The Buzz: The Importance of Sequencing in Treatment Options
Physicians should constantly consider the sequence for which they use antiviral drugs in their patients (sequencing therapies). HIV positive individuals are living longer with the help of effective treatment, but an increasing number of patients are developing resistance to their regimen. If a patient develops resistance to his or her regimen, the next regimen, one that is not cross resistant and allows for further options, should be well thought out. Thus, the raison d'être for properly sequencing HIV drug treatment allows for the maximum number of options and alternatives to be available for the long term. With the probability of keeping patients on treatment for 20 or more years, antiretroviral drugs must be properly sequenced.
Physicians may need to change a patient's therapy perhaps as early as 18 months into treatment. While newer drugs become available, sequencing should encompass the specific resistance characteristics of all antiviral agents. For example, patients who have had long experience to the nucleoside class (nukes, or NRTI) and whose virus in resistant to, for example, 3TC may have resistance to other nukes, such as abacavir or Ziagen. Those with high resistance to this class of drug may alternatively be very susceptible to the non-nuke class (NNRTI) or have increased susceptibility to tenofovir (an experimental drug). However, individuals developing resistance to their new NNRTI will likely have cross-resistance to other NNRTIs. Likewise, various protease inhibitors bear cross resistance within their family of drugs. However, using them in a particular order may allow for further use in salvage regimens and in various dual protease inhibitor regimens (two protease inhibitors in the same drug regimen).
For these reasons, changing therapy should be well thought out, not done haphazardly. For highly experienced patients newer drugs should be reserved whenever possible. A basis for changing to another regimen includes treatment failure, but toxicities or intolerance to the current antiviral regimen are also grounds for switching an existing regimen. Pharmaceutical companies are attempting to develop newer drugs, acutely aware of the urgency and marketability of drugs effective against resistant virus. A new protease inhibitor recently approved, Kaletra, is being used in salvage regimens. Three other agents from differing drug classes are in development and key in on resistant virus; they include tenofovir DF, T-20 and DPC-083. These significantly improve our options for patients who need alternatives.
Kaletra (lopinavir/ritonavir or ABT-378/ritonavir) has only been available and on the market for a relatively short period of time. It has been studied in naïve and protease-experienced patients in combination with non-nucleosides. The data holds up regarding the advantages of using this protease inhibitor in certain situations. Being new, Kaletra has not been studied as extensively as other drugs, and regarding sequencing protease inhibitors, it is not quite clear as to where Kaletra should fit in with the overall treatment scheme of individual patients. Questions regarding its appropriate use as first line treatment, and the proper sequencing of this drug because of cross-resistance to other protease inhibitors have been raised. However, it is well tolerated and has become a useful addition to the antiviral armamentarium. Like most new drugs coming to market, the reported studies were designed to get the drug FDA approved. Later studies and further clinical experience will add to our understanding.
Abbott Labs has promoted Kaletra and a post-marketing switch protocol (FDA approved) called PLATO. A switch study generally denotes discontinuing an existing drug therapy and changing to the promoted product. This particular study involves switching patients who are intolerant to other therapies to Kaletra. During the study, Abbott provides Kaletra free-of-charge to the patient, afterwards it becomes the patient's responsibility to pay for the drug.
While observed for a period of only eight weeks, patients are evaluated for quality-of-life changes. While touted as a "quality-of-life" study, PLATO disregards side effects impacting this very issue, such as lipodystrophy and metabolic complications. While lipodystrophy changes usually arise later, when they do occur, they can have huge quality-of-life consequences. Studies of Kaletra have shown that the drug is associated with hyperlipidemia (increased cholesterol and triglycerides) which are often associated with lipodystrophy. Other symptoms can appear later than eight-weeks of treatment which may affect quality-of-life. But Abbott's Medical Director of Global Antiviral Marketing Product Development denies that the study was done as a marketing vehicle, simply to get people on their drug, claiming there are "probably cheaper ways to market drugs, such as starter packs and coupons." However, it is widely known that starter samples and coupons are rarely used for HIV prescriptions of antiviral drug therapy. Many physicians and treatment advocates believe the scientific value of studies are improved by designing conventional longer-term projects that seriously delve into the important issues of quality of life and metabolic complications.
Tenofovir DF (developed by Gilead Sciences) is part of a new class of drugs called nucleotide reverse transcriptase inhibitors. Its active metabolite (duration of drug lasting in the blood stream) has a half life between 10-30 hours and the intracellular half life is equal to or greater than 30 hours, therefore it can be given at convenient once daily dosing. In vitro (test tube) toxicity studies show tenofovir having little effects on the mitochondrial enzymes and not limiting the mitochondrial DNA, predictors of mitochondrial toxicity. Most current schools of thought believe that it is this toxicity to mitochondria that causes lipodystrophy complications in HIV disease.
Also, tenofovir has activity against HIV with various Retrovir (AZT), Videx (ddI), and Hivid (ddC)-associated mutations and shows increased activity against HIV with Epivir (3TC) resistance. Indeed, an earlier study (study 902) demonstrated antiviral effect of this agent; 94% of the study patients had NTRI resistance mutations prior to study. The most recently reported study (study 907) enrolled more than 550 treatment-experienced patients. There was significant viral load reduction observed in this group, who had tenofovir added to their existing drug regimen and 45% achieved viral loads below 400 copies. Thus, once available, tenofovir appears to be an attractive choice for use in antiviral regimens.
Tenofovir is currently available on a compassionate program to patients with CD4 T-cells below 100 count who are failing their regimens (two protease inhibitors or one protease inhibitor and a non-nuke) and for patients with recent (within 90 days) opportunistic complications, the CD4 cells can extend to 200 count for eligibility. Gilead Sciences is on track for submission of its New Drug Application to the FDA by mid-year.
A second-generation non-nuke, DPC-083, developed by DuPont Pharmaceuticals, is continuing in clinical trials. Phase II studies are being conducted in Europe and at only five sites around the US, one being here at NorthStar Medical Center in Chicago. This particular protocol is studying individuals who are failing their first regimen containing a non-nucleoside and is still open for enrollment. As a non-nucleoside, DPC-083 has similar potency to Sustiva (efavirenz) against wild type virus, however it has other significant advantages: the drug is effective for virus that is potentially resistant to Sustiva or Viramune (nevirapine), including against the infamous K103 mutant, and is two to eleven times more potent than Sustiva against other potential resistant virus. It has a long half-life, and is administered once daily. Thus far the drug has been found to be well tolerated and side effects have been found to be of minor severity and of short duration.
DuPont Pharmaceuticals is currently up for sale. We hope that a pharmaceutical company experienced in HIV drug development acquires DuPont and will show the same commitment and ability to develop further antiviral options, and continues to support the HIV community.
T-20 is another novel agent in a new drug class called fusion inhibitors. T-20 blocks the ability of HIV to combine or fuse with the CD4 receptor (T-cell). Preliminary studies have shown that T-20 is effective in patients with resistance to other antiviral agents. Cross-resistance is unlikely due to the unique mechanism of action. Because the chemical structure of this agent is a chain of amino acids, it is easily broken down by stomach acids. Thus the drug needs to be administered by subcutaneous injection. The drug, developed by the small biotech company Trimeris, sold marketing rights to Roche. This larger pharmaceutical company will definitely aid in its faster development and production. T-20 will also become available on a limited compassionate track program (see News Briefs).
New antiviral agents are being developed with resistance in mind. With more drugs becoming available and as we expect to see our patients living to old age, effective drug sequencing becomes even more crucial and we'll need to conserve as many options for treatment as wholly possible.
Daniel S. Berger, MD is Medical Director for NorthStar Medical Center; Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDS infosource (www.aidsinfosource.com). He also serves as medical consultant for Positively Aware.