Anti-HIV Drugs: New Findings
Maintenance Therapy for HIV
For the past couple of years, anti-HIV treatment combinations (often called HAART, for "highly active antiretroviral therapy") have usually included two NRTI (nucleoside analog reverse transcriptase inhibitor)-type drugs (AZT, ddI, ddC, 3TC, d4T, abacavir) and a protease inhibitor (Crixivan, Fortovase, Norvir, Viracept). Because these can be complicated to take, some studies have tried "stepping down" -- seeing if just one or two drugs can keep HIV under control after a person has been on HAART for six months to a year.
Unfortunately, none of these studies have shown good results. After stepping down to fewer drugs, a significant number of people had increases in viral load.
Recently, a group of French researchers has tried a slightly different approach. Instead of stepping down to fewer drugs, they changed the protease inhibitor to an NNRTI (non-nucleoside analog reverse transcriptase inhibitor) drug, similar to the lipodystrophy studies reported previously in "Simply Medical." Eighteen people were included in the study. All study participants had been taking a HAART combination including a protease inhibitor for at least a year. Study participants were also required to have had a viral load of less than 200 copies for at least six months. No one in the study was allowed to have taken an NNRTI-type drug before.
Sixteen people switched their protease inhibitor for the NNRTI drug Viramune (nevirapine) given at a dose of 400 mg once daily. Viramune is usually given twice daily, but recent studies have suggested that once-daily dosing may work just as well. The other two participants switched to Sustiva (efavirenz) at the standard dose of 600 mg once daily. Everyone stayed on the same two NRTI drugs that they were already taking (d4T/3TC, AZT/3TC, or d4T/ddI).
After the switch, study participants have been followed for an average of about four months. The study is ongoing. So far, all but one participant have maintained viral load levels less than 200 copies. The one person whose viral load increased (to 38,000) was found to have taken the NNRTI drug called Rescriptor (delavirdine) several years ago.
The likely explanation is a problem called cross-resistance. HIV can mutate in ways that stop anti-HIV drugs from working. This is called drug resistance. When HIV mutates in a way that stops one NNRTI-type drug from working, it often means other NNRTI drugs won't work either. This is what's known as cross-resistance. The same problem can happen with protease inhibitors. The important point is that the option of switching from a protease inhibitor to an NNRTI is only open to people that have never taken an NNRTI drug before.
In terms of side effects, only one of the sixteen study participants who took Viramune developed a rash. The rash was mild and went away on its own. Other studies have suggested that Viramune-related rash can be avoided by giving either antihistamines or low-dose prednisone during the first two weeks of treatment. One person was started on Sustiva, but changed to Viramune after three days due to severe vertigo (dizziness).
All in all, switching from a protease inhibitor to Viramune or Sustiva looks like a promising strategy for simplifying HIV treatment. Six of the eighteen study participants had a history of CD4 cell counts less than 50, which also suggests that the strategy can work for people at varying stages of disease. Larger studies are now needed to confirm these results.
Amprenavir (trade name Agenerase) is the latest in the class of anti-HIV drugs called protease inhibitors. The other available protease inhibitor drugs are Crixivan, Fortovase, Norvir, and Viracept. These drugs work by blocking a part of HIV called protease. When protease is blocked, HIV makes copies of itself that can't infect new cells. Agenerase is now approved for prescription and should be available in pharmacies by the time you read this article. The standard dose of Agenerase is 1,200 mg (eight pills) taken twice a day with or without food. It's worth mentioning that these pills are pretty big.
Trial Results: One study compared the triple combination of Agenerase, AZT (Retrovir), and 3TC (Epivir) to the double combination of AZT/3TC. This study started some time ago. The double combination of AZT/3TC is no longer recommended for the treatment of HIV. No one in this study had taken anti-HIV drugs before.
The study only lasted six months. At the end of the study, just over half (53 percent) of the 116 people taking Agenerase/AZT/3TC had viral loads less than 400 copies. In the AZT/3TC group, only eleven percent (one in ten) of people had viral loads less than 400 copies. The average increase in CD4 cell counts was about the same in both groups.
Another study compared Agenerase taken with two NRTIs (the approved NRTI drugs are AZT, ddI, ddC, d4T, 3TC, and abacavir) to the combination of Crixivan (indinavir) with two NRTIs. People in this study were allowed to have taken NRTI anti-HIV drugs in the past. This study has only been going on for six months. So far, 109 of the 254 people (43 percent) in the Agenerase/AZT/3TC group have viral loads less than 400 copies. In the Crixivan/AZT/3TC group, 132 of the 250 people (53 percent) have viral loads less than 400 copies.
It's very difficult to compare the strength of Agenerase's anti-HIV effect with that of other approved protease inhibitors based on these results. The only direct comparison is the second study, comparing Agenerase to Crixivan. Unlike many other protease inhibitor studies, this study enrolled people who already had taken NRTI drugs. Also, both studies have only been going on for six months. Still, it does appear from these results that the anti-HIV effect of Agenerase may be slightly weaker than that of other approved protease inhibitors. Further study results should provide clearer information about the strength of Agenerase compared to other protease inhibitors.
Side Effects: The major side effects of Agenerase are nausea, vomiting, diarrhea, headache, stomach pains/gas, rash, and numbing sensations on the skin, particularly around the mouth. Skin rashes have occurred in about one in four people taking Agenerase. In some cases the rash is mild and treatment can be continued. About one percent of people taking Agenerase developed a severe, life-threatening allergic reaction called Stevens-Johnson Syndrome. In cases of severe rash, Agenerase must be stopped. In studies, about one in three (around thirty percent) of people taking Agenerase chose to drop out and stop taking the drug. About half of these dropouts were due to side effects.
So far, Agenerase does not seem to be causing increased fat levels in the blood, a known side effect of the approved protease inhibitors. There are also some test-tube studies that have suggested that Agenerase may be less likely to increase fat levels than other protease inhibitors. However, Agenerase studies in people may not have been going on long enough for this side effect to show up. People taking Agenerase should still have triglyceride and cholesterol levels monitored regularly. Protease inhibitors have also been associated with high blood sugar and diabetes, and these side effects should be watched for if you're taking Agenerase.
Combining Agenerase with Other Anti-HIV Drugs: There are no serious interactions between amprenavir and nucleoside analog anti-HIV drugs (AZT, ddI, ddC, d4T, 3TC, abacavir).
An early study found that amprenavir can be safely used in double protease inhibitor combinations. The following combinations have been studied in a small number of people: Agenerase/indinavir (Crixivan), Agenerase/nelfinavir (Viracept), and Agenerase/saquinavir (Fortovase). No changes in doses were needed. The combination of ritonavir (Norvir) and Agenerase has not been studied.
The NNRTI drugs delavirdine (Rescriptor) and nevirapine (Viramune) have not been studied with Agenerase. Based on what is already known about the drugs, it is likely that Rescriptor will increase Agenerase levels. Viramune is likely to reduce Agenerase levels. A study has shown that efavirenz (Sustiva) lowers Agenerase levels in the body. For these reasons, combinations of NNRTIs with Agenerase should be avoided until correct dosing has been worked out. It is rather surprising that the U.S. government would approve Agenerase without knowing how it combines with all available anti-HIV drugs. People interested in encouraging the manufacturer -- Glaxo-Wellcome -- to conduct interaction studies with Agenerase and NNRTIs urgently should call Michael Joyner, Glaxo-Wellcome Healthcare Coalitions, (919) 483-2987.
Other Drug Interactions: The drugs astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion), midazolam (Versed), and drugs called ergot derivatives should not be taken with Agenerase, as the interactions can be life-threatening. The tuberculosis drug rifampin should not be taken with Agenerase, as it lowers the amount of amprenavir in the body. If rifabutin must be taken with Agenerase, the dose of rifabutin should be cut in half.
The manufacturer of Agenerase has set up a patient assistance program for people having trouble obtaining or affording the drug. Call (800) 722-9294 for more information.
This article was provided by Body Positive. It is a part of the publication Body Positive.