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Every day a barrage of HIV research is published and presented around the world. Even if you were to read all the journal articles and research meeting coverage related to HIV, how should you evaluate the importance of individual studies? That's when it helps to know someone who is himself knee-deep in the research.

Welcome, Dr. Wohl. Tell me, what did you think was the number one HIV research study of 2007?

There were actually a bunch of important research studies. The big story is that there are new drugs, and they work really well. In 2007 there were a few different studies of new drugs that are opening up a whole new opportunity for people with HIV infection.

I've heard people say that it's just like it was in 1996, when HAART [highly active antiretroviral therapy] was approved. There's a lot of hope now in the air because of all these new drugs.

What do you think is the most important area of HIV treatment research today? Figuring out when, and with what, to start HIV treatment Developing new meds for people with HIV drug resistance Finding ways to fight HIV besides antiretrovirals Creating HIV meds that don't cause difficult side effects Finding causes for metabolic and cardiovascular problems in HIVers Learning how gender and race affect the way HIV and meds work Finding a cure None of these

I think the difference between 1996 and 2008 is that we're smarter. That doesn't mean we're smart, it just means we're smarter. I think we've learned a lot from our mistakes, from the science that's gone on, and from our patients. What we're seeing now is a new day in HIV care, where there are some more options, and they're not what I call "me too" drugs. They're not retooled versions of old drugs. These are actually new compounds that can work against the virus. I don't know if it's completely analogous, but in many ways it is like 1996 for someone who hasn't had very much in the way of options, but now does and is really committed to taking his or her therapy. We have to remember that a person can have all the new drugs in the world and they can all be potent, but unless the person is committed to taking his or her medicines and taking them as directed, it doesn't matter how novel and new or potent it is.

Can you list these new drugs?

There are several of them. The first one that I want to mention is Isentress [raltegravir, MK-0518].^1,2 This is a totally new drug in a new category of drugs. It works on an enzyme called integrase, which was never targeted before. It works within the HIV virus to keep the HIV virus from making more copies of itself.

Another one is called Selzentry [maraviroc, Celsentri].^3,4 Selzentry is a very new type of drug; it blocks the entry of HIV into the cell by blocking a receptor that the virus needs to get into the cell. Very exciting.

Another new medicine that is now available is Intelence [etravirine, TMC125].^5,6 It's part of a new generation of non-nucleoside reverse transcriptase inhibitors. The previous generation of non-nucleosides includes Viramune [nevirapine] and Sustiva [efavirenz, Stocrin].

Another new medicine that I think is exciting is called Prezista [darunavir, TMC114]. It's a potent protease inhibitor that works against protease inhibitor-resistant virus.⁷

These are four really exciting new drugs that are making a tremendous difference for people who have experience with HIV drugs and have resistant virus.

There are really good data to show that, in people who are HIV infected and who have resistant virus, each of these drugs -- in combination with other drugs -- can get their viral load undetectable. One thing we're seeing consistently throughout these studies is that the more new drugs that are active against your virus, the better, and the greater the chance that your viral load will become undetectable. This is true even if you have dripping red genotypes that show so much resistance that nothing else is predicted to work.

What we're seeing is that when you have two, or possibly even three, newer agents that work against your virus, it works great. Before we had these newer medicines, there just wasn't a critical mass. There weren't enough new medicines to craft a regimen that was likely to work in people whose HIV was already resistant to a lot of HIV medications. With these newer drugs, there's now more to pick from. Two, or even three, active medications should work against a person's virus. It opens up tremendous new opportunities for people who, before these drugs came about, didn't have any opportunities.

Are these drugs going to be used at all for people just starting therapy?

There's always an interest among the manufacturers of drugs like these to try to get the use of their drugs to expand beyond one niche. A drug comes out that's used in what we call salvage therapy -- meaning people who need new drugs to rescue them because they have resistant virus and the other drugs aren't working -- and then the manufacturer tries to get it to work in a treatment-naive person. "Treatment-naive people," that's our jargon for people who've never been on HIV therapy before. It makes sense, because then the drug manufacturer gets a broader market for its product. In every single one of these cases, there's some interest in using these medications early on.

For different drugs, there's a different amount of data supporting them. We know that there's a big interest in using Prezista early on, because it's a protease inhibitor and we do use protease inhibitors early in HIV therapy, including as initial therapy.⁸ That's a no-brainer.

I think there certainly is interest in using more novel agents such as Selzentry and Isentress early on, and studies are ongoing of those medicines.⁹ For Selzentry, there was one study that looked at it against Sustiva early in HIV therapy.¹⁰ It didn't do as great as Sustiva, but it looked pretty decent. I think it's encouraging.

Intelence is a drug that people will also look at for initial treatment. The answer to your question is definitely yes.

Let's move on to the number two most important study of 2007.

Is this the dawn of a new era in HIV care? I think arguably it is. But one thing we're still dealing with is too many people are coming in too late to HIV care.

There was a very important study done by the Johns Hopkins group.¹¹ The investigators looked at the immune status of people presenting for care in their clinic in Baltimore. The bottom line was that over time, we really haven't seen improvements in this. In fact, if anything, we're seeing people come in with lower CD4 cell counts. There are data that have been presented before that indicate that the average T-cell count of people presenting for care in the United States is under 200.¹² It's about 187.

What the Hopkins group was able to do was to look at their patient population over different chunks of time.¹¹ They found that, again, people are entering care who have never been on HIV therapy before, with decreasing CD4 cell counts.

This is really concerning, because it means people are showing up late. It means people are not getting tested earlier in the course of their HIV infection. We know that people who start therapy at lower CD4 cell counts have a greater risk of side effects, and may not respond as well as people who have higher CD4 cell counts.

So it's very concerning. It shows that we are not doing a good job of offering HIV testing and having people utilize HIV testing on a more regular basis.

So this is a failure in HIV prevention?

I think this is a failure in HIV detection.

Detection?

Certainly there is, taking a step back, a failure in prevention and that's why people are getting infected. But what we're seeing here is that we are not doing a very good job of diagnosing infection as evidenced by the fact that:

1. Twenty-five to 30 percent of people with HIV in this country do not know they're HIV infected,¹³ and
2. People who are diagnosed are getting diagnosed pretty late in the course of their disease.

That has implications not only for that person's health, but also for the public health. That means under-diagnosis leads to people having sex with people and possibly transmitting their virus unbeknownst because they didn't know they were HIV infected.

I think there are a few different dimensions here that are very concerning. In this analysis, it's very interesting that being older, being male, and being African American were independently associated with having a lower CD4 cell count on presentation. That tells us that not only is there a problem, but that there's a problem among certain subpopulations that's very concerning.¹¹

Did the researchers suggest anything?

The glaring neon light shining here is that we should be doing more testing. The CDC [U.S. Centers for Disease Control and Prevention] came out with some important recommendations, saying that anyone who's in medical health care should be tested for HIV.¹⁴

I think that's really important. I think we should have routine HIV testing. You visit your doctor for your annual physical and the doctor offers you an HIV test. If you have risk behaviors, the doctor should continue to offer you that regularly.

I think we're under-testing people, and we're not using our health care system as a tool. It's a very important tool in HIV prevention when used to detect people with HIV. We've done it with pregnant women; pregnant women know that when they come into perinatal clinics, they're going to be offered HIV testing. We need to have that happen for people coming in to get their blood pressure checked, their cholesterol checked.