared with 35 percent of those taking two-drug regimens.

Safety/Side Effects: There were some dramatic differences in reported side effects between this study and the Sustiva study described above. Nearly half the participants in the three-drug group experienced nausea (feeling sick), malaise (weak, sick feeling), fatigue (tiredness), and vomiting. A slightly smaller percentage taking the two-drug combination reported similar problems. For now, side effects may be a reason to be cautious about using abacavir/ AZT/3TC as a first-line treatment combination.

Twice-Daily nelfinavir (Viracept): A study compared the standard thrice-daily 750 mg dose of Viracept with a 1250 mg twice-daily dose (both groups also took d4T and 3TC as part of their combination.) After 48 weeks the two groups had similar results, with nearly 80 percent of people in each group having viral loads below the limit of detection. A more sensitive viral-load test revealed that about 60 percent of people in each group had viral-load counts below 50 copies. Average T-cell increases were also comparable (189 CD4+ cells in the twice-daily group; 166 in the thrice-daily group). Viracept is well known for causing diarrhea and twice-daily dosing did not seem to increase diarrhea. Many doctors now support using of a twice-daily 1250 mg dose.