Treatment Issues: Newsletter of Experimental AIDS Therapies - Volume 17, Number 3, March 2003

T-20 is the first drug of a new class of HIV inhibitors that perform entry inhibition. More specifically, T-20 is one of a subset of entry blockers called fusion inhibitors. It acts by preventing the envelope of HIV from fusing to its target's cellular membrane. For treatment-experienced individuals with multiple-drug resistant virus, adding a drug from a new inhibitor class in combination with drugs from previously used classes is thought to be the most effective strategy for achieving durable viral suppression. As with all other HIV therapies, T-20 must be used in a combination, preferably with other new agents, in order to have the biggest punch.

Overview of Issues

Although therapeutically promising, unfortunately T-20 is not an easy drug to use and may be difficult for some to access. Drawbacks include:

Twice daily injection: Because it is a complex protein peptide, T-20 has to be administered by subcutaneous (subQ) injection twice daily, a substantial issue for most people. Adherence to life-long oral HIV therapies is already inherently difficult and we expect the technical demands of self-administering twice-daily injections to be even more so. We find the Roche/Trimeris video of people effortlessly incorporating T-20 into their daily lives misleading. A specific educational program is needed to deal with the complexity of drug reconstitution and self-injection. Patient experience may be very helpful in elucidating some basic dos and don'ts. Fuzeon also elicits concern from many former injection drug users in recovery that the use of needles may act as a potential trigger for relapse.

Reconstitution: The need to reconstitute T-20 is a significant drawback to ease of use. After mixing sterile water with the drug powder, T-20 can take up 30 minutes or longer to dissolve completely. It is unclear whether total reconstitution is necessary for maximum efficacy. Often drug powder is drawn up into the syringe before the drug has completely dissolved. Does injection of unreconstituted substance contribute to PISRs?

Problematic Injection Site Reactions (PISRs): The Achilles heal of T-20 may be the injection site reactions. T-20 injections cause a local, painful skin reaction, somewhat like a wasp sting, and have happened to almost all (98%) people studied thus far. Fifty percent of the reactions are reported as mild, while the other 50 percent range between moderate and severe. Redness at the site of injection (of more than 4") and pain have been reported in 80 percent of people and hardness around the injection site (2" or more) in 85 percent of people. Twenty percent of the PISR nodules do not go away even after 7 days. For some, there seems to be no improvement over time.

Supply: Producing enough T-20 for all the research, the expanded access program and expected market demand has been a major stumbling block in the development of this drug. Because of the production difficulties, and the fact that a drug of this complexity has never been produced before, there is no promise that enough drug can be produced in a timely manner to reliably supply all who need it.

Price: A price of over $21,000 has been announced for the European market. Is this the drug that will break payers' backs? Will providers be unable to justify or afford the high cost and refuse to add T-20 to their formularies, despite patient need?

The Community Demands:

Commit to informed access
An aggressive commitment to patient and provider education will be needed as the number of people using T-20 swells from 2,000 to perhaps 15,000 by year's end. So far, the sponsor has not been ready, willing, or able to do this. Education, for both the user and provider, must be the top priority on the Roche/Trimeris agenda and the educational programs must be scaled up and made accessible to all providers, including those who primarily serve Medicaid beneficiaries.

Minimize barriers to adherence
Toxicity management issues need to be better studied. Health care providers and patients need to understand the time commitment required to use T-20 correctly and to obtain the best advantage from its use. Treatment fatigue is common even with oral HIV treatments. Simply skipping one dose per month may be risky with this drug's resistance profile. Adherence issues and PISRs must be dealt with aggressively by finding ways to make administering T-20 more user-friendly and through additional programs to counsel people on the best and safest methods of injection. The sponsor should create a patient/provider advisory board to work on these issues. It is important that T-20 not join a person's list of quickly "used up" therapies.

Get to the bottom of PISRs
In an analysis of the pathology of (P)ISRs presented at the 10th Annual Retrovirus Conference, one patient (out of seven studied) who did not experience (P)ISRs "had insulin-dependent diabetes and had self-injected insulin for many years using optimum injection techniques." Are PISRs nothing more than bad injections? If so, the sponsors' education plan has not worked. Some experienced insulin injectors have suggested warming the syringe before injection. If PISRs are caused by something else (allergy, etc.), then that needs to be clarified. Does the incomplete dissolution of T-20 have anything to do with the PISRs? Is there a point when, although not completely dissolved, the drug is safe and efficacious to use?

Many users of T-20 are frustrated with the lack of importance given to this issue by the sponsor. Because both the cause and the resolution of the injection site reactions may be a key to success with this drug, Roche/Trimeris needs to learn more about why PISRs occur and they must look into other delivery mechanisms for the compound.

Continue dosing research
Questions have been raised concerning the potency of the control regimen and the small sample size used in the Phase II dose-finding study T20-206. Trimeris never ascertained the maximum tolerated dose for T-20 and based its dosing decision solely on the tolerability of the number of injections. Roche/Trimeris should continue to look for the maximum tolerated dose, which will mean more investigation into delivery systems.

Help identify optimal background regimens
In multi-drug experienced people, therapy optimization should be ascertained via genotyping and phenotyping. The recent news that only 25 percent of practicing clinicians know how to use the results of these resistance tests is very disconcerting. Providers who offer T-20 must know they need to have a good understanding of resistance test results in order to optimize the background therapy and maximize response.

Availability for those who need it most
With only a 16 percent success rate for keeping viral load below 50 copies at 24 weeks in heavily pre-treated trial participants, and with drug supply expected to be limited, T-20 may need to be rationed to those most in need — people without other treatment options. Use in other populations has not yet been studied, and the risk-benefit ratio in a treatment-naive population has not been determined. Finally, it should be noted that there are no study results demonstrating the impact of T-20 on the clinical progression of HIV disease.

Assure equitable access
Roche/Trimeris must assure that scaled-up production will be able to meet demand with no further supply issues. Roche/Trimeris must ensure that there is an adequate supply of the drug for continued clinical trials, expanded access, and for sale throughout the world. Roche should move to register the drug and assure access in all countries that have participated in clinical trials for T-20. Sufficient drug to conduct Phase IV studies of treatment options and side effects should be assured.

Roche/Trimeris needs to come to reasonable terms over its price with all payers, whether they be insurance companies, Medicaid or ADAPs. Details of the sponsor's "Patient Assistance Plan" (PAP) need to be defined (Roche has verbally promised one-third of drug to those most medically needy). The entry criteria for the PAP may well be determined by those who are unable to enter state ADAP plans. Administration of PAP eligibility should be coordinated with the ADAPs.

Tell the truth
The FDA needs to take its role as monitor of pharmaceutical advertising very seriously and remember that the wording on the label and in advertising for this drug should not be ambiguous or misleading regarding target populations. The FDA should insist that those people most likely to benefit from T-20 have first access.

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