Coverage of 2006 International
Conference on AIDS

August 14–18, 2006, Toronto, Canada

Going It Alone with Monotherapy?

Paul Dalton, Treatment Advocate, Project Inform
August 17, 2006

Monotherapy (an anti-HIV drug regimen of a single drug) was once among the most feared words in anti-HIV therapy. Now, it is making a bit of a comeback.

Spurred by a small study by Dr. Joe Gathe that showed surprisingly good results using the anti-HIV drug, Kaletra, scientists have been re-examining the current three-or-more drug rule. Two late breaking presentations at the International Conference on AIDS in Toronto highlight further research on this topic.

The 96-week MONARK trial is comparing a relatively small group of people (136) taking Kaletra (ritonavir/lopinavir) + Combivir (a combination pill containing Retrovir [AZT , zidovudine] and Epivir [3TC , lamivudine]) to people taking Kaletra alone. , Using a conservative analysis after 48 weeks of follow-up, 71% of people on Kaletra alone had viral load below 50 copies, compared to 75% of those onKaletra + Combivir. Study leaders did not say whether this was a statistically significant difference or not.

A much bigger difference was seen when just looking at people still in the study at 48 weeks (called an as treated analysis). Looked at this way, 84% of people on Kaletra alone had viral loads below 50 copies, while 98% of people on the Kaletra + Combivir combination had HIV levels below 50. This suggests that when people are able to tolerate three-drug combinations, they may be more likely to achieve undetectable viral loads with the current three-drug approach than this experimental one-drug approach. It is important to point out that people did well in both groups.

In response to a question in Toronto, the lead investigator of the study claimed that everyone taking Kaletra alone who started the study with fewer than 100,000 copies of virus achieved viral load under 50 copies at 48 weeks. This suggests that a person’s initial viral load before starting treatment may be an important factor in determining whether it is safe to use a monotherapy regimen. However, this needs to be confirmed in larger and longer lasting studies.

In another study presented in Toronto, people with undetectable viral loads taking a three-drug combination of Kaletra and two nucleosides, were randomized either to stick with their three-drug combination or switch to a maintenance regimen of Kaletra alone. This approach to therapy is frequently called an “induction/maintenance strategy.” After 48 weeks, 85% of people taking Kaletra alone maintained viral loads below 50 compared to 90% of people taking Kaletra and two nucleosides. The difference was not considered statistically significant.

There are four important reasons to continue looking at reducing the number of drugs people with HIV must take. The first is long-term toxicity. Hopefully by reducing the number of drugs people take, the less long-term, accumulated toxicity will result. Second, fewer drugs in a person’s regimen could lead to an increase in the number of regimens available to a person over the course of their lives. Third, fewer pills are simply easier to take. Fourth, reducing the number of drugs can greatly reduce the cost of therapy. In the international setting, this reduced cost could result in a much greater number of people being treated.

While early reports of monotherapy strategies look encouraging, people should not rush to stop combination therapy or detensify regimens. Lessons learned from previous research on simplifying regimens showed us that short-term success fell apart over the longer-term and many who acted on early data risked developing resistance. This is definitely important research to follow, but it’s likely too soon to start making changes in therapy based on these early results.

The results of these two studies are encouraging and argue for more research on simpler anti-HIV drug regimes. Earlier this year at the Conference on Retroviruses and Opportunistic Infections, researchers presented early research looking at monotherapy using another boosted protease inhibitor, Reyataz (atazanavir). For a drug to be a good candidate for monotherapy it must be potent and be difficult for HIV to develop resistance to. Such drugs are said to have a high genetic barrier to resistance, which means the virus must acquire a number of mutations before it shows resistance to a drug. Currently, only boosted PIs meet these criteria (like Kaletra), but novel drug targets, like integrase, might offer more potential for this approach down the line. Another study presented at Toronto also shows this kind of result from Lexiva (fosamprenavir), a protease inhibitor from GlaxoSmithKline.