Earlier HIV/AIDS Treatment Recommended in New Guidelines: Expert Summarizes

Table of Contents

• Introduction
• Nuanced Changes to First-Line Treatment Recommendations
• Changes to the Preferred List of First-Line Therapies
• Clinical Management of Treatment-Experienced Patients
• Managing Patients With HIV-2
• Positive Prevention in the Clinic
• References

Introduction

David Wohl, M.D.

On Dec. 1, the U.S. Department of Health and Human Services updated its Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. We are pleased to have with us David Wohl, M.D., to provide a summary of the major changes. Dr. Wohl is not only one of the top HIV clinicians and researchers in the United States; he's also a guidelines panel member.

Can you walk us through what you think are the most important updates to the guidelines?

Let me first say that, while I'm on the guidelines committee, I'm going to be speaking to you today from my own personal experience and not as a representative of the guidelines themselves.

I think people should first recognize that the guidelines are important to use in a variety of different ways. For the clinician who is well versed in HIV therapy, there's a lot here that he or she is already aware of and knows. There is a lot of background. It is a really good primer on the management of HIV, with an updated perspective about state of the art HIV management in adult and adolescent patients, particularly those who are treatment naive.

For a clinician who doesn't see a whole lot of HIV, I think the guidelines are an excellent resource about the foundations of the management of HIV, and in addition, contain many references that the clinician can use to further explore.

Click here for a full PDF of the revised Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.

I often tell people, this is one of the things they should read. While it looks like a daunting document with lots of pages, half of it are references and a good proportion of it consists of tables. It's very, very readable and you can pick and choose the sections that are most apropos to what your concerns and interests are.

This particular revision reflects a lot that's happened in our field over the last year since we had updates to this guideline. The last full revision was about a year ago. In that time, a lot of data have come up, both in regards to when to start HIV therapy and also regarding different HIV regimens and their comparative efficacy and tolerability.

Nuanced Changes to First-Line Treatment Recommendations

Would you say that, for someone who followed all the HIV meeting news, there's nothing surprising in this document?

I think if people are hip and wise and come to TheBody.com or TheBodyPRO.com and keep up with what's going on, there will be few big surprises here. As you can see with the section on initiating HIV therapy in treatment-naive individuals, there is room for surprise here. This is an interesting recommendation, which suggests that we consider therapy at a higher CD4 cell count than we historically have done, at least in more recent history.

Antiretroviral therapy continues to be recommended for patients who have a CD4 cell count of less than 350, or an AIDS-defining illness or other qualifying illnesses. But now, it is also recommended that therapy be initiated for those patients with a CD4 cell count of between 350 and 500.

There is this interesting bullet that indicates that 55% of the panel voted for a strong recommendation, that's an A rating, while 45% voted for a moderate recommendation. There was consensus that there should be treatment recommended for patients with a CD4 cell count of between 350 and 500. However, the strength of that recommendation was split between an A (meaning a strong recommendation) and a B (meaning a moderate recommendation). This is something that's very important in the recommendations and in the guidelines.

One thing people don't always pay attention to is the rating of the panel's recommendations and the rating of the evidence. We really do think hard about this, as do all guideline committees.

A means strong; B means moderate; and C means that it is up to you, it's an optional recommendation. The number that comes after that is I, II or III.

"I" indicates that the evidence for the recommendation is based on data that are from randomized control trials, i.e., it's a slam-dunk from really important studies that are considered the gold standard. "II" indicates data from well-designed studies that are not randomized, such as observational cohorts. "III" indicates that it is just the opinion of the people on the guideline committee.

Thus, the strength of the recommendation that therapy be initiated in patients with a CD4 cell count of between 350 and 500 is strong to moderate, and it's based on II, meaning observational data, non-randomized trials.

For patients with a CD4 cell count above 500, the panel was evenly divided, 50/50, regarding starting therapy at this stage of disease. Fifty percent of the panel viewed initiating therapy at this stage as optional, while the rest felt more strongly. You can see that B (where it was moderate strength) to C (meaning it was almost optional) rating. The data here is mostly based upon non-randomized studies, observational cohorts and other types of studies, including pathogenesis studies. I think the biggest thing that people are going to talk about is when to start therapy, particularly in that over 500 range.

Don't you think that these recommendations could have been made easier for both clinicians and patients to understand and therefore put into practice if it did away with the rating scheme?

We want to make sure we reflect what we know, and there are gaps in what we know. I think guidelines should reflect what is known. There is a division among experts regarding what should be done. That's why you see in this document a very nicely laid out argument for both why therapy should be initiated earlier and some of the concerns regarding that.

This mirrors what we see clinically. We see clinicians who feel very strongly that we should do one or the other. In the absence of data, that's not atypical. We see that all the time, whether it is a question of, "Should we start therapy in people with opportunistic infections? Should we start with one drug verses another?" Until we have data, we basically are working in a vacuum. That's the case for when to start therapy in patients with a CD4 cell count greater than 500: we don't have as much data as we'd like; we don't have the forms of data. I think the general equipoise that we see in our treating community is well reflected in this document, but I think it allows people to start making decisions for themselves.

I also think you're right. This is a document that could be challenging for people to read front to back. I know that clinicians are busy, however, they're schooled and they can read this material. It just depends upon where they do it, when they do it and how they do it. It's really important to read the relevant sections that you care most about and that influence your practice. I don't think it would take too long for someone to read through the arguments laid out here, I think very thoughtfully, on when to initiate therapy and what to initiate, because both of those really influence how we practice.

You can't put all the arguments and all the discussion in one grey box. I think that the words that follow help people understand and then make a decision for themselves. The guidelines could tell you exactly what to do, and where there's strong evidence, it does that. Where there is less evidence, it says, this is something you have to think about. Your patient population may influence dramatically which way you go.

I was in New York not too long ago. I went to an academic medical center where a discussion about starting therapy at a higher CD4 cell count led to a lot of people saying, "No way. We have a challenged patient population. It's hard enough to get people on therapy that need it with low CD4 cell counts. How are we possibly going to get people who are well and are going to be on therapy for many years to take therapy earlier?"

The next day I was in the Bronx at a very small clinic -- small in size as far as space, but it sees lots of patients -- and they were completely down with treating people as early as possible. They see a lot of people with early HIV infections because there's a huge HIV testing outreach in the South Bronx. This clinic doesn't wait and has great success in reaching out to people and making sure they stay on their medicines.

Until we get more data, it's very hard for the guidelines to say, you should do this, or you should not do this, because there's harm in not doing something as well. I think that's reflected here.

Near the conclusion of the completely revised section on starting treatment, was an admission that most people are not diagnosed at anywhere near as high a CD4 cell count as 500, and that in order for the current guidelines regarding the earlier initiation of therapy to have maximal impact, early diagnosis through routine HIV screening is essential. I thought that very interesting. Is the recommendation to consider early treatment moot?

I don't think it's moot completely. I think what we are going to see over the next year or two or three is the diagnosis of people at higher CD4 cell counts. If the data we're seeing from the Bronx and from Washington, D.C., where there are increased efforts to test people --

Is this the test and treat program?

Yes. Not everybody who gets tested, even under these guidelines, would be treated immediately. But by testing people, we're going to find people at higher CD4 cell counts. We know that opt-out testing is becoming increasingly embraced across the country -- that took a while, since the CDC's [U.S. Centers for Disease Control and Prevention] recommendations emerged at the end of 2006, but it's happening.¹

I actually think that we are going to see more and more people diagnosed at higher CD4 cell counts, whether it be in our correctional systems or clinics. In our own clinic here in Chapel Hill, the median CD4 cell count at first presentation to our clinic is 300. It's no longer down in the low 200s, so we're seeing a slow creep up in the CD4 cell count of people coming into clinic for the first time. That's going to continue.

And so I don't think this is going to be moot at all in the next few years as we do more and more testing outreach.

Yesterday I talked to a social worker who has been in the HIV field for a very long time. I mentioned that the HIV treatment guidelines had been changed and it's now recommended that therapy be initiated earlier. Her response was, "Oh, wasn't 500 the threshold for starting therapy 10 years ago?"

It does swing back and forth. It's ironic that years ago we started people with a CD4 cell count of 500 on therapy when we had AZT [zidovudine, Retrovir] as our only therapy basically. Then, when we had combination HIV therapy, to initiate therapy the guidelines indicated that based upon the available data we should wait until a patient's CD4 cell count reached 200.

We're learning and the data are accumulating, but at the same time, our therapies are getting more advanced. If we had the perfect HIV therapy that was a pill a day, had no toxicity, was resistant to resistance and was cheap, we'd be treating everyone at the get-go, like we do for almost all infectious diseases. We don't wait for an infectious disease to get worse before we generally treat it. Most of them we treat from the time of diagnosis.

HIV has been an exception because of the toxicity of the therapy, because of the issues with drug resistance and because once therapy is started, it's for life. We've been trying to find this sweet spot: the perfect time at which to start therapy when there wouldn't be irreparable harm to the individual and he or she wouldn't be exposed to excessive HIV therapy. I think we're getting closer to that ideal therapy. We're obviously not there yet, but we have therapies that appear to be much less toxic than what we've been dealing with in the past and are much more convenient and are more potent and resistant to resistance.

Many smart people have pointed out that someone getting diagnosed now can anticipate being on therapy for 30 or more years. I think that we can't minimize the possible impact of exposure to HIV therapy, the cost of therapy and the potential for toxicity that we don't yet know about from therapy. I think those are all important points that we have to consider. Even though the guidelines may not be as concrete as individuals sometimes want, I do think that laid out here is a very nice discussion pointing out how people should be thinking about practicing.

Changes to the Preferred List of First-Line Therapies

Let's switch now to the initial combination regimens that are recommended. Kaletra [lopinavir/ritonavir] was removed from the "preferred" list. It's the last of the older drugs to leave the preferred list.

Right, and it says a lot about Kaletra.

This is a drug that's co-formulated and I don't think we can minimize co-formulations and their benefit. Coformulation has been a wonderful advance in HIV medicine and it's something we're going to see a lot more of. Adherence has always been problematic for our populations, and co-formulation really solves a lot of the problems.

In this case though, a couple of different studies showed that, compared to other protease inhibitor [PI] combinations (namely darunavir [TMC114, Prezista]/ritonavir [Norvir] and atazanavir [Reyataz]/ritonavir), over a longer period of time, it does look like, at least statistically, people can do better overall with these alternative boosted protease inhibitors compared to lopinavir/ritonavir. I think what we're seeing here is something we have observed in clinic, which is that people do pretty well on lopinavir/ritonavir, but over time there is a fatigue factor where we see people trailing off of it. That may be due to the ritonavir exposure, the pill count or the side-effect profile, which is a little bit rougher, though it's not horrible, than what we see with the newer protease inhibitors.

I do know people still cling to their co-formulated boosted PI and I understand that. We're in an era when copays can determine what the best therapy is for someone because you can have a great therapy, but if that person can't afford the copays and can't ingest that therapy, it does you no good. However, the guidelines reflect the science more so than anything else and that's appropriate. The data that we've seen emerge from comparative studies are reflected in what the panel is recommending.

Can you describe the specific studies that were the basis for this change in more detail?

Two really nice studies compared lopinavir/ritonavir with darunavir/ritonavir and with atazanavir/ritonavir.² Those have now gone on for at least 96 weeks. We got a really nice picture from those well-powered, head-to-head studies. Early on we see very comparable responses to both arms of these individual studies, but over time there is this trailing off in the lopinavir/ritonavir arms of these two studies, where people just don't seem to have virologic suppression, often times due to tolerability issues with lopinavir/ritonavir.

That's not to say that the drug doesn't perform well. It does, with over 70% of people generally still doing well at two years. But compared to the other two boosted protease inhibitors in these individual studies, we're seeing a little bit less of a response that's statistically significant.

Clinicians have to decide for themselves whether that is clinically significant enough for them to change their practices. If you're going strictly by randomized clinical trials and the data that emerge from those, then that's something that carries a lot of weight and should carry a lot of weight, you can see that there are differences between these regimens.

The tolerability issue should be emphasized when you look at darunavir/ritonavir. Compared to lopinavir/ritonavir, darunavir/ritonavir has about half the rate of GI [gastrointestinal] disturbance, including diarrhea, which is significant for a lot of our patients. If you go from 10%, which is not horrible, on lopinavir/ritonavir to 5% with darunavir/ritonavir, for instance, that can mean a lot. It can keep some people on therapy and keep them more comfortable. I think those are the kind of data that we need. That's why we like these head-to-head studies. You don't know which drug is going to be better for your individual patient unless you're able to compare the drugs side by side.

Does this change in the guidelines signify that any changes need be made for patients who have been on suppressive therapy with Kaletra?

This always comes up when people get new data or when guidelines change. But what we're talking about here is a change in what is recommended for a group of people who are just starting on therapy. What would be the best thing to start them on? That's a different question than what should you now do for someone who's on therapy and who is doing very well.

For the patient who's doing well on therapy, it's very hard to change therapy -- you'd have to have a good reason. If they're having side effects, then I might say, "Here's an alternative for you. This might be something that would give you less side effects."

Again, I don't mess too much with success unless there's a compelling reason. An example might be people who remain on therapy with Trizivir, the co-formulation of AZT, abacavir [Ziagen] and 3TC [lamivudine, Epivir]. Even if they're doing well, I'm still a little uncomfortable because we know that there are late failures that do occur with that regimen compared to regimens that include an NNRTI [non-nucleoside reverse transcriptase inhibitor] or a boosted PI. That would be an example where I would change someone. But if someone's doing really well on lopinavir/ritonavir, these data do not compel me to make a change in that person's therapy, and that's not what these studies were about.

A lot is made about HIV medications that make the preferred first-line chart versus those that are relegated to the alternative list. How big is the chasm between "preferred" and "alternative?"

An "alternative" is a therapy that should be considered, but the data, for whatever reason (whether it be efficacy, tolerability or other considerations), indicate that there may be a regimen that, all things considered, would be preferred. For an individual patient, however, it could easily be that one of the "alternatives" is preferred. For that individual patient who can't take, for whatever reason, one of the drugs that are listed in the "preferred" panel of drugs, an alternative may actually be preferable.

A perfect example is: We like historically to give people tenofovir [Viread] and FTC [emtricitabine, Emtriva]. That's one of the most popular, if not the most popular, nucleoside combinations to give as a part of initial therapy. Abacavir/3TC [Epzicom, Kivexa] is listed as an "alternative." Clinically, we look at someone and say, "Is there any reason I shouldn't use tenofovir/FTC [Truvada]? If there is, then I'm going to go to abacavir/3TC."

The "alternative" is there if you can't use the "preferred." The alternatives work, but there may be individual reasons why they should or should not be used in your patient.

Could you talk about the addition of raltegravir, also known as Isentress, to the "preferred" list of drugs for initial therapy?

For many of us, the addition of another class of drugs to use in treatment-naive folks is an important one. We know well the NNRTI and boosted PI strengths and weaknesses. While these combinations are very helpful for our patients, there's certainly room for improvement. Having another choice helps us and gives us greater flexibility in responding to the needs of our individual patients.

The integrase inhibitor raltegravir is a drug that I think has some important features, namely it doesn't have ritonavir and it doesn't give the patient bad dreams and that says a lot for it. It is twice a day, which is a little bit of a drag on its success, I think, since we're trying to keep things simple for our patients. There are now data that show that the drug is very effective in treating treatment-naive folks compared to efavirenz [Sustiva, Stocrin], which is considered practically a gold standard when we're thinking about what to treat people with initially.³ Responses and tolerability were really great in a head-to-head comparison.

This is a very good option and there are data to support the use of the drug. There are now enough data over time that we can get a sense of its tolerability and safety. Its placement in the recommendation reflects on the data we have available right now. I think it's hard not to consider this as a first-line option alongside the boosted PI and NNRTI efavirenz-based regimens.

Didn't a lot of clinicians start patients on raltegravir a while ago? There was such an enormous excitement when raltegravir was first approved and there was this feeling about it -- I don't know if it was based on strong data -- but it was felt that it was more powerful than other drugs. Has that been borne out?

In some of the work that had been done initially with the drug, and subsequently, you see really rapid virologic responses, where the decay of the virus over the first couple of weeks of therapy with raltegravir is pretty dramatic.³ But over time, efavirenz catches up. We don't know exactly what the significance is of that for longer-term health and the well being of our patients, but I think that these studies instilled this concept that raltegravir was potent.

The data showed that it is powerful and comparable to drugs that we're using more commonly for initial therapy. It's good to have the option. Not everyone can take a ritonavir-based regimen. Not everyone can take efavirenz. It's nice to have something else that people can go to and the data indicate that if someone wanted to use that preferentially, there's no reason not to. I think what you have now with these preferred regimens is a broad panel of drugs that in clinical trials have basically shown themselves to be just as good as one another or as good as the comparator drug that they were compared to, usually efavirenz.

What do you think about clinicians trying regimens that are not on this list? There are some clinicians who feel that all of the new drugs are good, so they'll concoct a first-line regimen of raltegravir, etravirine [TMC125, Intelence] and maraviroc [Selzentry, Celsentri]. Is that a good idea?

Like you said, there are clinicians who use raltegravir commonly and have done so for the last year or so, but I think most HIV treaters are a little bit slow on adopting some of the more aggressive regimens.

There is lots of room for creativity in HIV and that's one of the things that attracts me to this field. You're not going to have every study done that compares every single regimen or even every single strategy. What we do have is spelled out in the guidelines -- and I think this is what's very nice about having a very complete set of guidelines that includes references to data. These are the comparisons that have been made. These are the studies that have been done. Sure, there are studies that could be done or should be done, but we don't have those yet.

We've been burned in the past. We've made assumptions thinking that, "If this works and this works, then this should work," only to find out, "It didn't work."

I'm not saying that we have to be strictly evidence-based. Evidence-based is important. We make decisions based upon evidence and the guidelines reflect the evidence that's available, but we all know that, in clinical practice, we have to be creative. That creativity is something that I think is vital to the practice of medicine -- something, I think, we do here in the U.S. very, very well.

There usually has to be a reason though to be creative. If you're going to say to someone, "I'm going to put you on this regimen that may be wonderful that hasn't really been studied yet, but I just feel like it's going to work better for you," that may be your style, but that's not my style. I think there has to be really good reasons to do something that deviates from what's laid out here in the guidelines and what the data support.

Now, there are special cases where you have to be flexible and you have to think on your feet. That's where that creativity and that knowledge and that extrapolation come in handy. But you can't concoct a creative, bold regimen for a certain circumstance without understanding the fundamentals of HIV management and understanding what's given traditionally, what the data support, and why you're deviating from them.

Isn't one of the real dangers of using novel regimens for first-line patients the issue that it's wise to think of the future and sequence for possible resistance in the future?

Absolutely. You can throw the kitchen sink at someone, but why? We're learning more and more that some of these potent regimens are just fantastic at reducing viral load and keeping it down. Both the "preferred" and "alternative," regimens work. Over 65%, 70%, close to 80% of people on these drugs get undetectable and stay there long term in clinical trials.

To start mucking around and coming up with things that are not standard when you have all these choices, there has to be a compelling reason. You can screw people up and we know that. You don't want to do that. Good thing is, we have new classes of drugs. We have the integrase inhibitors. We have the CCR5 antagonist. Other therapies are still coming down the pipeline, but you can still hurt people.

I really feel clinicians have to be very thoughtful. Your first shot continues to be your best shot. Even though we now have more bridges to build if we burn bridges, I think you should still get someone on a good therapy initially and keep them on that for years. The goal is for someone to start on therapy and I tell them, "I want you to be on this for five, 10 or more years."

To start coming up with some other things ... that's great in the setting of a clinical study, but I don't think it's for practice. I try to treat my patients as I would want myself or a family member to be treated. I don't know that any of us would want to start on some kitchen-sink approach and if you do, well, then that's something that you should explain to your patients.

Clinical Management of Treatment-Experienced Patients

Let's switch to the management of treatment-experienced patients. I noticed that having a low viral load is no longer an indication of treatment failure or reason to change treatment. Can you discuss this?

I thought a lot about this clinically because we do see patients with low levels of viremia and the question is how aggressive should we be about that? Part of the problem is, when a patient has low-level viremia, clinicians don't have as much data, because you don't have the genotypic or phenotypic resistance data that can help you devise a new combination.

Also, with our current assays being so highly sensitive, we are starting to see a little bit of noise with at least some of them. We have assays now that have a huge dynamic range, from a very low threshold of detection of 50 all the way up to a 100,000 or more for the top threshold. So we're starting to see that some people have low-level virus with these newer assays. We also know that people who have low-level viremia don't seem to do poorly. Certainly, resistance seems to be unusual and people with very low levels of virus --

There have been studies that have tried to take people who have this low-level viremia (e.g., 50 to 200), and intensify their therapy with raltegravir or enfuvirtide [T-20, Fuzeon]. And you know what? The viral load doesn't go down. If it was replicating virus, many of us feel it should have gone down when you intensified therapy with drugs that the virus should be susceptible to.

Is this trafficking virus? Is this virus that's really replicating and mutating? Probably it's not the latter and it might be the former. It doesn't necessarily indicate that there's failure going on or that you should switch therapy that is effective. I think many of us have also learned from experience that changing therapy or intensifying therapy in such patients has diminishing returns. We don't really see big changes in that low-level viremia. Low-level viremia doesn't scare me. We have to realize the limitations of our current assays. Just because an assay may not detect virus one day doesn't mean that the next day it's not 51 or 199. We have to realize that there is biological variability and then there's lab variability.

Then there is this whole issue of virus that's flowing from different compartments. I think that the risk of resistance is very low from all the data we're seeing. If you don't have a lot of replication, you don't have a lot of chances for a mutation to develop, because it's only when you have a replicative cycle that mutations can emerge and persist. If there's such a low level of replication, the chances that there's going to be resistance is very low as well. I don't try to change regimens in people with low-level virus (i.e., 50 to 200) and expose them to a whole new set of drugs, new schedule, new pill count, etc.

There are very few new drugs in the pipeline for treatment-experienced patients over the next couple of years. Was anything mentioned in the guidelines about what kinds of things could be done for this population?

We have just come from a very nice wave of newly released therapies that have given our patients a new lease on life. We have drugs now that are in new classes to which people should be fully susceptible, such as the integrase inhibitor and the CCR5 antagonist.

We have drugs now that work against virus that's resistant to other members of drugs in the same class, such as etravirine in the NNRTI class, and darunavir/ritonavir in the PI class. We have salvage therapies. We have drugs that can be used upfront and drugs that can be used later on.

I think that we have a really nice portfolio of drugs now to help people, almost regardless of how much treatment experience they have. That wave of new drugs, and that critical mass of new drugs that we can use together, means that we can devise really good regimens, even for people who are experienced and have multidrug-resistant virus.

As you point out, there may be a lull for a while where we can't expect there to be great and novel new drugs, two or three at a time every year. That's asking a lot. But I do think that on the horizon there still are some important drugs that may emerge in the existing classes. We'll see a new integrase inhibitor come out with a different resistance profile that's exciting. I think we'll see other drugs come out even in different classes and new classes.

I don't think that the door is shut for people. I do feel strongly that the new drugs that have come out have really benefited a tremendous number of our patients. I'm really excited about what we're seeing in clinic and how many of our patients who had few options left are doing exceedingly well. Even if they don't get the gold medal and they're undetectable, they get silver and bronze medals where their viral load is under better control, their T-cell counts have gone up and they're not sick. That's a testament to the ability to combine drugs that work against people's viruses.

I don't think the guidelines necessarily are a crystal ball and indicate what to do, but they do talk about strategies for trying to reduce the need to be on salvage therapy and I think help people understand what to do with the existing drugs. It's hard to predict what will come out and what will work, but we all know in this field that drugs continue to be developed and that there are clinical trials continuing to go on and even novel agents that may emerge that could help us quite a bit just as we've seen with the integrase inhibitors and CCR5 antagonists.

Let's switch briefly to genotypic testing. Is it still recommended for people who walk into the clinic and for switching regimens?

Absolutely, so all the arguments that were made previously are still salient. We get a lot of information from genotypic testing as is outlined. A beauty of these guidelines is that you can just take the bullet point home and say, " I've got to do resistance testing here, here and here." You can read on and understand what are the data that support that and how strong the data are. There is really good rationale that's laid out nicely in the document about why genotypic resistance testing is preferred, and why we should do it early in the course of HIV disease and before we start therapy.

I noticed an interesting paragraph about resistance testing for integrase and fusion inhibitor resistance and the limitations of that. Can you talk about this?

Yes. This is an emerging area. We have to understand that integrase resistance is not yet included in our standard resistance-testing panel. Over time, I think we will see more of this integrated into our resistance testing. We're going to have to think about integrase resistance as we use the drug more and when additional integrase inhibitors come out. You may have to order a specialized test, a separate test at additional cost. We'll see what commercial laboratories do with this and I expect that over time we will see barriers to getting this type of testing reduced.

Can you summarize what's new for people who have both HIV and hepatitis C?

This is another area that is going to be exciting. There's a lot of ongoing research regarding hepatitis C and HIV coinfection , and also in hepatitis C in general. There are limitations to the current therapy that we have, which is ribavirin [Copegus, Rebetol] and interferon, as many people are well aware. There's certainly room for therapy to be more efficacious and better tolerated. I think what we're seeing in the guidelines is discussion for us to pay attention to hepatitis C coinfection and how that influences both HIV progression and hepatitis C.

There's a lot of thought being given to the sequencing of hepatitis C and HIV therapy. Many of us feel that there's traction for an argument to be made to aggressively treat both of these infections. Treatment of HIV can perhaps improve responses to hepatitis C therapy and we know that hepatitis C may facilitate HIV disease progression. These are two viruses that are intricately linked and have significant morbidity.

We also understand that there is a risk of drug-related toxicities with treatment for both of these. If you treat the HIV, you may have hepatotoxicity due to the therapies we use for HIV and people with hepatitis C. Conversely, we know that we can hurt people with hepatitis C therapy and make HIV therapy toxicities worse -- namely anemia, if someone's on a drug that can cause anemia, like AZT, so we avoid that.

We don't have a definitive study about when you should start one or the other. The section in the guidelines just details some of these considerations and what people feel based upon what we know. I think that most of us are comfortable treating hepatitis C or recommending our patients to get hepatitis C therapy. The important point is of course first to diagnose hepatitis C, to understand the staging of hepatitis C and the things that influence whether to treat it. I think we've got that down pat.

We've come a long way over the last few years. I think we're also becoming more comfortable with using HIV therapies in people with hepatitis C with liver dysfunction, and in using hepatitis C therapies in people who are on HIV therapy. I don't think there's a lot that's bold and new. I think it's spelled out pretty nicely from the considerations. I think that that's a nice feature in this particular version of the guidelines.

Managing Patients With HIV-2

There's also an entire new section about the HIV-2 strain. Are we seeing more HIV-2 in the United States? I know there are a lot of West African immigrants in certain states in United States.

I don't know if we're seeing more HIV-2, if the prevalence is increasing in the United States. It may well be given what you're talking about. But I think that it's nice to get a little bit more information about what antiretrovirals are known to work in HIV-2 and which ones seem not to work as well. A lot of this of course is based upon in vitro testing. This is another one of those fields where we just don't have as much data as you'd think we should.

We don't have good viral load testing abilities for HIV-2, so that can be a problem. How do you determine efficacy of therapy and how do you study this? Hopefully there will be more information coming along that helps us understand how to manage this, because some of us do see this once in a while. As you mention, there are people who come here from other parts of the world where HIV-2 is endemic, such as West Africa and parts of the Caribbean. I think this is a real research need. Just reading this section, you can see how limited our understanding is of how to treat HIV-2.

Positive Prevention in the Clinic

There's a section about positive prevention sort of buried at the end. Could you talk a little bit about that section and what it means for an HIV specialist?

Whatever is at the end is always talked about as being unfortunately at the end, but something has to be there. I think that it's really important that we think about HIV prevention within the context of these treatment guidelines. They do a good job of trying to integrate the concept of treatment as therapy and not ignoring treatment as a really important part of preventing secondary HIV transmission. That's something you see throughout the document; there is more and more mention of that made, whether it be in the when to start therapy section or in the prevention section.

I think what we're also discussing though is that there could be a marriage between biological interventions (namely getting someone's viral load down so that they don't transmit the virus in either semen or genital secretions) and behavioral interventions. Something that I think is nice in this document are important references to evidence-based interventions that are adapted for clinical use that have been shown to reduce people's likelihood to transmit the virus to others.

We want people to be aware of that. I think what the guidelines do recommend what should be done clinically and how the risk behaviors of our patients should be assessed. We should understand more about what works and doesn't work and try to integrate interventions that have been found to work better, especially interventions that are brief and are not work intensive so that they can be used in hectic clinics. They're there. Our tax dollars have gone to try to develop these.

Alongside of our giving people antiretrovirals to reduce their viral load and thus their risk of transmitting the virus to others, we should be aware of some of these other behavioral practices and we should be regularly screening for STDs [sexually transmitted diseases], which we probably don't do enough of.

In our clinic, we check on RPR [rapid plasma regain] every year now in people along with the hepatitis C antibody test because we're seeing so much syphilis here in the South. People have to be cognizant of the role of STDs and I think this section in the guidelines lays it out very nicely.

These are guidelines. They give a lot of information that people have to take home and think about. Hopefully, some people will look at this and say, "I should go to this Web site. I should understand more about brief interventions that could be delivered in clinic to help people change their behavior, especially with my particular patient population," Guidelines can point you in the right direction. I think over time this section that will increase and may not even be at the end.

There's a note stating that for two weeks after an update to the guidelines, which was Dec. 1 in this case, so until the 15, the public can submit comments to the panel and another note that says that comments to the guidelines are always accepted. Are there a lot of people who do this?

I think that in many ways it's been such a privilege to be part of being on a panel. Anyone who's been on any sort of guideline committee, whether it be your local infection control committee or the P&T [Pharmacy and Therapeutics] committee at your hospital or a guideline panel such as this, it's really a wonderful opportunity to see how people think and work together. I think that all of us who work collaboratively do see that.

It's also nice that most of us work in a fairly democratic way. I think that feedback is incredibly important for all of us and another beautiful thing beyond the creativity that we see within HIV medicine is the advocacy. People are passionate about what they do in HIV and this is just wonderful to see that within our treating community.

It's important that people who have feelings about the guidelines be heard, whether it be, "Thank you very much for doing such a complete job," or "I take issue with this one thing," or "This is what I'm thinking about," or "Here's a suggestion how you can make this better." There are a lot of really, really intelligent, thoughtful people taking care of HIV in our country and that's why we're doing such a great job treating HIV among the patients who come to our clinics.

I'm glad you mentioned it. I know that many of us who do all sorts of work want to hear about how well we're doing. So I would encourage people to certainly respond and let people know what they think about these particular guidelines and anything they think about in the future that should be changed.

Great. I'm afraid we've come to the end of our time talking together. Thank you so much, Dr. Wohl, for taking the time to talk with me.

It's been my pleasure. Thank you, Bonnie.

This transcript has been lightly edited for clarity.

To browse through the latest guidelines, click here (PDF).

Got comments on the new guidelines? The guidelines committee will accept comments at any time via e-mail at contactus@aidsinfo.nih.gov.

References

1. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. September 22, 2006;55(RR14):1-17.
2. Mills A, Nelson M, Jayaweera D, et al. ARTEMIS: efficacy and safety of darunavir/ritonavir (DRV/r) 800/100 mg once-daily vs lopinavir/ritonavir (LPV/r) in treatment-naive, HIV-1-infected patients at 96 wks. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-1250c.
3. Lennox JL, DeJesus E, Lazzarin A, et al, and STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. September 5, 2009;374(9692):796-806.