Codevelopment of new antiretrovirals in very treatment-experienced HIV-infected individuals
Lancet. 2004 Sep 18;364(9439):1036-7.
A major clinical problem exists in the treatment of highly antiretroviral drug-experienced HIV-infected individuals with so-called salvage therapy. (1) This group represents an ever increasing proportion of our patients and encompasses those at greatest risk of clinical disease. The availability of new therapies within existing classes of antiretrovirals--eg, tipranavir (2)--and of novel classes--eg, enfurvitide, the first fusion inhibitor (3) --has greatly improved the options for these patients. However, the pathophysiology of HIV and the available clinical trial data (4) suggest the successful outcome of future combination therapy will be determined by the number of new drugs used as well as retained susceptibility to previous agents, including some for which resistance mutations might be archived.
Assessment of the use of more than one new drug simultaneously in the subsets of patients who are at greatest risk of clinical disease would, therefore, seem logical. For instance, within the TORO (T-20 vs Optimized Regimen Only) studies (3) there was a direct correlation between the success of virological suppression and immunological benefit with the number of active agents within the optimised background therapy used to support enfuvirtide. Unfortunately, to date, planned codevelopment of investigational agents has not occurred, and patients continue to be offered serial monotherapy along with potentially weakening regimens.
Scientific concerns exist, such as the potential for drug-drug interactions as well as the difficulties of assessing safety issues. But these issues could be addressed by rapid pharmacokinetic combination studies in HIV-uninfected individuals, and since the two, or more, assessed agents will probably eventually make it to market, it will be vital to have safety data at an early stage, so why not sooner rather than later? To that end, the potential scientific and clinical benefit of such codevelopment in patients resistant to multiple agents seems favourable.
One probable hurdle is the reticence of regulatory departments within pharmaceutical companies to compromise the clarity of the single agent development programme to licensing and a perceived fear that the US Food and Drug Administration (FDA) would consider this action inappropriate. However, as has been publicly stated, (5) few barriers exist to combining experimental agents in prelicensing studies of clinically stable patient populations who might potentially benefit from such an approach.
While there will remain surmountable issues, such as intellectual property rights, to be addressed when more than one company is involved, some potential combinations exist, such as TMC114 and TMC125, where both agents are owned by the same manufacturer.
We believe awareness of these issues needs to be increased, and now is the time for action. We urge the pharmaceutical industry to come together with the FDA, and the research and patient communities to address the potential these changes in HIV and other drug-development programmes could bring to both themselves and more importantly to those patients who desperately need more than one new agent.
*Mike Youle, Cal Cohen, Christine Katlama, Dan Kuritzkes, Sharon Walmsley
*Royal Free Centre for HIV Medicine, Royal Free Hospital, London NW3 2QG, UK (MY); Community Research initiative, Boston, MA, USA (CC); Hopital de la Pitie Salpetriere, Paris, France (CK); Brigham and Womens' Hospital, Harvard Medicacl School, Cambridge, MA, USA (DK); Toronto General Hospital, Toronto, Ontario, Canada (SW).
1 Deeks SG. Treatment of antiretroviral-drug-resistant HIV-1 infection. Lancet 2003; 362: 2002-11. [Text]
2 Yeni P. Tipranavir: a protease inhibitor from a new class with distinct antiviral activity. J Acquir Immune Defic Syndr 2003; 34 :(suppl 1) S91-94. [PubMed]
3 Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348: 2186-95. [PubMed]
4 Ciancio C, Trotta MP, Lorenzini P, et al. The effect of number of mutations and of drug-class sparing on virological response to salvage genotype-guided antiretroviral therapy. Antivir Ther 2003; 8: 611-16. [PubMed]
5 Cheng B.The challenges of clinical trial design in assessing the effects of anti-HIV therapy in heavily pre-treated patients: HIV forum for collaborative research report, 1999. http://www.hivforum.org/ publications/clinicaltrial_design.pdf (accessed July 12, 2004).