Table of Contents

• Introduction
• Etravirine: The First FDA-Approved Second-Generation NNRTI
  • Etravirine Adverse Events
  • Etravirine Dosing
  • Drug Interactions
  • Summary
• New Protease Inhibitors
  • Darunavir: The First FDA-Approved Second-Generation Protease Inhibitor
    • Darunavir in Patients With Limited Antiretroviral Experience
    • Darunavir in Treatment-Naive Patients
    • Summary
• Raltegravir: The First FDA-Approved Integrase Inhibitor
  • Raltegravir in Treatment-Experienced Patients
  • Raltegravir in Treatment-Naive Patients
  • Summary
• Maraviroc: The First FDA-Approved CCR5 Antagonist
  • Tropism Testing
  • Enhanced Tropism Assay in Development
  • Maraviroc in Treatment-Experienced Patients
  • Maraviroc in Treatment-Naive Patients
• Conclusion
• References

Introduction

Thank you for joining us for this program entitled "An Update on New HIV Antiretroviral Agents." I am Edwin DeJesus, Medical Director of the Orlando Immunology Center and the HUG-Me adult clinic at the Orlando Regional Medical Center in Orlando, Fla.

On behalf of The Body PRO, it is my pleasure to discuss with you the topic of new HIV antiretroviral agents.

In the past few years, we have witnessed the development and approval of several new antiretroviral agents. The surge in the development of new antiretrovirals has been prompted by the limitations of older agents with regards to:

• resistance barriers,
• safety and tolerability,
• cost of treatment, and
• simplicity and convenience that will allow for lifelong therapy.

With the availability of not only all these new agents, but also two agents in new antiretroviral drug classes, we have made significant progress in addressing some of these issues. However, it can be argued that there are still significant limitations to overcome and room for improvement.

Resistance, for example, remains a problem for some patients. It is estimated that primary drug resistance occurs in 5% to 15% of the untreated HIV-infected population.^1-3 Resistance, of course, is a major problem for patients who have been on multiple antiretroviral classes.^3,4

There is also a need for agents that are safer and, ideally, not associated with metabolic complications such as dyslipidemia and lipoatrophy. We also need agents that are better tolerated, with fewer side effects such as CNS [central nervous system] adverse events, rashes and GI [gastrointestinal] symptoms.

We can also argue that the cost of treatment itself remains an incentive to look for new agents. For example, in heavily treatment-experienced patients who need megaHAART (five or more antiretroviral agents to control HIV infection), it is possible that with the availability of potent new agents, we may be able to treat these patients with fewer active drugs, resulting in cost savings. There is also something to be said about how much we can save when we are able to maintain virologic suppression and prevent the disease's progression.

Also important is the need for very simple regimens and convenient agents that are suitable for lifelong therapy, given the fact that patients are living longer and HIV treatment interruptions are not recommended.⁵

It is well-stated in HIV treatment guidelines -- both in the DHHS [U.S. Department of Health and Human Services]⁶ and the IAS [International AIDS Society]⁷ versions -- that the goal of HIV therapy for both treatment-naive and treatment-experienced patients is to achieve and maintain virologic suppression with an HIV RNA of less than 50 copies/mL. These goals have become achievable for most antiretroviral-experienced patients with the availability of these newer agents.

Now let's take a closer look at these newly approved agents. In the past three years alone -- since 2006 -- four agents from four different antiretroviral drug classes were approved for the treatment of HIV infection because they bring something new to the treatment armamentarium. Two of the drugs do so by virtue of belonging to a new antiretroviral drug class: the CCR5 antagonist maraviroc [MVC, Selzentry, Celsentri] and the integrase inhibitor raltegravir [MK-0518, Isentress]. The other two drugs are second-generation agents of previously existing antiretroviral drug classes: they are the NNRTI [non-nucleoside reverse transcriptase inhibitor] etravirine [TMC125, Intelence] and the protease inhibitor [PI] darunavir [TMC114, Prezista].

Etravirine: The First FDA-Approved Second-Generation NNRTI

Let's start by discussing etravirine, the first agent in a new generation of NNRTIs to be approved by the FDA [U.S. Food and Drug Administration]. There are a multitude of reasons why we need a second-generation NNRTI. For one thing, we need agents that can overcome some of the existing limitations of the first-generation agents in areas such as tolerability and toxicity. We also need to expand the target population that can be treated with these agents. And, as I previously mentioned, resistance to the first generation of NNRTIs remains a key issue.

All of these factors have led to the development of second-generation non-nucleosides. The first one to be approved is etravirine,⁸ while others (such as rilpivirine [TMC278],⁹ which also appears to overcome many of these limitations) are currently in development.

Etravirine is very potent; it has an EC₅₀ for wild-type virus of 1.4 nmol/L, and it maintains susceptibility even in the presence of some non-nucleoside-associated mutations,¹⁰ such as K103N, Y18C, Y188L and L1001.

Etravirine has a very long half-life, almost 30 or 40 hours, and it is mainly metabolized by cytochrome P450 CYP3A.⁸ This is a compound that, a few years ago, made a lot of noise when, in the phase 2A study, it was able to demonstrate an impressive 2.0-log decline in plasma HIV RNA over a period of seven days in treatment-naive patients.¹¹ It was this first clinical study that led to the development of other studies in treatment-experienced patients.

Click to enlarge

In the slide to the left, we have the proof-of-concept for using etravirine to treat treatment-experienced patients who have non-nucleoside resistance.¹² In this study, 16 patients who were failing on a regimen of nevirapine [NVP, Viramune] or efavirenz [EFV, Sustiva, Stocrin] plus two nucleosides substituted their non-nucleoside for etravirine for a week before they were able to optimize their background regimen. After they substituted the nevirapine or efavirenz for etravirine, there was a 0.86-log reduction in HIV RNA.

This response is quite significant, because these patients were already resistant to first-generation NNRTIs. Etravirine is the first NNRTI agent we've ever had that can be used in sequence after failure with a first-generation NNRTI. The results of those studies led to the further development of etravirine.

The registrational studies that were used for the approval of etravirine in the United States and Europe were known as the DUET studies.^13,14 There were two DUET studies: DUET-1 and DUET-2. They have a similar study design and involve similar patient populations, but they were conducted in different parts of the world.

There were about 1,200 patients combined in both studies, all of whom had a baseline viral load greater than 5,000 copies/mL and evidence of significant antiretroviral resistance (i.e., one or more NNRTI resistance mutations or three or more PI mutations). These patients were very treatment experienced.

Click to enlarge

The patients were randomized one-to-one to receive etravirine or a placebo, plus an optimized background regimen. All patients received an optimized background regimen that included darunavir as well as some nucleosides. Investigators could add enfuvirtide [T-20, Fuzeon] based on genotypic testing.

The results of the studies were quite striking. In the DUET-1 study, in patients who received etravirine plus an optimized background regimen, the proportion of patients achieving a viral load of less than 50 copies/mL was 60% versus 39% for patients receiving placebo plus an optimized background regimen.¹⁵

When we combine the data from the DUET-1 and the DUET-2 studies -- we can do that because the patient population and the study design of both studies were very similar -- we see that 61% versus 40% of patients achieved a viral load less than 50 copies/mL on etravirine versus placebo, respectively, which is very similar to what was seen in the DUET-1 study. These results are, of course, very statistically significant, confirming the potency and the efficacy of etravirine in the treatment of this heavily treatment-experienced patient population.

Click to enlarge

When we look at these results based on the number of active drugs that were used in the optimized background regimen, we can confirm that the virologic responses are greater as the number of active drugs in an optimized background regimen increases.

Because all the patients in the study received darunavir, we can also look at these analyses using the lower and the upper darunavir susceptibility cutoff.

If we look at virologic response by darunavir's lower cutoff (FC [fold change] less than 10) and upper cutoff (FC greater than 40), we essentially see similar results. For patients who had a non-active agent in the optimized background regimen, the response in the etravirine arm was 46% versus 6% in the placebo arm.

For patients who had two or more active drugs, the response was 78% in the etravirine arm versus 67% in the placebo arm when a darunavir susceptibility cutoff of less than 10 was used -- maybe a little less when we use a darunavir susceptibility cutoff of less than 40.

This tells us that the combination of these two agents -- even if no other drug is added to their optimized background regimen -- is associated with a significant response, but that that response can be increased if another active agent is added to the optimized background regimen.

Etravirine Adverse Events

Click to enlarge

Now let's take a look at the safety data observed in the pooled DUET studies. The incidence of adverse events and discontinuation due to adverse events and serious adverse events was very similar between the etravirine and the placebo arms.

Etravirine may cause allergic reactions and rashes, and this was noted in the study. Rash was the most common adverse event seen, and it was the only adverse event whose incidence was higher in the etravirine arm than in the placebo arm.

The other adverse events (such as CNS adverse events, psychiatric disorders and even hepatic adverse events) are interesting because they have also been observed with the first generation of NNRTIs. These events were not seen with any significant incidence in the etravirine arm versus the placebo arm, which tells us that this new agent is able to overcome some of these toxicity limitations that the first NNRTI agents were associated with.

The virologic data, in terms of resistance, were carefully analyzed in the pooled 24-week results.¹⁶ The researchers identified 13 mutations that are associated with significant etravirine resistance. When we look at those mutations, the most important aspect is that the mutation K103 -- which is the mutation that has been associated with resistance to efavirenz, and is the mutation that has emerged with the most frequency after efavirenz failure -- is not a mutation associated with decreased susceptibility to etravirine.

On the other hand, the mutation Y181C, which is selected for after nevirapine failure, is one of the mutations that has been associated with etravirine resistance. This maybe explains why patients who fail on an efavirenz-containing regimen tend to respond better to etravirine than do patients who fail a nevirapine-containing regimen.

The important part of this virologic data is that if the patient has accumulated three or more etravirine-associated mutations, the response that the patient is going to obtain with the use of etravirine is pretty much the same as the responses that were observed with the use of placebo in the DUET studies. We don't expect etravirine to have any significant antiviral activity in the case of a patient with three or more of those mutations.

Etravirine Dosing

Etravirine was approved for a dose of 200 mg twice a day, to be taken with food.⁸ It doesn't have to be a heavy meal. For patients who don't like to take pills, one of the interesting properties of etravirine is that it can be dispersed in a glass of water. It doesn't dissolve, but forms a suspension that a patient can drink. A bioequivalency study has been conducted on that suspension; results from that study are due to be presented at the XVII International AIDS Conference in August 2008. Preliminary results confirm that patients are getting the full activity of the drug taken this way.

As mentioned previously, etravirine is metabolized by cytochrome P450 CYP3A and other enzymes, and rash remains the main adverse event that has been observed in clinical study, with an incidence of about 9%, although discontinuation due to rashes in clinical studies has been very low, about 2%.

The mutations V179F and Y181C are the most commonly selected mutations in patients failing an etravirine-containing regimen. Recently, both Monogram¹⁷ and Virco¹⁸ have released the susceptibility cutoff of their phenotypic tests.

For Monogram, a less than three-fold change is considered susceptible. For Virco, it's less than 1.6, with a value between 1.6 and 27.6 considered to be intermediate susceptibility.

In terms of taking etravirine during pregnancy, etravirine is a category B drug,⁸ which differs from efavirenz, which is a category C drug¹⁹ and cannot be taken by patients at risk for or planning for pregnancy.

And finally, no real dose adjustment is needed when etravirine is administered to patients with mild to moderate liver disease.

Drug Interactions

Click to enlarge

Now let's take a look at drug interactions associated with etravirine. Because etravirine is metabolized via cytochrome P450, drug interactions can be expected.

No dose adjustment is required for etravirine when it is used with commonly prescribed HIV medications such as didanosine [ddI, Videx] or tenofovir [TDF, Viread] or even with darunavir, raltegravir or lopinavir plus saquinavir [SQV, Invirase]. But there's a dose modification needed when etravirine is used with maraviroc.

Etravirine is actually contraindicated for use with some antiretroviral medications. This includes: tipranavir [TPV, Aptivus], atazanavir [ATV, Reyataz] and fosamprenavir [FPV, Lexiva, Telzir] with ritonavir [RTV, Norvir], as well as any unboosted PIs and all three first-generation NNRTIs.

There are a lot of additional drugs that are contraindicated with the use of etravirine. Review the package insert to get more information about the drug interactions with the use of those agents.

Summary

As you can see, etravirine has been able to overcome some of the limitations we discussed earlier with respect to first-generation NNRTIs, such as the barrier for resistance and cross-resistance and even perhaps the fact that it can be used in other patient populations in which some of the first-generation agents cannot be used.

But etravirine has not been approved for treatment-naive patients and it still requires a BID [twice a day] administration. Etravirine actually has a long half-life, so the reason it requires a BID administration has nothing to do with pharmacokinetic issues, but rather pill burden. Two pills twice per day is preferable to four pills once a day plus the nucleoside background.

Etravirine's limitations leave the door wide open for other second-generation NNRTIs. Perhaps NNRTIs currently under investigation and at different stages in development will be able to make up for some of etravirine's deficiencies.

New Protease Inhibitors

We can now divide protease inhibitors into those that are first-generation and those that are second-generation. The first-generation PI has been limited mainly by issues of cross-resistance and, to some extent, tolerability -- adverse events such as lipidemia and even GI symptoms.

A few years ago, tipranavir -- the first second-generation PI -- was able to show improved efficacy in heavily treatment-experienced patients compared to other PIs.²⁰ Since then, darunavir was approved and has been found to be very effective, not only in patients with a long history of antiretroviral treatment,²¹ but also in the less treatment-experienced antiretroviral population.^22,23

Click to enlarge

In the past few years, we have seen multiple clinical studies comparing different protease inhibitors. In the table to the right we can see the efficacy of some of these studies comparing several PIs.

For example, the KLEAN study²⁴ showed similar efficacy when fosamprenavir + ritonavir was compared to lopinavir/ritonavir [LPV/r, Kaletra]. The GEMINI study²⁵ and the CASTLE study²⁶ both showed non-inferiority when comparing saquinavir [in the case of GEMINI] or atazanavir + ritonavir [in CASTLE] to lopinavir/ritonavir.

The only study that differed, even if just a little bit, was the ARTEMIS study.²² It was different because it used an unapproved dose of a protease inhibitor -- in this particular case, darunavir + ritonavir at a once-daily dose of 800 mg/100 mg. It was also different because, in some of the efficacy analyses, darunavir + ritonavir was actually shown to be superior to lopinavir/ritonavir among a treatment-naive patient population.

Darunavir: The First FDA-Approved Second-Generation Protease Inhibitor

Since its approval, darunavir has undergone quite an evolution. It was first studied and approved for heavily antiretroviral-experienced patients,²¹ but since then, several studies have been conducted on less antiretroviral-experienced patients^22,23 and have shown better -- and, in some analyses, superior -- results when compared to lopinavir/ritonavir, which for many of these patients has long been considered standard of care.

Darunavir in Patients With Limited Antiretroviral Experience

Let's review some of these studies, starting first with the TITAN study,²³ which was conducted in patients with limited antiretroviral experience.

TITAN was a randomized study in which patients who were treatment experienced, but lopinavir/ritonavir naive, and had a viral load greater than 1,000 copies/mL were randomized to receive either darunavir + ritonavir at the standard dose of 600 mg/100 mg or lopinavir/ritonavir twice per day.

When we look at the characteristics of the patients who participated in TITAN, we can see that about one third of those patients were naive to PIs. Another one third of those patients had been exposed to only one PI. The other third had been exposed to two or more PIs. It was a diverse patient population, yet the patients had limited experience in terms of antiretrovirals.

Click to enlarge

One of the most striking findings observed in the study is that, overall, darunavir + ritonavir outperformed lopinavir/ritonavir at all time points. At week 48, 71% in the darunavir + ritonavir arm versus 60% in the lopinavir/ritonavir arm achieved a viral load less than 50 copies/mL, a difference of 11%. That difference in response is quite significant. Darunavir + ritonavir was not only non-inferior, it was also statistically superior compared to lopinavir/ritonavir -- which, again, has been the standard of care for the treatment of these patients.

If we take those results and analyze them more carefully based on the baseline lopinavir/ritonavir fold change, we see some interesting findings.

Looking at patients with susceptibility to lopinavir/ritonavir -- defined as a lopinavir fold change less than 40 -- and comparing the darunavir + ritonavir response with the lopinavir/ritonavir response, we see that the difference in response was 10%. That, too, was not only non-inferior, but also superior.

Click to enlarge

If we go one step further and examine the patients who were really sensitive to lopinavir/ritonavir at baseline -- those with a fold change equal to or less than 10 -- and we make the same comparison, we see the difference in response was 7%. That was also non-inferior, and barely meets the margin of superiority.

This indicates that the efficacy that was seen in these patients -- in terms of a better response in the darunavir + ritonavir arm over the lopinavir/ritonavir arm -- occurred almost irrespective of baseline lopinavir/ritonavir susceptibility.

In addition to the significantly better efficacy, there was some advantage with darunavir + ritonavir in terms of adverse events. In the TITAN study, diarrhea was more prevalent in patients who were treated with lopinavir/ritonavir (almost 42%) versus darunavir + ritonavir (almost 32%), and that was statistically significant.

Click to enlarge

If we look at study discontinuation due to adverse events, we see that the adverse events that led most to study discontinuation were diarrhea, nausea and rash. Among those, diarrhea was twice as frequently a cause of study discontinuation in the lopinavir/ritonavir arm compared to the darunavir + ritonavir arm.

Rash was seen with more frequency in the darunavir + ritonavir arm -- 3%, versus 1% in the lopinavir/ritonavir arm. That was statistically significant, but this was no surprise since rash with darunavir + ritonavir has been observed in other clinical studies.

The TITAN study is important because it is the first study comparing two boosted PIs in patients with limited antiretroviral experience that was actually able to show superiority of one boosted PI over another. No other boosted-PI comparison has been able to show that. The results of this study are also very significant because, in my opinion, the superior efficacy and safety of darunavir + ritonavir make this boosted PI a clear choice for this particular patient population.

Darunavir in Treatment-Naive Patients

In addition to being studied in patients with limited antiretroviral experience, darunavir + ritonavir has also been studied in patients who are naive to therapy.²²

In ARTEMIS, almost 700 treatment-naive patients with a viral load greater than 5,000 copies/mL were randomized to either receive darunavir + ritonavir or lopinavir/ritonavir along with the coformulation of tenofovir and emtricitabine [FTC, Emtriva].

Darunavir + ritonavir was administered once daily at a dose of 800 mg/100 mg. That dose is different from the dose used in TITAN, which was 600 mg/100 mg BID. Patients in the lopinavir/ritonavir arm were able to receive the drug either once per day (800 mg/200 mg) or twice per day (400 mg/100 mg), and in either capsule or tablet form. All patients, in addition to their PI, received the coformulation of tenofovir and emtricitabine.

Click to enlarge

Just as we saw in the TITAN study, darunavir + ritonavir outperformed lopinavir/ritonavir in ARTEMIS. At week 48, 84% in the darunavir + ritonavir arm versus 78% in the lopinavir/ritonavir arm achieved a viral load below 50 copies/mL -- a 6% difference -- meeting the non-inferiority margin.

The study mandated that if the non-inferiority margin was met, a superiority analysis should be conducted. That analysis was not able to show superiority, although the confidence interval was very close to zero (-0.3). However, that was for the entire study population. When the researchers stratified those patients whose baseline viral load was less than 100,000 copies/mL or greater than 100,000 copies/mL, superiority was observed for darunavir + ritonavir specifically in patients with a baseline viral load greater than 100,000 copies/mL.

Looking at the 48-week virological responses for the lopinavir/ritonavir arm, much better responses were observed in patients who received lopinavir/ritonavir twice-daily versus once-daily. But we need to be careful, because patients were not randomized at baseline to allow for that type of comparison.

Click to enlarge

If we compare the darunavir + ritonavir once-daily arm, which had a response rate of 84%, to the lopinavir/ritonavir once-daily arm, which had a response rate of 71%, we see that there was a significant difference -- in fact, darunavir + ritonavir was statistically superior. But again, we have to be careful, because the study was not initially randomized to make that comparison. This finding was just the result of a post-hoc analysis.

Next, let's look at the safety results from the ARTEMIS study. We will start with the grade 2 to grade 4 adverse events that were observed. More patients in the lopinavir/ritonavir arm had GI symptoms -- specifically, diarrhea -- than did those in the darunavir + ritonavir arm. Again, as we discussed before, rash was more frequently seen in patients who received darunavir + ritonavir than patients who received lopinavir/ritonavir, which is similar to what we observed in the TITAN study.

Click to enlarge

In addition, there were significant differences in triglyceride levels. Most patients who received darunavir + ritonavir did not experience an increase in triglyceride levels above the NCEP [National Cholesterol Education Program] cutoff. A large amount of patients who received lopinavir/ritonavir experienced significant elevations in triglyceride levels. This was, of course, very statistically significant.

On the other hand, when we look at the ratio of mean total cholesterol and HDL [high-density lipoprotein] cholesterol, we can see that there was no difference between the study drugs. That was because there were better total cholesterol levels in the darunavir + ritonavir arm, but there were better HDL cholesterol levels in the lopinavir/ritonavir arm. That ratio then became similar for both patient populations.

Summary

The results of all the studies that we have discussed have powerfully documented both the efficacy and safety of darunavir in the heavily treatment-experienced population (POWER and DUET), in patients with limited antiretroviral experience (TITAN) and in treatment-naive patients (ARTEMIS).

But there are a few more things that we should mention about darunavir. The first is that the original formulation of darunavir was 300 mg, which required two tablets to be taken twice per day in addition to ritonavir.²⁷ A new formulation of 600 mg is now available that decreases the pill burden to one tablet twice per day, with of course the addition of ritonavir.²⁸ A new formulation of 400 mg is expected to be released soon for treatment-naive patients. Those patients will then be able to use two 400-mg tablets of darunavir plus 100 mg of ritonavir as the boosted-PI component of their regimen.

Another important consideration with the use of darunavir is that its drug label has been recently updated to include a warning about drug-induced hepatitis.²⁹ This complication was observed during the development program, and was mainly experienced among patients with a lot of treatment experience. The hepatitis occurred mainly during immune reconstitution. In addition, most of these patients already had a history of liver dysfunction. The incidence of drug-induced hepatitis was estimated to be around 0.5%.

Finally, another important point is that, when you combine darunavir and etravirine, perhaps with another active agent, in the way that they were utilized in the DUET studies, you significantly increase the possibility of crafting a complete regimen for treatment-experienced patients. What's great about this is that many HIV providers are already familiar with these existing antiretroviral classes and many providers feel more comfortable using drugs from the classes that they have already been using for quite some time.

That having been said, those of you who do have an interest in new antiretroviral classes should stay tuned, since I will take the rest of this presentation to discuss them.

Raltegravir: The First FDA-Approved Integrase Inhibitor

First, let's move on to a discussion of raltegravir, which is the only integrase inhibitor approved so far by the FDA. It was approved for use by treatment-experienced patients at a dose of 400 mg to be taken twice per day.³⁰

It is important to note that raltegravir is metabolized mainly by glucuronidation and not by cytochrome P450, so it has minimal drug interactions.

Raltegravir in Treatment-Experienced Patients

The studies that led to the approval of raltegravir in the treatment-experienced population are called BENCHMRK-1 and BENCHMRK-2.^31,32 These two studies were very large, had similar study designs and were conducted in similar patient populations (namely, patients who were heavily experienced to NNRTIs, NRTIs [nucleoside reverse transcriptase inhibitors] and PIs). Patients were randomized to receive an optimized background regimen along with either raltegravir 400 mg twice per day or placebo.

(The optimized background regimen was selected by the investigator based on the results of baseline genotypic and phenotypic tests.) The investigator could select protease inhibitors, and/or use enfuvirtide.

Click to enlarge

In BENCHMRK-1, 65% of patients receiving raltegravir achieved a viral load of less than 50 copies/mL after 48 weeks, compared to 31% of patients receiving a placebo.³³ The results were similar for BENCHMRK-2 (60% versus 34%).³⁴

The difference between the percentage of patients achieving an undetectable viral load on raltegravir versus placebo is very much statistically significant (P < .001), again confirming the efficacy of this agent in heavily treatment-experienced populations.

In addition, as we have seen in analyses for other new agents, the more active drugs that we are able to add to the optimized background regimen, the better the responses we observe.

Click to enlarge

In the BENCHMRK studies, if the patient took enfuvirtide and darunavir, in addition to taking raltegravir, we see that an astonishing 89% achieved an undetectable viral load at week 48. This is very remarkable: These are patients who had a lot of resistance to three drug classes, so to see a response rate of 89% is absolutely extraordinary.

Meanwhile, among patients who received a placebo instead of raltegravir, but who were treated with darunavir and enfuvirtide, the response rate was 68%. For patients who received neither enfuvirtide nor darunavir, but who did receive raltegravir, 60% achieved a viral load of less than 50 copies/mL. These are both good responses, even in the absence of a very potent optimized background regimen, but they would be better yet if we could optimize these patients' regimens with a greater number of active drugs.

Click to enlarge

In addition to these efficacy results, the slide to the right displays the drug-related adverse events seen in both BENCHMRK studies. The incidence of diarrhea, fatigue, headache and nausea did not differ in a statistically significant manner between the raltegravir arms and the placebo arm.^33,34

Ultimately, based on the data obtained in the BENCHMRK-1 and BENCHMRK-2 studies, raltegravir was able to demonstrate excellent potency and safety, which eventually led to the approval of this agent for the treatment-experienced population on Oct. 12, 2007.³⁵

Raltegravir in Treatment-Naive Patients

In addition to being studied in experienced patients, raltegravir has also been studied in treatment-naive patients. Protocol 004 was a pilot study conducted in about 200 treatment-naive patients who were randomized to receive a background regimen of lamivudine [3TC, Epivir] and tenofovir along with either efavirenz or one of four doses of raltegravir.³⁶

The results of this study were quite impressive. Patients who received raltegravir exhibited a rapid rate of viral decay and were able to achieve virologic suppression very early in therapy, as shown in the graph in the slide below.

Click to enlarge

An important point to make here is that patients who received raltegravir were able to achieve virologic suppression earlier than patients who received efavirenz. However, by week 24, efavirenz patients had "caught up": The same proportion of patients in both groups had achieved virologic suppression to less than 50 copies/mL.

The question, then, is: What is the significance of achieving virologic suppression earlier in therapy? Some people postulate that this may prevent the patient from accumulating resistance mutations during the viral decay phase that could become a problem in the future, but the true clinical significance of earlier suppression has not been completely elucidated.

Another issue that became very apparent in this study had to do with the performance of efavirenz. Some believed that, because of the difference in early responses, efavirenz may have underperformed in this study. But when the data set in the efavirenz arm was compared with those of other, well-known studies in which efavirenz had been one of the components, it was found that the efavirenz arm in Protocol 004 achieved results that were very similar to what had been previously observed in multiple other clinical trials. In sum, efavirenz performed in Protocol 004 as well as it had performed in many studies in the past; the raltegravir arms simply performed better, at least before week 24.

Protocol 004 also looked at safety data, and in terms of the incidence of adverse events, the results were largely similar between raltegravir and efavirenz. One exception was headache, which was more common among patients who received efavirenz compared to patients who received raltegravir.

Click to enlarge

There were also statistically significant differences in total cholesterol and triglyceride levels between patients who received raltegravir and patients who received efavirenz: Generally, patients on raltegravir experienced a slight reduction in these levels, while patients on efavirenz experienced an increase.

Summary

In sum, what we see in this pilot study of raltegravir versus efavirenz is that patients were able to achieve a similar amount of virologic suppression on either drug, but they were able to achieve it earlier on raltegravir. Raltegravir patients were also less likely to experience headache or dyslipidemia.

Currently, there is another large study being conducted in treatment-naive patients that compares raltegravir and efavirenz (both taken in combination with emtricitabine and tenofovir).³⁷ If this study is able to reproduce results similar to those seen in Protocol 004, raltegravir has the potential to become an effective option for treatment-naive patients -- and an attractive one, I must say, given its apparently excellent safety and tolerability.

In fact, if this ongoing study shows success for raltegravir, there will be only two potential drawbacks I can see regarding the use of raltegravir in treatment-naive patients: 1) it needs to be dosed twice per day, and 2) no coformulation exists with other antiretrovirals. We should see results from this ongoing study very soon.

Maraviroc: The First FDA-Approved CCR5 Antagonist

The last new antiretroviral from a novel class that I will be discussing is maraviroc, an entry inhibitor, a CCR5 coreceptor antagonist.³⁸

This agent is truly a novel concept, given that every other antiretroviral agent acts by inhibiting a viral-encoded enzyme. Maraviroc is the only antiretroviral medication that does not block a viral enzyme, but rather a human receptor present on the surface of lymphocytes, monocytes and other mononuclear cells.

Click to enlarge

This mechanism of action has generated different opinions regarding what is good about this drug, what is bad, and what still remains unknown.

Among the good things about maraviroc is the fact that it does prevent entry of the virus into the cell. Further, this is a new mechanism of action, and there is no anticipated cross-resistance in patients who have not been exposed to a CCR5 antagonist. Maraviroc also has very potent antiviral activity, as has been demonstrated in several clinical trials.^39,40 It has also been shown to be very well tolerated.

The potential negative issues surrounding the use of CCR5 coreceptor antagonists have to do mainly with tropism. CCR5 (or R5, for short)-tropic virus is more prevalent among patients who are in an early stage of HIV disease,^41,42 yet maraviroc was approved for use in heavily treatment-experienced patients.³⁸

CXCR4 (or X4)-tropic virus is associated with disease progression, so the possibility of seeing the emergence of X4 virus after treatment with an R5 coreceptor antagonist is not something that we really want to see.⁴³ Also, the assay that is used to differentiate between R5 virus and X4 virus lacks sensitivity. (More on that in a moment.)

Finally, there remain some unknown issues associated with the use of CCR5 antagonists. We do not yet fully understand, for instance, if there are any long-term safety issues related to blocking the R5 coreceptor. Although we have theorized that it is probably safe, this remains an area of some uncertainty to many scientists.

Tropism Testing

Click to enlarge

Turning back to issues related to the tropism test, the slide to the right outlines the manner in which the Trofile assay works. If a patient has R5-tropic virus, the tropism test results will be marked as such, which indicates that the patient's HIV exclusively uses the CCR5 coreceptor to enter a CD4+ T cell. As a result, activity with a CCR5 antagonist is anticipated. By contrast, if a patient has X4-tropic virus, a mix of R5- and X4-tropic virus, or virus that is both R5- and X4-tropic, little to no activity with a CCR5 antagonist is anticipated.

The standard Trofile test that is currently being used has been proven to have a very good negative predictive value, meaning the test very accurately shows that a patient's HIV is R5-tropic, X4-tropic or dual/mixed.⁴⁴

However, the test is only able to detect X4-tropic virus with 100% accuracy if X4-tropic virus comprises 10% or greater of the patient's viral population. For patients who have dual/mixed virus and an X4-tropic viral population of less than 10%, there is a possibility that those patients will be diagnosed as having R5-tropic virus when indeed they are dual/mixed-tropic. As a result, there is a risk that those patients will be prescribed a CCR5 antagonist even though they will likely not respond to this agent.

Enhanced Tropism Assay in Development

Encouragingly, there is an enhanced Trofile assay under development that appears to have about a 10- to 100-fold greater sensitivity over the standard Trofile assay.^45,46 This assay has been used in an ACTG [AIDS Clinical Trials Group] study, ACTG 5211, in which patients were being given vicriviroc [SCH 417690, SCH-D], a CCR5 antagonist in development.⁴⁷

Patients who entered the ACTG 5211 study were treatment experienced, and all of them -- there were 116 patients -- were R5-tropic, according to the standard Trofile assay. However, when the enhanced Trofile assay was used to reassess those patients retrospectively, it was discovered that 25 of the 116 patients did not have R5-tropic virus, but instead had dual/mixed-tropic virus. Of those 25 patients, 15 had received vicriviroc during the study, and 12 of them -- 80% -- experienced virologic failure.⁴⁶ All of which, again, emphasizes the importance of having the right tropism test results before initiating therapy with an R5 coreceptor antagonist.

How this all relates to maraviroc is clear: The drug is, as we will see in a moment, very effective and has a good safety profile. But until this issue with the Trofile test is resolved and the new, enhanced Trofile assay becomes available, we face a significant limitation in clinical practice, especially when treating patients who have other treatment options.

Maraviroc in Treatment-Experienced Patients

Now, on to an analysis of maraviroc itself. The studies that led to the approval of maraviroc are the MOTIVATE-1 and MOTIVATE-2 studies.^39,40 These were two large studies with similar designs that were conducted in heavily treatment-experienced patients. Patients were randomized to receive an optimized background regimen along with placebo, maraviroc once daily or maraviroc twice daily.

Click to enlarge

The 48-week pooled results from the MOTIVATE studies are shown in the slide to the left.⁴⁸ The slide is a bit busy, but it shows a significant difference between patients who received maraviroc versus patients who received placebo, in terms of a viral load less than 50 copies/mL or less than 400 copies/mL. Viral suppression to less than 50 copies/mL was between 43.2% and 45.5% among patients who were receiving maraviroc, versus just 16.7% among patients receiving a placebo. These results were highly statistically significant (P < .0001).

Additionally, if we look at the four lines on the top of this graph, we see that patients who received maraviroc twice daily had better responses than patients who received maraviroc once daily. Viral suppression to less than 400 copies/mL was 56.1% among patients receiving maraviroc twice daily and 51.7% among patients receiving maraviroc once daily. Viral suppression to less than 50 copies/mL was 45.5% among patients receiving maraviroc twice daily and 43.2% among patients receiving maraviroc once daily.

But, again, the difference in virologic response between maraviroc and placebo was starker. For example, the proportion of patients who achieved an HIV RNA level of less than 400 copies/mL was 56.1% in patients who received maraviroc twice daily, versus 22.5% in patients who received a placebo. In fact, it is primarily based on this virologic data that maraviroc was approved for the treatment of experienced patients who are documented to have R5-tropic virus. There is no question that this drug is a very potent option for the treatment of patients who have significant antiretroviral experience, as long as they have R5-tropic virus.

Click to enlarge

As we saw in some of the studies we discussed earlier, the more active drugs we are able to include in the optimized background regimen, the better the responses we're going to see in the treated population. Similarly, in the MOTIVATE trials, we saw that patients who had no active drugs in their background regimen had low rates of suppression to below 50 copies/mL -- just 18% for the patients who received maraviroc once daily and 29% for patients who received maraviroc twice daily.^49,50 These response rates were greater the more active drugs that were added to the optimized background regimen: with two other active drugs, for instance, suppression rates jumped to 53% and 52% for patients who received maraviroc once daily or twice daily, respectively.

Thus, one of the take-home messages from all of these studies is that we really need to combine new agents with many active background drugs. According to the analyses that have been conducted in these studies, at least two -- or, even better, three -- active drugs are needed to maximize the response that we can get from these new agents.

Click to enlarge

Turning back to the issue of tropism, let's look at rates of virologic suppression to less than 50 copies/mL in patients who had R5-tropic virus at baseline compared to patients who had a dual/mixed-tropic virus at baseline.⁴³

It is worth noting that all patients who participated in this study had an R5-tropic virus at initial screening, but had their tropism test repeated just before beginning day 1 of treatment (i.e., at baseline).

What the researchers found was that about 10% of patients who had R5-tropic virus at initial screening were found to have dual/mixed-tropic virus at the time that they started the study and took their first study dose.

The virologic responses in patients with dual/mixed-tropic virus who received maraviroc were not that much different than the responses in patients who received a placebo: Among patients who had dual/mixed-tropic virus at baseline, 27% of patients who took once-daily maraviroc achieved a viral load below 50 copies/mL, compared to 18% of patients who took twice-daily maraviroc and 18% of patients who took a placebo. This indicates, again, that we do not expect much antiviral activity if the patient has dual- or mixed-tropic virus.

On the other hand, if the patient still had R5-tropic virus at baseline, we can see that responses in the maraviroc once-daily (50%) and twice-daily arms (50%) were significantly higher than among patients who received a placebo (26%).

Of course, as we have shown with the other new agents that we have discussed, efficacy may be important, but so is safety. The MOTIVATE studies are remarkable because the adverse events that were seen in the maraviroc once-daily and twice-daily arms were very similar to the adverse events seen in the placebo arm.⁴⁸ There was nothing really that "sticks out" in terms of adverse events with the use of this agent in heavily treatment-experienced patients. A similar frequency of serious adverse events was seen across all treatment arms, as were the rates of discontinuation due to adverse events.

Maraviroc in Treatment-Naive Patients

In addition to being studied in treatment-experienced patients, maraviroc has also been studied in treatment-naive patients. This took place in a study called MERIT, in which maraviroc was compared to efavirenz.⁵¹ In this trial, treatment-naive patients were randomized to receive either drug plus the coformulation zidovudine/lamivudine [AZT/3TC, Combivir].

Click to enlarge

Something very important to note with this study was that, although the rate of adverse events in the efavirenz arm was significantly higher than in the maraviroc arm, the number of patients who discontinued the study due to a lack of efficacy was higher in the maraviroc arm than in the efavirenz arm. Those discordant discontinuation rates essentially cancel each other out.

In the end, we see that there was some difference between both treatment groups in terms of patients achieving an undetectable viral load at week 48.

Click to enlarge

If we look at the proportion of patients with a viral load of less than 400 copies/mL, there was a trend towards the patients in the efavirenz arm (with 73.1% achieving suppression) doing slightly better than those on the maraviroc arm (with 70.6% achieving suppression).

In this comparison, maraviroc barely met the lower bound of the predefined study criteria for showing non-inferiority to efavirenz in treatment-naive patients. By contrast, maraviroc barely missed the lower bound of non-inferiority in a comparison of the proportion of patients who achieved a viral load of less than 50 copies/mL.

What these findings ultimately suggest is that, despite the promising safety data, it is unlikely that maraviroc can be used in treatment-naive patients unless we can better understand and overcome the differences between the results observed in the efavirenz arm and the maraviroc arm in the MERIT trial.

Click to enlarge

Finally, there is one more potential limitation regarding the use of maraviroc: pharmacokinetic interactions, specifically as they relate to the fact that the drug is metabolized by cytochrome P450.³⁸ The regular dose for maraviroc should be 300 mg twice daily, which we should prescribe if the patient is not taking any CYP3A inhibitor or inducer. If a patient is taking a CYP3A inhibitor, such as ritonavir, then the dose needs to be reduced to 150 mg twice daily. In other words, every time that we concurrently prescribe a boosted protease inhibitor -- with the exception of tipranavir -- we need to decrease the maraviroc dose to 150 mg twice per day. On the other hand, if we're using a CYP3A inducer, then the maraviroc dose needs to be increased to 600 mg twice daily.

It's very important that we keep in mind that there are three different maraviroc dosages that we need to choose from when we dose this medication with other antiretrovirals.

Conclusion

Looking back over all four of the new antiretrovirals we have discussed in this activity -- darunavir, etravirine, maraviroc and raltegravir -- there is no doubt that their introduction has completely changed the landscape of HIV treatment, and has reenergized the armamentarium that we use to treat our patients today.

In my clinical practice, the impact that these new agents have had has been enormous. It is similar to -- although not quite of the same magnitude as -- what we observed in the mid-1990s, when PIs were first introduced to the HIV arena. And it's possible that patients who have less antiretroviral experience can also benefit from the introduction of these agents.

Of course, with so many agents approved in a very short period of time, there's so much we still have to learn. Our understanding of the use of these agents remains a work in progress. I hope that this presentation has helped elucidate some of the highlights of what we know so far and hinted at what we still have to learn.

References

1. Yerly S, Kaiser L, Race E, Bru J-P, Clavel F, Perrin L. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet. August 28, 1999;354(9180):729.

2. Brenner B, Wainberg MA, Salomon H, et al, and investigators of the Quebec Primary Infection Study. Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Int J Antimicrob Agents. December 2000;16(4):429-434.

3. Wheeler W, Mahle K, Bodnar U, Kline R, Hall I, McKenna M, and the US Variant, Atypical and Resistant HIV Surveillance (VARHS) Group. Antiretroviral drug-resistance mutations and subtypes in drug-naive persons newly diagnosed with HIV-1 infection, US, March 2003 to October 2006. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Poster 648.
   View poster: Download PDF

4. Napravnik S, Keys JR, Quinlivan EB, Wohl DA, Mikeal OV, Eron JJ Jr. Triple-class antiretroviral drug resistance: risk and predictors among HIV-1-infected patients. AIDS. April 23, 2007;21(7):825-834.

5. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.

6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (PDF). Washington, DC: US Dept of Health and Human Services; January 29, 2008.

7. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. August 16, 2006;296(7):827-843.

8. Intelence [package insert]. Raritan, NJ: Tibotec, Inc.; January 2008.

9. Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 144LB.
   View slides: Download PowerPoint

10. Andries K, Azijn H, Thielemans T, et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. December 2004;48(12):4680-4686.

11. Gruzdev B, Rakhmanova A, Doubovskaya E, et al. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS. November 21, 2003;17(17):2487-2494.

12. Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC 125-a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS. December 5, 2003;17(18):F49-F54.

13. Madruga JV, Cahn P, Grinsztejn B, et al, on behalf of the DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. July 7, 2007;370(9581):29-38.

14. Lazzarin A, Campbell T, Clotet B, et al, on behalf of the DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. July 7, 2007;370(9581):39-48.

15. Haubrich R, Cahn P, Grinsztejn B, et al, on behalf of the DUET-1 study group. DUET-1: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1-infected patients. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 790.
    View poster: Download PDF

16. Cahn P, Haubrich R, Leider J, et al. Pooled 24-week results of DUET-1 and -2: TMC125 (etravirine; ETR) vs placebo in 1203 treatment-experienced HIV-1-infected patients. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-717.
    View slides: Download PowerPoint

17. Benhamida J, Chappey C, Coakley E, Parkin NT. Monogram HIV-1 genotype algorithms for prediction of etravirine susceptibility: novel mutations and weighting factors identified through correlations to phenotype. In: Program and abstracts of the XVII International HIV Drug Resistance Workshop; June 10-14, 2008; Sitges, Spain.

18. Bacheler L, Van Der Borght K, Van Craenenbrosck E, Winters B, Lecocq P. Virco etravirine clinical cutoffs: exploring etravirine resistance among recent routine clinical samples submitted for resistance testing. In: Program and abstracts of the XVII International HIV Drug Resistance Workshop; June 10-14, 2008; Sitges, Spain.

19. Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; March 2008.

20. Hicks CB, Cahn P, Cooper DA, et al, on behalf of the RESIST investigator group. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. August 5, 2006;368(9534):466-475.

21. Clotet B, Bellos N, Molina J-M, et al, on behalf of the POWER 1 and 2 study groups. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. April 7, 2007;369(9568):1169-1178.

22. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at week 48: ARTEMIS. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-718b.
    View slides: Download PowerPoint

23. Valdez-Madruga J, Berger DS, McMurchie M, et al. Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naive, treatment-experienced patients: a randomised, controlled phase III trial (TITAN). In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB101.
    View slides: Download PDF

24. Eron J Jr, Yeni P, Gathe J Jr, et al, for the KLEAN study team. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet. August 5, 2006;368(9534):476-482.

25. Walmsley S, Ruxrungtham K, Slim J, Ward D, Larson P, Raffi FL. Saquinavir/r (SQV/r) BID versus lopinavir/r (LPV/r) BID, plus emtricitabine/tenofovir (FTC/TDF) QD as initial therapy in HIV-1-infected patients: the GEMINI study. In: Program and abstracts of the 11th European AIDS Conference; Madrid, Spain; October 24-27, 2007. Abstract PS1/4.

26. Molina J-M, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 37.
    View slides: Download PDF

27. Prezista [package insert]. Raritan, NJ: Tibotec, Inc.; February 2008.

28. New 600-mg tablet strength for Prezista (darunavir). Rockville, MD: U.S. Food and Drug Administration; February 26, 2008.

29. Important drug warning. Rockville, MD: U.S. Food and Drug Administration; March 2008.

30. Isentress [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; May 2008.

31. Cooper D, Gatell J, Rockstroh J, et al, for the BENCHMRK-1 Study Group. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 105aLB.

32. Steigbigel R, Kumar P, Eron J, et al, for the BENCHMRK-2 Study Group. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 105bLB.

33. Cooper D, Gatell J, Rockstroh J, et al, and the BENCHMRK-1 Study Group. 48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 788.
    View poster: Download PDF
    View slides: Download PowerPoint

34. Steigbigel R, Kumar P, Eron J, et al, and the BENCHMRK-2 Study Group. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 789.
    View poster: Download PDF
    View slides: Download PowerPoint

35. FDA Approval of Isentress (Raltegravir). Rockville, MD: U.S. Food and Drug Administration; October 12, 2007.

36. Markowitz M, Nguyen B-Y, Gotuzzo E, et al, and the Protocol 004 Part II Study Team. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment HIV-1 infected patients: 48-week data. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104.
    View slides: Download PowerPoint

37. A study to evaluate the safety and antiretroviral activity of MK0518 versus efavirenz in treatment naive HIV-infected patients, each in combination with Truvada. ClinicalTrials.gov [serial online]. June 27, 2008.

38. Selzentry [package insert]. New York, NY: Pfizer Labs; August 2007.

39. Gulick RM, van der Ryst E, Lampiris H, et al. Efficacy and safety of once-daily (QD) compared with twice-daily (BID) maraviroc plus optimized background therapy (OBT) in treatment-experienced patients infected with CCR5-tropic-HIV-1: 24-week combined analysis of the MOTIVATE 1 and 2 studies. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB116LB.

40. van der Ryst E, Cooper D, Konourina I, et al. Efficacy of maraviroc in combination with at least one other potent new antiretroviral drug: 24-week combined analysis of the MOTIVATE 1 and 2 studies. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB115LB.

41. Daar ES, Kesler KL, Petropoulos CJ, et al, for the Hemophilia Growth and Development Study. Baseline HIV type 1 coreceptor tropism predicts disease progression. Clin Infect Dis. September 1, 2007;45(5):643-649.

42. Goetz MB, Leduc R, Kostman JR, et al, and The Terry Beirn Community Programs For Clinical ReSearch On Aids. Prediction of disease progression by HIV co-receptor tropism (CRT) in persons (P) with untreated chronic HIV infection. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-1027.
    View poster: Download PowerPoint

43. van der Ryst E, Westby M. Changes in HIV-1 co-receptor tropism for patients participating in the maraviroc Motivate 1 and 2 clinical trials. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-715.
    View slides: Download PowerPoint

44. Whitcomb JM, Huang W, Fransen S, et al. Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrob Agents Chemother. February 2007;51(2):566-575.

45. Reeves JD, Han D, Liu Y, et al. Enhancements to the Trofile HIV coreceptor tropism assay enable reliable detection of CXCR4-using subpopulations at less than 1%. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-1026.

46. Reeves J, Han D, Wilkin T, et al. An enhanced version of the Trofile HIV co-receptor tropism assay predicts emergence of CXCR4 use in ACTG5211 vicriviroc trial samples. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 869.
    View poster: Download PDF

47. Gulick R, Su Z, Flexner C, et al, for the ACTG 5211 Study Team. ACTG 5211: phase II study of the safety and efficacy of vicriviroc in HIV-infected treatment-experienced subjects. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0217.
    View slides: Download PowerPoint

48. Hardy D, Reynes J, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 792.
    View poster: Download PDF

49. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104bLB.

50. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104aLB.

51. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: week 48 results of the MERIT study. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS104.
    View slides: Download PowerPoint