A Rare Moment in Time
There are three new drugs coming to pharmacy shelves in the next 12 months that might conceivably herald a revolution for HIV-infected people who have developed resistance to many or most available drugs. (This group of so-called "salvage patients" also includes previously untreated people who were infected with drug resistant HIV.)
Thousands of people live with unsuppressed HIV infection because they cannot benefit from or cannot tolerate enough of the currently approved drugs to construct an effective combination antiretroviral (ARV) regimen. During the ten years following the first flowering of HAART in 1996, whenever researchers developed a new drug that could help highly treatment-experienced people, there often were no other new drugs to add along with it, and treatment success was short lived. Eventually, HIV physicians and patients learned that simply adding one new drug to a failing regimen composed of previously prescribed drugs was virtually the same as using the new drug alone, the result being treatment failure due to resistance.
What is special about this time is that these toughest-to-treat patients will -- if their doctors are smart about it -- be able to combine several new drugs that have the power to knock down viral replication and keep it down for years to come.
Etravirine (TMC125), an NNRTI from J&J/Tibotec, seems to be effective against some (but not all) HIV that is resistant to efavirenz (Sustiva) and nevirapine (Viramune). Raltegravir (Isentress), from Merck, is the first drug to attack the HIV integrase protein, and it should be active against multidrug-resistant HIV by virtue of its first-in-class status. Raltegravir impressed the 2006 International AIDS Conference by showing it could knock down HIV viral loads twice as rapidly as efavirenz in a treatment-naive study population. Its performance in studies with highly treatment-experienced patients has been equally impressive.
Because these two drugs do not interfere with one another pharmacologically, the sponsors allowed their combined use in expanded access protocols aimed at treatment-experienced patients. The response to the opportunity to add at least two new active drugs has been dramatic. Enrollment in the etravirine and raltegravir expanded access programs has been brisk. It is not yet clear if most expanded access patients are combining these two drugs or are incorporating darunavir or enfuvirtide (T20) as a second, third, or fourth drug in their combination. Regardless, even normally dour researchers have been uncharacteristically enthusiastic as reports trickle in about long-time salvage patients achieving undetectable viral loads for the first time. Indeed, if these people remain undetectable, then the talk may be justified.
The third new drug on the scene is the CCR5 antagonist, Maraviroc (Celsentri), from Pfizer. This first-in-class drug is capable of benefiting patients with long, troubled treatment histories, although a few limitations have held back enrollment in its expanded access protocol. The first problem is that blocking the CCR5 coreceptor molecules that HIV uses to infect new target T cells does not help every person who has HIV. Some forms of HIV use a different coreceptor, and the likelihood of having a virus that uses the alternate coreceptor increases the longer one is infected. Thus, perhaps only 50% of people with more advanced disease can benefit from maraviroc.
For those with CCR5-tropic virus, the maraviroc's antiviral efficacy has been impressive. Before someone starts taking the drug, though, it is highly advisable to undergo a viral tropism test to determine which kind of HIV the person has and to predict its susceptibility to CCR5 blocking. Currently, the tests are expensive and can take up to two months to obtain. Another possible deterrent is the concern of a few scientists about the safety of a drug that sticks to one of the body's own immune messenger proteins (all previous HIV drugs have targeted viral proteins). These issues -- and the enthusiasm with which raltegravir has been received -- suggest that maraviroc may not be as quickly accepted as a major player in the new salvage therapy paradigm, although it has already proved its worth in large studies in highly treatment experienced patients.
This is a rare moment of opportunity for people who have struggled to get their virus under control to finally become undetectable. At least that is the hope, and it represents a convergence of circumstances that could have a huge impact on the nature of the epidemic in the wealthy nations.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.