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New Data on Boosted Protease Inhibitors: An Expert Interview With Dr. Douglas Ward


Editor's Note:

The selection of the initial antiretroviral regimen may be one of the most important, if not the most important, decisions to be made in the treatment of HIV disease, affecting not only the success of treatment at the outset, but also the durability of response and the potential for future treatment options. Guidelines formulated by groups of experts can help to guide these decisions but may be limited by a lack of data or special circumstances for an individual patient. At the XVI International AIDS Conference (IAC) in Toronto, Ontario, Canada, Scott Williams, Editorial Director of Medscape HIV/AIDS, spoke with Dr. Douglas Ward, Internist and Infectious Disease Specialist at Dupont Circle Physicians Group in Washington, DC; Associate Professor of Internal Medicine at George Washington School of Medicine; and Associate Professor of Internal Medicine and Family and Community Medicine at Georgetown University School of Medicine, Washington, DC. Dr. Ward is a highly experienced expert in the treatment of HIV disease and an investigator in numerous clinical trials. This IAC occurs a decade after the first reports of the success of triple-drug regimens including protease inhibitors (PIs). Dr. Ward offered his clinical and scientific insights into the current status of boosted PIs and where we might go from here.

Medscape: At the IAC this year, we mark a decade since the introduction of highly active antiretroviral therapy (HAART). Since that time, several PIs have been added to the therapeutic armamentarium. Various studies over the years have attempted to tease out similarities and differences, risks and benefits that are associated with some of the more commonly used boosted PI regimens. For instance, at 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado, this year, we saw data from a clinical trial comparing unboosted vs boosted atazanavir.[1] Today, at the IAC, we heard results of a head-to-head comparison of ritonavir-boosted fosamprenavir and ritonavir-boosted lopinavir. What were the key elements in the design of the study before we talk about the results?

Dr. Ward: The KLEAN study[2,3] was a large clinical trial that compared ritonavir-boosted fosamprenavir, Lexiva, to Kaletra, ritonavir-boosted lopinavir, in treatment-naive patients. The study subjects were randomly assigned to receive one of these boosted PIs along with one coformulated abacavir (ABC)/lamivudine (3TC) tablet once daily.

Medscape: In terms of both efficacy and safety, what were the notable results that people should be aware of?

Dr. Ward: The 48-week results were presented, and in terms of efficacy, the results of the 2 drug arms were virtually superimposable. At all time points, the virologic success or failure rates on either drug had absolutely no difference. I think for any clinician who uses boosted PIs, this was no great surprise.

Medscape: And in terms of safety and tolerability?

Dr. Ward: Somewhat more surprisingly, there was also virtually no difference in safety or tolerability between the 2 drugs, looking at the lipid profiles, cholesterol, triglycerides, or other side effects, specifically diarrhea. The 2 different arms were essentially identical.

Medscape: Another ongoing debate centers around the broader question of the best antiretroviral class to use as the "third drug" in initial therapy, whether this might be a nucleoside reverse transcriptase inhibitor (NRTI), which is far less common now, a nonnucleoside reverse transcriptase inhibitor (NNRTI), a boosted PI, or a NNRTI and a boosted PI together. What data were presented at this meeting that addressed this question?

Dr. Ward: There were 2 large trials that looked at the question of what third drug or what class of drugs to use in a triple combination therapy. One of these was the CPCRA First trial,[4] a large clinical trial looking at patients who were randomized to receive 1 of 3 treatment regimens: (1) PI + NRTIs; (2) NNRTI + NRTIs; or (3) PI + NNRTI + NRTI(s). This trial was originally recruited many years ago; as a result, the most commonly used PI was nelfinavir, which was not ritonavir boosted, and the results may not extrapolate completely to today. In this trial, there was some evidence of improved outcomes with NNRTI-based regimens. However, as I mentioned, it's unfair to compare these results to the more commonly used ritonavir-boosted PIs used today.

But in the latebreaker session this afternoon, we heard the results of the ACTG 5142[5] trial, which compared 3 different "class-sparing" regimens: (1) lopinavir/ritonavir (LPV/r) + efavirenz (EFV), (2) LPV/r + 2 NRTIs, and (3) EFV+2 NRTIs. The results among the 3 arms were really very similar, although any EFV-containing regimen (EFV + NRTIs or EFV + LPV/r) had slightly better virologic outcomes over the course of the trial.

Medscape: Although these class-sparing data are certainly of interest and relevant to HIV management, for treatment-naive patients, both the US Department of Health and Human Services (DHHS)[6]and the International AIDS Society-USA (IAS-USA)[7] guidelines recommend either an NNRTI or a boosted PI as the third drug or the third class to be used with particular NNRTI pairs. Given no baseline drug resistance, what is your own algorithm when you must determine what type of agent is more appropriate for your treatment-naive patients?

Dr. Ward: Choosing therapy for a treatment-naive patient is complicated. I consider the question much more complex than simply going by those guidelines and also requiring more patient-specific tailoring of the regimen.

I like to make the regimen as nontoxic as possible in the long term, also aiming for simplicity-- regimens that can be given once a day. And we certainly have had improvements in terms of coformulations that combine drugs and require very few pills. Atripla, which was recently approved, is a complete HIV regimen in one pill, once a day.

I tend to use NNRTIs because of their reduced long-term toxicity and ease of administration. I like to start off some patients with boosted PIs, particularly if they have a very high viral load or low CD4 cells and later consider simplifying the regimen by changing the boosted PI either to an NNRTI or perhaps an unboosted PI such as atazanavir.

Medscape: While we were at the conference, the new IAS-USA guidelines[7] were released. What were the significant changes in the document? Do you think these will have an effect on your own clinical practice or the practice of other physicians?

Dr. Ward: The new IAS-USA guidelines[7] really broaden the recommended PI-based regimens. These new guidelines include boosted PIs such as fosamprenavir, saquinavir, or atazanavir. They also widened the choice of NRTIs that can be used with these drugs: abacavir or tenofovir along with emtricitabine or lamivudine.

I think this probably won't make a major difference in my prescribing, in that I have felt for quite a while that the other protease inhibitors probably are equivalent to LPV/r in efficacy. The KLEAN study,[2] which was presented at this conference, demonstrates that equivalence for fosamprenavir. Head-to-head trials against LPV/r are in progress for both saquinavir and atazanavir.

Hopefully, the DHHS guidelines will also be modified in the near future because I think we do have many more treatment options that physicians can use to adapt treatment to the patient's specific needs.

Medscape: Both patients and their doctors have been interested in reducing long-term exposure to antiretroviral drugs obviously because of concerns about toxicities. Pilot studies[8,9] have looked at induction-maintenance strategies that used boosted PIs without NRTIs as maintenance regimens for patients who have sustained virologic suppression and no evidence of drug resistance. We saw more data about this approach this afternoon. What did we learn?

Dr. Ward: People have been looking at LPV/r monotherapy in various treatment situations. At the International AIDS Conference this week, there were actually 4 different presentations of LPV/r monotherapy[10-13] used either as initial therapy or in an induction maintenance setting.

Interestingly, the results were really all very similar. Statistically, the LPV/r monotherapy regimen was not inferior to continuing LPV/r with NRTIs, although there was a subtle occurrence of more treatment failure with the monotherapy and possibly an increased rate of resistance to PIs developing in the patients on monotherapy.

One concern I have also is that I'm not sure what toxicity we're reducing by going to monotherapy with a ritonavir-boosted PI. I feel that a lot of the toxicity from these regimens probably comes from the ritonavir, and that a better approach to reducing toxicity may involve switching the boosted PI to either non-ritonavir-boosted PI or an NNRTI.

Medscape: People have looked at trying to use agents other than ritonavir to boost PI levels, and that really hasn't panned out thus far. Where do things stand with that?

Dr. Ward: There are other agents that are cytochrome P450 inhibitors, which may raise PI levels — drugs such as the antifungal ketoconazole or the NNRTI delaviridine. Although they may increase protease inhibitor levels somewhat, none of these are nearly as potent as ritonavir at increasing drug levels. Certainly none of them have shown significant efficacy in boosting PIs to the levels we need.

Medscape: What additional evidence do you think we need to see from these early trials of induction/maintenance before we could really move out of our research setting and potentially have this used in a clinical setting?

Dr. Ward: Induction/maintenance is still a wide open field. I think we have at least preliminary evidence that you can keep the overwhelming majority of patients undetectable on simpler regimens, although the degree of simplification that was attempted many years ago — for instance, going to a single NRTI — does not work.

But be it monotherapy with a boosted PI, NNRTI-based regimens, or other simpler, hopefully less toxic regimens, there are many options. It's important to be creative in designing these trials and to look at not just the virologic efficacy, but also the reduction in toxicity.

Medscape: Boosted darunavir is the most recent addition to our treatment armamentarium for HIV, and it's considered to be an important PI option for treatment-experienced patients in particular, as is tipranavir, which was approved last year. What new data were presented here, and what were the key take-home results and conclusions for clinicians?

Dr. Ward: The 48-week data from the darunavir POWER-1 and POWER-2 registrational trials[14] were presented at this conference, and really reemphasized the results we saw at 24 weeks. The degree of virologic suppression, the success rate in use of darunavir in highly treatment experienced patients was maintained through the 48 weeks.

Certainly, we did see, as would be expected, that darunavir was more effective at lowering viral load and getting patients' viral loads to an undetectable level when used with other active agents, be those active NRTIs or enfuvirtide, which is an agent to which most patients with HIV are naive, so most remain susceptible to that drug, in particular.

Medscape: Were there other antiretrovirals in the pipeline that are being studied with respect to ritonavir boosting? For instance, new PIs, NNRTIs, CCR5 antagonists?

Dr. Ward: There are quite a few drugs in the antiretroviral pipeline that show a great deal of promise. Many of them are in early development, and we still need to learn how to use them.

Data were presented at this conference on an investigational NNRTI from Tibotec Pharmaceuticals, TMC125 (etravirine)[15]; this new NNRTI has shown significant efficacy, particularly when used with darunavir in highly treatment-experienced patients.

One of the most interesting classes of drugs in development is the integrase inhibitors. There was a presentation at the latebreaker session today of the Merck integrase inhibitor, which shows significant potency in most patients[16] and has been previously shown to have efficacy in highly treatment-experienced patients. Once again, being a whole new drug class no resistance to this drug would be expected. In the highly treatment-experienced patient, it will likely have a great deal of efficacy when used with a combination of other drugs.

Medscape: Is it boosted or is the Gilead integrase inhibitor boosted?

Dr. Ward: The Merck integrase inhibitor is not metabolized by the cytochrome P450 enzyme pathway, so is not being given with ritonavir boosting. The Gilead integrase inhibitor[17] is P450-metabolized. At the doses they're using in the current clinical trial, it is being given once daily with ritonavir boosting, although if used at a significantly higher dose, it could conceivably be used without ritonavir.

Medscape: Last year, you presented data on the investigational PI brecanavir — I believe it was at ICAAC.[18] What's the key feature of this protease inhibitor?

Dr. Ward: Brecanavir is another protease inhibitor in development, currently in phase 2 trials. Biochemically, it's actually somewhat similar to darunavir. It is a very potent protease inhibitor with very high binding affinity to HIV protease and a very low IC50. In very early trials, it has shown excellent effect in a small number of patients with highly resistant virus.

Medscape: I believe at this conference we did see some interesting pharmacokinetic data on brecanavir. Could you tell us a little about that?

Dr. Ward: There was a presentation of pharmacokinetic interactions of brecanavir at this conference.[19] It must be remembered that there are currently virtually no data on the use of double boosted protease inhibitors, although in the patient with highly resistant virus, that treatment approach is being used.

Importantly, the investigators looked at the interaction of brecanavir, ritonavir-boosted lopinavir, and atazanavir. And the interactions were really what could have been predicted knowing the pharmacokinetics of the different drugs.

When given along with atazanavir, brecanavir blood levels did not change significantly, although atazanavir levels are increased somewhat. This would be predicted because when given with brecanavir, you're actually using twice as much ritonavir as is normally taken with atazanavir. So you get even more ritonavir boosting.

When brecanavir and lopinavir were given together, lopinavir blood levels did not change significantly. Brecanavir levels are reduced slightly, which would be predictable since lopinavir is a cytochrome P450 inducer, although the degree of reduction is probably not clinically significant.

Medscape: And didn't they also show data with tipranavir in this study?

Dr. Ward: Yes. Basically, they were suggesting that it was contraindicated. As would be expected, and as we have seen with all other protease inhibitors, tipranavir is a very potent inducer of cytochrome P450 enzymes, as well as the P-glycoprotein system, so that there were significant reductions in brecanavir blood levels. In addition, the ritonavir-boosted brecanavir plus tipranavir study was discontinued due to asymptomatic hepatic transaminase elevations, which returned to baseline after discontinuation of study drugs.

Medscape: Well, thanks so much for talking to us today. We really appreciate it.

Dr. Ward: Thank you.

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