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Fosamprenavir: A New PI Option

February 2004

The improved tolerability, dosing flexibility, and resistance properties of new protease inhibitors (PIs) have triggered a reassessment of the role that PIs may play in first- and second-line antiretroviral therapy. The US Food and Drug Administration (FDA) approved two new PIs -- atazanavir (ATV) and fosamprenavir (fos-APV) -- last year for use in the United States. Atazanavir has been available for clinical use for approximately six months, and US treatment guidelines were revised November 10, 2003, to include information on its use in HIV-infected adults and adolescents.1 Fosamprenavir, which is a new formulation of the existing PI, amprenavir, was approved October 20, 2003, for use with or without ritonavir (RTV) boosting in antiretroviral-naive and -experienced patients. Current treatment guidelines do not include information on its use in either patient population.

Craig Sterritt, Program Director of Medscape HIV/AIDS, recently interviewed Jeffrey Nadler, Professor of Medicine at the University of South Florida College of Medicine, in Tampa, Florida. Nadler served as principal investigator of the pivotal NEAT study, which examined the use of fos-APV as initial therapy in previously untreated HIV-infected patients.2 Although Nadler has a professional relationship with GlaxoSmithKline, which markets fos-APV, Sterritt interviewed Nadler for this Q&A article because of his extensive clinical experience with this new antiretroviral drug.

Sterritt: Will fos-APV have a place at the table for initial therapy despite the popularity of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens among clinicians and declining acceptance of PI-based therapy among patients?

Nadler: Yes, I think it very well may have. For initial PI-based regimens, the latest US treatment guidelines recommend the use of lopinavir/ritonavir (LPV/r). I think the advent of fos-APV, and also ATV, calls for a reassessment of that, even though they are new drugs. There is strong evidence that these new agents are better tolerated than LPV/r, and there is accumulating evidence that ATV, and possibly fos-APV as well, have markedly better side effect profiles than existing PIs with respect to lipids. And, in terms of patient acceptance and adherence, both represent a considerable step forward in terms of convenience, as they can be administered once daily. Certainly in terms of first-line or first-PI therapy, they appear to perform at least as well as previously available PIs in terms of potency.

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Sterritt: What advantages does fos-APV offer in terms of convenience?

Nadler: One key advantage of fos-APV is that it can be used either once a day or twice a day. This flexibility allows one to tailor the administration of fos-APV to whatever NRTIs are included in the regimen. One of the things that we've come to learn from research of adherence issues is that the requirement of different numbers of pills at different dosing intervals represents an added disincentive to optimal patient adherence. In other words, many patients prefer symmetrical dosing, whereby the same number of pills is taken every time.

The other key advantage to fos-APV is that, like its predecessor APV, it has no food requirement. This means, for example, that someone using fos-APV once daily can wake up in the morning, take their pills, and be done for the day. They don't have to worry about waiting an hour after meals or anything like that. Food just isn't an issue. And, compared with its precursor, APV, it really is a new chemical entity. It's water-soluble like nelfinavir (NFV), so it's formulated as a very compact tablet. One 750 mg tablet is bioequivalent to four of the old APV capsules, but without the excipients that caused most of the gastrointestinal side effects.

So you've got a low pill burden, flexibility, and convenience, which make it an attractive option to patients in early stages of therapy. And it's got the potency that we like about the PIs and a high genetic barrier to resistance, which some would argue make PIs preferable to the NNRTIs for initial therapy, at least in some cases.

Sterritt: Fos-APV is approved for use either once daily in combination with RTV or twice daily with or without RTV boosting. Should fos-APV be boosted in all or in some patients?

Nadler: In the NEAT study, which looked at first-line therapy, twice-daily fos-APV was equally as effective as NFV when used unboosted. However, I really don't think that's the best way to use fos-APV. Optimally, I believe fos-APV should be boosted in PI-naive as well as PI-experienced patients, and regardless of dosing frequency.

Sterritt: How do you feel that fos-APV compares with the other new PI option, ATV, which appears to have a unique advantage over other PIs in terms of lipid side effects?

Nadler: Well, again, they're certainly comparable in terms of their low pill burdens. Fos-APV, when used unboosted, requires only two pills twice a day; but even when it's boosted with RTV, you still have a maximum of four pills a day, whether you take it once or twice a day.

In terms of side effects, with fos-APV you don't have the problem of hyperbilirubinemia, even though with ATV that's probably more of a number to worry about than a clinically significant problem, unless the patient becomes icteric, which can be stigmatizing, even if otherwise benign. Of course, in the case of both new PIs, we have yet to see how issues of tolerance and side effects will play out in the real world as opposed to the clinical trial setting.

Further, at least for now, there appear to be fewer drug-drug interactions with fos-APV as compared to ATV. And, where that plays out is that with ATV, which must be taken with food to optimize absorption, if you have patients on gastric-acid inhibitors, whether proton-pump inhibitors or H2 blockers, that can have a significant impact on the bioavailability of ATV -- especially when it's used without boosting. There are also some antiarrhythmic interactions with ATV that are apparently less of a problem with fos-APV. Again, we will have to wait and see whether this potential distinction will be validated in the clinical setting.

With respect to lipids, although blood lipids do go up with boosted fos-APV, the increases are fairly modest. And although the LDL cholesterol (LDL-C) and triglycerides go up on average, levels do not commonly go above the National Cholesterol Education Program treatment intervention cutoffs. Also, as was recently presented at the 9th European AIDS Conference in Warsaw,3 HDL cholesterol (HDL-C) levels go up as well with fos-APV, so that the HDL-C/LDL-C ratio remains fairly stable. This phenomenon, which is seen with nevirapine (NVP), is not commonly seen with other PIs.

As yet, though, we don't know whether this will translate into actual "cardioprotective" effects associated with higher HDL-C levels when they occur naturally, or whether this will offset any potential deleterious effects associated with increases in LDL-C levels. But if you have a patient with multiple risk factors for cardiovascular disease -- male, smoker, overweight, sedentary lifestyle, family history of cardiac disease in a first-order relative, etc. -- you'd want to look for agents that are least likely to disturb lipid levels. Atazanavir appears to fit that profile, and there's accumulating evidence that fos-APV looks pretty good in that regard as well.

Sterritt: Are there situations in which you presently prescribe a PI-based regimen, rather than an NNRTI-based one, as initial therapy? Will the advent of fos-APV, and for that matter ATV, affect your practices in this regard?

Nadler: Certainly. You can profile patients and I try very hard to tailor my selections for first-line therapy to the needs and circumstances of the individual patient. And the improved pill burden, flexibility, and convenience of the newer PIs make it easier to do so, as there are now fewer tradeoffs between the NNRTIs and the PIs.

Sterritt: Can you give us an example?

Nadler: The current treatment guidelines state that efavirenz (EFV) plus Combivir (zidovudine [ZDV]/lamivudine [3TC]) is an excellent and generally preferable first-line regimen; that recommendation is based on excellent long-term and comparative data, and that regimen has kind of become the benchmark. However, you need to take your Combivir with food (due to the ZDV component), whereas EFV is best taken on an empty stomach, at or shortly prior to bedtime. As we know, there are some patients who won't do as well with nighttime dosing, because they have a more disruptive evening schedule. For instance, a working mother with small children or a person with a history of sleep disturbance, especially if it's associated with underlying psychiatric disease; such a person may not tolerate the early central nervous system (CNS) symptoms associated with EFV. For such patients, a morning dosing routine may be much more practicable, and morning dosing of a once-a-day fos-APV- or ATV-based regimen may prove a superior option. Then you have to consider other variables: If the person is known to never eat breakfast in the morning, then ATV won't be the way to go, due to the food requirement.

Of course, when there are reasons not to use EFV, many would opt for NVP. But there are those who, in the case of, say, your typical 35-year-old ex-heroin user with hepatitis C coinfection, might shy away from using NVP because of its potential (albeit uncommon) hepatotoxic effects. Again, in this instance, the newer PIs, which are very well tolerated and permit once-daily dosing, represent attractive new options.

This is nothing new, and most clinicians are accustomed to prescribing LPV/r-based initial regimens for selected patients. The new PIs, though, appear to offer more in the way of convenience and tolerability and, in the case of ATV and possibly fos-APV as well, improved lipid profiles. In these ways, they compare more favorably to the NNRTIs, and for this reason will probably come to be used more frequently in first-line therapy.

Sterritt: Where and how do you see fos-APV fitting in for patients who have failed one or more PI-containing regimens?

Nadler: I think that with respect to using fos-APV as a second PI, we can look back to APV, and its "Achilles' heel," the 84 mutation, which is the least common of the four major protease-associated mutations (PRAMs): 33, 82, 84, and 90. So, unless there's really advanced PI failure, with accumulation of multiple PRAMs and secondary mutations (and you have to look out for the 46 and 54 series of mutations in this regard), I think it's likely that fos-APV will prove an equal -- and in many cases superior -- option to most other PIs, including ATV, for patients who have failed other PIs.

Sterritt: Is that true with respect to LPV/r as well?

Nadler: In the CONTEXT trial, RTV-boosted fos-APV was found to be equivalent to LPV/r by two of three measures of efficacy.4, 5 At 48 weeks, however, boosted fos-APV failed to demonstrate noninferiority to LPV/r by the measure designated by the protocol as the primary endpoint for efficacy.5 But it was only fractionally off in that regard and, again, boosted fos-APV did show equivalence to LPV/r by the two other measures. My opinion is that there really isn't any real difference between the two drugs in this setting, which isn't surprising, as the mutational patterns for the two agents overlap significantly.

Something that is important to note here is that in contradistinction to the major study of ATV/r in PI-experienced patients, the CONTEXT study included patients who had documented failure on one or more previous PIs, as well as documented PI resistance. The AI424-045 study, which compared boosted ATV with LPV/r in PI-experienced patients, did not require that subjects have documented drug resistance; many of the patients enrolled had only a single previous PI failure, and a number of those were due to intolerance.

Sterritt: So you feel that there are more robust data for fos-APV in advanced stages of therapy. Do you think fos-APV will prove a better option for patients with multiple PI failures?

Nadler: Perhaps, but here we're talking about patients with very narrow options. In my own practice, and especially with regard to new agents, I feel that this may be the time to order a high-quality resistance test, such as an actual phenotype, as opposed to a genotype-predicted phenotype, to help guide selection of agents that retain the greatest degree of activity against the patient's virus.

Sterritt: What about the use of fos-APV in salvage therapy?

Nadler: I think its use in true salvage therapy is pretty limited, because of the overlap with the PRAMs, which is true for all available PIs, and that includes ATV. I think for true salvage in the PI class we're still awaiting new agents. I think some patients will respond to tipranavir (TPV), and that if preliminary findings for TMC 114 hold true in larger trials, we may yet see useful agents for true salvage in this class of drug.

Selectively, however, and with the use of high-quality resistance testing, we may still be able to get some bang for our buck with currently available PIs, including fos-APV and also, possibly, ATV.

Editor's Note: Reprinted with permission from Medscape HIV/AIDS. This "Expert Interview" was first e-posted January 8, 2004.

References

  1. US Department of Health and Human Services and Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. November 10, 2003.

  2. Nadler JP, Rodriguez-French A, Millard J, et al. The NEAT study: GW433908 efficacy and safety in ART-naive subjects: Final 48 week analysis. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections. February 9-14, 2003. Boston, Massachusetts. Abstract 177.

  3. Horban A, Staszewski S, Walmsley S, Pierone G, Sexton A, Stark T. Favourable increases in high-density lipoprotein cholesterol (HDL-C) concentrations in chronic HIV-infected therapy naive subjects receiving 908/r QD in the SOLO Study. Program and abstracts of the 9th European AIDS Conference. October 25-29, 2003. Warsaw, Poland. Abstract F8/3.

  4. DeJesus E, LaMarca A, Sension M, et al. The Context Study: Efficacy and safety of GW433908/RTV in PI-experienced subjects with virologic failure (24 week results). Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections. February 9-14, 2003. Boston, Massachusetts. Abstract 178.

  5. Vertex Pharmaceuticals Incorporated. Vertex reports preliminary 48-week data from phase III study of 433908, an investigational HIV protease inhibitor [press release]. Cambridge, Massachusetts. July 24, 2003.


  
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This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.
 
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