Highly Active Anti-Retroviral Therapy (HAART), or combination therapy, is nearly ten years old. The first protease inhibitor, Invirase® (saquinavir hard gel capsule), was approved by the U.S. Food and Drug Administration (FDA) on December 6, 1995. One could say that March 1996 really kicked off the HAART era with the FDA's approval of Norvir® (ritonavir) and Crixivan® (indinavir) on March 1 and March 13, respectively. Either way, the advent of protease inhibitors dramatically shifted medication strategies from monotherapy to combination therapy and standardized HAART as the best clinical practice for treating HIV/AIDS.
At the end of 1995 -- ending the first 15 years of the AIDS pandemic -- only six antiretroviral medications were available for the treatment of HIV disease: five nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI). By the end of 2005, the number of HIV medications has swelled to 28. Four classes of HIV drugs are now available in the U.S., including a handful of reformulations of older medications, four fixed-dose combinations and one FDA-approved generic. Other fixed-dose combinations and additional generics are available outside the U.S.
In some respects, our progress over the last ten years has been limited. In 1995, the FDA approved Invirase. In 2005, the FDA approved Invirase ... again! The new Invirase is a 500 mg. tablet used with Norvir boosting, but it is still just a reformulation of an existing medication. This is not necessarily a bad thing. Reformulations of older medications have reduced pill counts, eased dosing schedules, lowered toxicity and side effects, and increased the efficacy of the medications. Research in the last ten years has yielded some significant advances (such as once-daily regimens and "boosting" strategies), but also some disappointing setbacks (such as the failed hope of structured treatment interruptions and potential new medications that never made it to market).
Some of these setbacks, however, ultimately yielded progress in other areas of virology. Some failed candidates, such as the non-nucleoside reverse transcriptase inhibitor (NNRTI) UC-781, show promise for other uses such as topical microbicides (products such as gels or creams with the ability to prevent the sexual transmission of HIV and other sexually transmitted diseases when applied topically). Adefovir, which did not receive FDA approval as an HIV medication, was later approved as a treatment for hepatitis B under the brand name Hepsera®.
Besides the setbacks, the advances in HIV research have also contributed to progress in other areas of treatment and prevention. Epivir® (lamivudine), one of the most widely used HIV medications, is also approved for the treatment of hepatitis B. Viread® (tenofovir), a nucleotide reverse transcriptase inhibitor, is currently being studied as a post-exposure prophylaxis (PEP) agent for HIV-negative individuals to prevent HIV infection.
So, what do the next ten years hold in store for HAART? Currently, there are over one hundred new HIV medications in development. As of October 2005, Treatment Action Group (TAG) identified 112 antiretroviral agents in the pipeline of new drugs coming our way. Of course, not all of these drug candidates will come to fruition. Toxicity, side effects, stability, dosing schedule and pill counts, effectiveness, cost and other factors will send scientists back to the proverbial drawing boards with many of these agents.
Of the 112 agents in development, 43 of them -- roughly 38% -- are from the three main classes of HIV inhibitors already in use -- nucleoside reverse transcriptase (NRTI), non-nucleoside reverse transcriptase (NNRTI), and protease (PI). Another 30 candidates -- about 27% -- are entry inhibitors (EI), like Fuzeon® (enfuvirtide), though many of them target different binding, fusion or entry mechanisms than the one EI currently available.
The remaining 39 agents -- around 35% -- represent new classes of medications that are not currently available commercially. These classes include integrase inhibitors, maturation inhibitors and other types of HIV antagonists. These novel agents, along with the various entry inhibitors, offer some of the most promising research to date.
A ten-year-old has a limited vocabulary, and HAART, at ten, has become accustomed to its base vocabulary -- mainly NRTI, NNRTI and PI. But in the coming years, HAART's vocabulary is going to expand significantly. So, start making your vocabulary flash cards now. I would start with the following: entry inhibitor, CCR5 inhibitor (or antagonist), and CXCR4 inhibitor. Some of these new drugs are far enough along in clinical trials that you will be seeing them soon. Hopefully, it will not be long before you are using these terms in casual conversations!
In 2015, ten more candles will be added to HAART's birthday cake. It is my wish that every one of us who is here for HAART's tenth anniversary will be around to celebrate its twentieth. And I trust that it will be these new and forthcoming HAART medications that help us get there.
Guy Pujol, D.Min., is the Executive Director of AIDS Treatment Initiatives (ATI) in Atlanta, Georgia.