a new class of AIDS drugs

As HIV continues to develop resistance to the present antiretrovirals a new class of drugs offer hope for the treatment of AIDS.

Aug 1, 2001
John Borchardt(JKBdeinker@aol.com)

The war on HIV infection wages as fiercely as ever, but if research into a class of drugs known as a fusion inhibitors turns out to be as promising as results presented this month to an international AIDS conference in Buenos Aires suggest, clinicians may soon have a powerful new addition to their armamentarium.

The drugs are badly needed fro two main reasons; HIV has developed resistance to existing therapies (protease inhibitors and reverse transcription inhibitors) and, secondly, drug companies and regulators have halted a number of early stage clinical trials because of adverse effects.

Whilst the detail is complex, the principal underlying fusion inhibitors is straightforward: they inhibit the fusion of HIV with receptors on the surface of the immune system cells — CD4+, a subset of T-lymphocytes — that HIV interacts with prior to infecting the cells. This inhibition reduces viral replication, hence progression form HIV infection to AIDS.

Of the range of fusion inhibitors currently at different stages of development, the one at the most advanced stage of testing is designated T-20. The drug is already in phase III clinical trials, and delegates in Buenos Aires heard evidence that it and other fusion inhibitors are also good candidates for combination therapies, something that will make them even more versatile for clinicians combating the development of HIV infection.

T-20 is a 36 amino acid synthetic peptide that binds to a key region of the HIV surface protein gp41. T-20 blocks HIV viral fusion by interfering with the gp41 structural rearrangements required for HIV to fuse with and enter a host cell. The first clinical evidence that inhibition of membrane fusion was a viable strategy for developing novel drugs to treat HIV-1 infection was reported by Kilby et al. (Nature Med 1998, 4:1302-1307). They showed that T-20 alone was at least as effective as antiretroviral combination therapy — the most effective treatment currently available — in reducing HIV viral load during a 14-day administration period. The authors say, "This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present."

The Phase I/II trial recruited 17 volunteers with a CD4+ cell count greater than or equal to 100 cells per microliter (any fewer CD4+ cells means that the person is already critically ill from AIDS) and plasma HIV RNA levels greater than or equal to 10,000 copies per microliter (the risk of HIV infection progressing to AIDS increases for plasma counts from 10 000 to 100 000, above 100 000, the risk of AIDS is high). Tolerance of doses up to 100 mg was good, and by day 18, the patients receiving 100 mg had 95% fewer copies of HIV RNA in their blood than pre treatment.

These findings prompted further clinical development leading to the phase III clinical trials, which began in June 2000. These are multiple-phase trials and even though the Phase III trials started in 2000, enrolment of additional patients only closed on 28 June 2001. It is likely that the results will not be known for some time.

Whilst the manufacturers of T-20, Trimeris and Roche, were pushing ahead with its clinical development, they decided that the laboratory results with T-20 had been so promising that it was worth a systematic investigation to see whether other synthetic peptides could be developed as fusion inhibitors. They found two promising candidate molecules: a 39 amino acid peptide, designated T-1249 (phase I/II clinical trials are already underway for this compound), and a 36 amino acid peptide, designated T-649. Both bind to a different region of the gp 41 receptor, opening the possibility of combination therapy, something that will make it harder for HIV to evolve resistance to the new class of drugs.

So far pre clinical testing suggests that combination therapy with fusion inhibitors may indeed be possible. Cell culture studies show that T-1249 is active against HIV-1 isolates resistant to T-20 and is also effective in cases of resistance against other AIDS drugs, foe example zidovudine (a nucleoside reverse transcriptase inhibitor) and saquinavir (a protease inhibitor).

The situation with T-649 is also beginning to look promising. Cynthia Derdeyn and colleagues at the University of Alabama at Birmingham studied T-20 and T-649. Their laboratory findings suggest "combination peptide therapy in vivo may delay the emergence of inhibitor-resistant viruses by targeting distinct regions of gp41."

Other groups are developing alternative molecules that employ the fusion inhibition strategy. For example, Cecile Tremblay and colleagues from Massachusetts General Hospital is studying the in vitro interactions of SCH-C with commonly used HIV antiretrovirals such as zidovudine (ZDV) and lamivudine (3TC), as well as T-20 and another CCR5 inhibitor AOP-RANTES. SCH-C is a small molecule targeting the HIV-1 coreceptor, CCR5, which interferes with the binding of the virus to the coreceptor. They observed synergistic interactions between SCH-C and all the other drugs tested.

It is likely to be some time before authorities license the first fusion inhibitor. A Trimeris spokesperson refused to comment on when FDA approval might occur, as satisfactory results from the Phase III trials are needed first. Trimeris and its partner Roche have paid the US Federal Drug Administration to fast track (taking only six months) the application procedure, following submission of all the relevant data on the drug. It is hoped that these drugs may fulfil the need expressed by David Ho, director of the Aaron Diamond Center for AIDS Research in New York, and a leading early proponent of combination therapies, when he said in a press release from Trimeris, dated 28 January 2000, "Developing regimens… designed to attack the virus in new ways is one of the most pressing unmet medical needs in HIV therapeutics today."