A needle-free way of delivering T-20 (enfuvirtide, Fuzeon) is easier to use and reduces, but does not eliminate, injection site reactions, according to the results of a Vancouver-based study presented at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro on Wednesday. However, the Biojector 2000 system is currently only available to around 5% of T-20 users worldwide, although T-20 co-manufacturers, Roche and Trimeris, have now filed an application with the US Food and Drug Administration (FDA) to include information on use of the B2000 in Fuzeon labelling, which may lead to widespread availability within a year.
The B2000 injection system, manufactured by Bioject Medical Technologies Inc., is a needle-free carbon dioxide-powered injector that disperses liquid medication through the skin. The B2000 has been available since 1996 to deliver subcutaneous and intramuscular injections and has been used in vaccine delivery, chronic therapy and other settings, delivering millions of injections worldwide.
A pilot study, T20-405, presented as a poster at the HIV DART conference in Jamaica last December, suggested that the B2000 provides the following advantages over needle-base T-20 delivery.
- Improved dispersion, no rubbing needed.
- Consistent technique, injection at same depth each time.
- Greater flexibility of injection site (one-handed delivery).
- Attractive to patients with phobia to needles, and recovering IDUs.
- Decreased biohazard and reduced biohazard elimination costs.
The T20-405 study, whose aim was to determine the relative bioavailability of T-20 after a single dose using the B2000 and a needle-based delivery system, found that drug levels were equivalent between needle and syringe and the majority of the 25 participants (75%) had a positive overall impression of the B2000. Compared with the needle-based system, 58% found the experience of using the B2000 favourable, and 38% were neutral.
Comparing injection site reactions
In Rio, Dr Marianne Harris reported more data from a median of 12 weeks', and a maximum of 24 weeks' real-life experience of B2000 use. In particular, she and her colleagues at the BC Centre for Excellence in Vancouver, Canada, were interested in injection site reactions (ISRs), which are the most common adverse events associated with T-20 use. According to product labelling, ISRs occurred in 98% of patients studied, and 4% discontinued T-20 due to ISRs. Signs/symptoms may include pain and discomfort, hardened skin, redness, bumps, itching and swelling. Eleven percent of patients had local reactions that required use of painkillers or limited usual activities. Cysts or nodules can also form at the injection site, and more rarely, several individuals have developed abscesses at the injection site.
The study, which enrolled 32 individuals between November 2004 and January 2005, and provides follow-up data to June 2005, also measured T-20 plasma levels, and assessed ease of administration. Twenty-seven treatment-experienced HIV-positive adults already receiving needle-based T-20 treatment, and five individuals new to T-20, were offered to switch to the B2000 after appropriate training. Study participants were assessed twice before the switch, weekly for four weeks, then every four weeks while using the B2000.
Plasma was collected pre-dose and one hour post-dose for T-20 levels. In agreement with the T20-405 study results, T-20 plasma levels did not differ between the needle and B2000, either at the pre-dose trough (median 1.635 versus 2.075 ug/mL, respectively: p= 0.4) or the one hour post-dose (median 2.275 versus 3.69 ug/mL, respectively: p=0.3). In addition, plasma viral loads either remained below 50 copies/mL or, if detectable, decreased after the switch to the B2000.
ISRs were graded from 0-31 for signs and symptoms (swelling, hardened skin, itching, nodules/cysts, and bruising), duration of individual nodules, and number of nodules. Patients rated ease of use from 0=easy to 3=difficult. Dr Harris reported that median ISR scores decreased from 11 (range 5-17) with the needle to 5 (range 0-11) after a median of 12 weeks using the B2000 (p
However, ISRs still occurred, and of the 32 individuals who started on B2000, only 20 (63%) are still using it, three of them alternating with needle-based delivery. Another individual returned to needle-based delivery of T-20.
Dr Harris reported that there were four cases of nerve bundle pain in three participants. This manifested itself in unusual ways: for example an injection in the buttocks area led to pain down one leg, and numbness that lasted for several weeks. She suggested that all the patients experiencing nerve bundle pain were "thin", and that this type of ISR was more likely to occur when the B2000 was used near joints.
Nevertheless, Dr Harris concluded that T-20 can safely be administered using the B2000 needle-free injection system, "with good patient acceptability and improvement in ISRs. It was at least as easy or easier than needle-based delivery," she said, "and our nurses also found it much easier to teach." In addition, T-20 plasma levels did not differ between the needle and B-2000.
Availability of the B2000
Next month, Roche and Trimeris will begin enrolment of the Fuzeon WAND (Fuzeon With A Needle-free Device) study, which will also assess patient acceptance and experience in administration of T-20 via the B2000 needle-free device compared to standard needle and syringe administration. The study will enroll 40 patients, in a month-long, crossover design evaluation, and similar to the Vancouver study, endpoints will include tolerability, injection site reactions and pharmacokinetics.
Roche and Trimeris also announced earlier this month that the FDA has accepted the filing of their supplemental new drug application to consider inclusion of information about the B2000 in T-20 labelling, based on data from the T20-405 study. It is anticipated that the FDA will provide feedback and a decision later this year
European treatment advocates, who have putting pressure on Roche for European access, have been told that the system will only become available outside of the US - where half of all T-20 users are - after the FDA has approved the B2000. The company that makes the B2000 stopped production several years ago, but Roche hopes to work with B2000 manufacturers to evaluate options to help facilitate access to the device in the US and Europe, once they have FDA approval.
Harris M et al. Enfuvirtide (T20) plasma levels and injection site reactions (ISRs) using a novel needle-free gas-powered injection system (Biojector) for subcutaneous administration of T20 in treatment-experienced HIV+ patients.Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WeFo0205, 2005.
Miralles D et al. Administration of Enfuvirtide with Biojector 2000 demonstrates bioequivalence to standard needle administration. HIV Dart, Jamaica, Poster 57, 2004.