December 17, 2001
This presentation was a description of a phase I/II study that detailed the clinical data on the virologic effects of T-1249, a fusion inhibitor, in the presence of drug resistant virus. Fusion inhibitors are a new class of HIV medication that inhibit the binding of HIV to a CD4 cell. In the presence of fusion inhibitors, HIV is not able to penetrate the cell membrane and therefore infect the cell.
The first drug in this class to be tested in HIV-infected people was T-20. This compound is in final phase III study. T-1249 is a close cousin of T-20 also in development. Both of these drugs bind to gp41 (a portion of the envelope, or outer coat of HIV), but in a slightly different location. These drugs must be given by subcutaneous injection. They are still evaluating the dose and dosing interval for administering T-1249. Since this compound acts upon an entirely different area of the virus compared to all the approved agents, it is important to understand if this drug has activity against patient HIV viral strains that are resistant to currently available agents.
The trial included 58 men and 5 women with a mean age of 42. Patients were heavily experienced in prior antiretroviral regimens. Inclusion into the study required a baseline viral load >5,000. In addition, subjects had to be off all HIV meds for a minimum of four weeks. Mean baseline viral load was 100,000 and the CD4 count was 121. There were six different dosing cohorts (6.25 µg to 50 µg), given either once or twice daily. T-1249 was given for 14 days as monotherapy.
The presentation involved a retrospective analysis of factors that influenced the virologic and immmunologic response to T-1249. The primary question the authors wanted to answer was whether background resistance to currently available HIV meds affected the viral load response. Eighty-five percent of the patients had resistance to at least one drug. Fifty-two percent were resistant to all three classes of drugs.
Using several statistical tests, including linear regression using univariate and multivariate analyses, the authors found that age, gender, race, baseline viral load or CD4 count, or the presence of one, two, or three class drug resistance, did not significantly affect the viral load response. The only variable significantly associated with a viral load response was the amount of T-1249 given. In other words, there was a strong dose effect. The higher the dose of T-1249 given, the greater the reduction in viral load. The analyses used are standard techniques to answer questions about what factors affect the response of a certain drug or combination of drugs. This is the first analysis of this type in this drug.
This central question is important because there are significant numbers of patients with multiple drug-resistant virus that have very few treatment options available. This is a new drug class with significant activity against HIV. However, it is important to understand whether this compound would work effectively against viruses that are resistant to currently available drugs. According to this retrospective analysis, the answer appears to be that it does.
It is still early in the development of T-1249. Although the results look quite promising, it will be quite some time before this drug is approved and widely available. T-20 demonstrates similarly favorable virologic results and will be available sooner. However, resistance to T-20 has been reported. Resistance develops by a different mechanism, but may be problematic in the future for this new class of compounds.
If these medications are approved, they will represent a new and potent class of medication that can be combined with currently available drugs. However, they will still need to be given by subcutaneous injection. This may limit the utility of this class of medications for some patients either because of preferences or logistical issues. However, many patients are already accustomed to the use of injectable medications such as interferon or insulin, and will view this class of compounds and approach as being acceptable.
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