A Banner Year
BY Bob Adams
November 09 2007 1:00 AM ET
It was a bold statement: 2007 will be a turning point in the treatment of HIV nearly on a par with 1996, the year the first protease inhibitors were approved and the triple-drug-therapy era began, John Mellors, MD, vice chair of the 14th Conference on Retroviruses and Opportunistic Infections' scientific committee, proclaimed at the annual gathering in February.
Mellors's foresight is panning out, and he isn't alone in his optimism. More and more AIDS experts are saying that for patients with drug-resistant infections, the breakthroughs coming this year will be as momentous as the arrival of highly active antiretroviral therapy.
The excitement centers around three medications--two in entirely new classes. In early August, Selzentry (maraviroc) was the first entry inhibitor to be approved by the Food and Drug Administration; before the end of the year, integrase inhibitor Isentress (raltegravir) and second-generation nonnuke etravirine are expected to get the FDA's nod as well. (At press time, Isentress had received a thumbs-up from an FDA advisory panel and was expected to get FDA approval in October.)
Pfizer's Selzentry works by 'jamming' CCR5 surface receptors on T-cells that HIV latches onto. Fuzeon (T-20) was the first entry inhibitor to receive FDA approval, in 2003, but that medication inhibits a protein in the virus itself. Selzentry is the first entry inhibitor--actually, the only antiretroviral at all--that targets human cells instead of HIV.
Isentress, being developed by Merck, will be the first integrase inhibitor to reach the consumer market. It works by blocking HIV's integrase enzyme, which inserts viral genetic information into cellular DNA, a process that turns the cell into a virus-making factory.
Because maraviroc and raltegravir attack the virus in new ways, they're effective against HIV that has mutated defenses against existing medications. That's especially good news for patients in 'deep salvage' who've exhausted or nearly run out of treatment options among the available meds.
'Of course, no drug is perfect for everyone, but these two--and others to come in these new classes--could revitalize the treatment regimens of many people with multidrug-resistant HIV,' says Reilly O'Neal, editor of San Francisco AIDS Foundation's Bulletin of Experimental Treatments for AIDS.
Another experimental drug that shows significant activity against resistant virus is etravirine. There are three nonnukes already on the market, but etravirine has advantages over the existing medications--chiefly that it is better able to thwart HIV's attempts to develop resistance to it, says Brian Risley, lead treatment educator at AIDS Project Los Angeles.
'Etravirine also has a very favorable safety and tolerability profile,' he adds, 'one without the pattern of central nervous system side effects linked with Sustiva.'
And while maraviroc, raltegravir, and etravirine initially will be approved to treat only patients with drug-resistant infections, treatment experts expect all three drugs to eventually be endorsed for first-line therapy for treatment-naive HIVers.
'Right now we already have great options
for initial therapy,' says Joel Gallant, MD, associate director of Johns Hopkins AIDS Service in Baltimore. 'But some of these new drugs still have potential for earlier use if their safety holds up over time.'
While expectations for the new medications are running high, some AIDS service providers are taking the flood of good news with a hefty grain of salt.
'It's a double-edged sword for us,' says Kevin Burns, executive director of Philadelphia's Action AIDS, which provides case management and support services to about 3,500 clients a year. 'Yes, the new drugs are exciting. But not everyone is going to have access to them because of funding cuts for programs aimed at removing barriers to treatment. Essentially, if you're poor, it's already very hard to get access to regular care and the existing drugs, let alone these new medications.'
Another financial hurdle--at least for newly approved maraviroc--is that the drug can be prescribed only to HIVers whose viral infections target CCR5 T-cell receptors. Although most HIV patients have CCR5-specific virus, some carry virus that targets a different cellular portal called CXCR4 or have infections that use both receptors.
Before maraviroc can be prescribed, a special diagnostic test--called a tropism assay--must be given to patients to determine that they carry only CCR5-specific virus. Currently only one company, Monogram Biosciences, manufactures HIV tropism tests, and they're not cheap at about $800 each.
It's anyone's guess as to when Medicare, Medicaid, and AIDS Drug Assistance Programs--and even private insurance companies--will begin to pay for tropism tests, says Burns. Until then, maraviroc will remain out of reach for those who can't afford the test's hefty price tag.
Our Cup Runneth Over
Fortunately, there are more than 50 other HIV entry inhibitors in various stages of development, including drugs that jam both CCR5 and CXCR4 receptors, such as Anormed's experimental medication AMD3451, currently in preclinical tests. If eventually proved effective, it could be prescribed regardless of which cellular receptor HIV targets.
There also are other candidates in the new integrase inhibitor class that are in human clinical trials, including Gilead's GS-9137 and GlaxoSmithKline's GSK364735.
Panacos's maturation inhibitor Bevirimat (PA-457) is in human clinical trials as well. Medications in this new class interfere with the assembly of viral copies inside infected cells or prevent fully formed copies from exiting the cells. Bevirimat shuts down a key viral protein, leaving HIV copies structurally defective and incapable of infecting other cells.
'PA-457 is at least several years off, but it is at the forefront of the next level of treatment options,' says Rowena Johnston, Ph.D., vice president of research at the American Foundation for AIDS Research. 'It's also in an entirely new medication class, which is exciting simply because it gives you yet another option to treat patients who've developed drug resistance.'
New Strategies, Added Excitement
Even a pair of basic science advances announced in the past few months sparked excitement among treatment advocates. Researchers at the National Institutes of Health reported having completed a three-dimensional map of HIV and uncovering what they call a 'gap' in HIV's armor--a portion of the virus that is vulnerable to the human b12 antibody. Laboratory studies are already under way to craft vaccines or drugs that boost the body's antibody production.
And German scientists have reported identifying a naturally occurring molecule in human blood--virus inhibitory peptide--which prevents HIV from infecting cells. Even more significant was the discovery that genetically engineering key portions of the molecule greatly increases its anti-HIV effects.
'There's a lot of excitement out there,' Johnston says of the drug development pipeline. 'And even though there are already more than 20 antiretrovirals available, people sometimes lose sight of why we need more. The reason is that HIV can so rapidly develop resistance to the drugs we already have and we lose people who run out of options to treat their infection. So we're always in a race against time to find new and better ways to attack HIV. And right now 2007 looks like it's going to be a banner year in that effort.'