Expert Opinion From Barcelona
Dr. Julio Montaner of the B.C. Center for Excellence in HIV/AIDS at St. Paul's Hospital in Vancouver, gave a talk on "new challenges and perspectives" regarding treatment of people with HIV who've already been on therapy. He focused on three topics: treatment failure, therapeutic drug monitoring and inhibitory quotient (IQ), and new drugs on the horizon.
He said his clinic does not favor the idea of keeping people on partially suppressive regimens, where the viral load is at detectable levels. Some researchers have found that such therapy still provides health benefits to people with HIV. Rather, Montaner prefers to switch people to a new regimen to aim for undetectable viral load. He said people can always go back on their old therapy if the new one doesn't work out. One problem of staying on a partially suppressive regimen is that the drug resistance that builds up may cut off access to new drugs down the road.
However, in one analysis conducted by his clinic, even the experienced people on a partially suppressive regimen had survival similar to those people new to therapy (called treatment "naïve"). Naïve people generally respond better to therapy (e.g., they may achieve undetectable viral load).
Montaner said his clinic is building on the good response people are having with Kaletra. The drug does well for people with single or multiple protease inhibitor (PI) failure. The problem, he said, is complex interactions with other medications. Nevertheless, some research shows benefits with Kaletra despite its negative pharmacokinetic profile. He's waiting for more data.
In dual protease inhibitor combinations, when combined with a mini-dose of Norvir (100 or 200 mg), he said that with Agenerase, pharmacokinetic problems may not prevent a beneficial response. However, with Crixivan, look for renal (kidney) toxicity.
The movement towards therapeutic drug monitoring (TDM) and inhibitory quotient (IQ) tries to measure an individual's blood level of drug. This adds to the understanding of a person's response to therapy. It goes above and beyond the question of drug resistance, for example. "We no longer see resistance as a black-and-white issue," Montaner said.
On the Viread/Videx interaction, Montaner said the increased blood level of Videx was greater than had been thought. Higher blood levels may increase the risk of side effects, including serious ones. He says prescribers should reduce the level of Videx EC from 400 mg a day to 250 when taken with Viread and food. That's the preference of his clinic, although he said clinical trials are needed. "But, until we have clinical trials," he said, "this is what we're doing. We have to go forward."
T-20, an experimental drug taken as a twice-a-day injection, shows significant viral load drops in experienced patients after 24 weeks of adding it to stable HIV therapy. [However, T-20 has been showing this power for years. Other doctors at the conference said the question is durability.]
Preliminary results with tipranavir, an experimental once-daily protease inhibitor, show a very favorable drug resistance profile in multiple PI failures, Montaner said. He said tipranavir looks like a good secondary (second regimen) PI to use.
Overall, Montaner said doctors should think carefully about starting their patients on HIV therapy, should identify and correct reasons for treatment failure quickly and should switch failing regimens early. Adding an active new drug -- one the patient is not resistant to -- is not a clear measure for success as once hoped. Instead, the patient's entire HIV drug background is important, as is their clinical history (diseases) and resistance profile.
That was the title of a talk by Dr. John Mellors, of the University of Pittsburgh. Resistance is the ability of HIV to mutate (change) in order to successfully fight drugs. Some of Dr. Mellors's remarks follow here.
"No antiviral is resistance proof, and it's very unlikely that one will be found. Incomplete suppression [a viral load that's still detectable] leads to resistance and resistance is common in the United States.
"Resistance limits treatment options and may lead to disease and death. Suppressing viral load to less than 50 copies can prevent resistance. Extensive evidence shows that resistance testing improves suppression when changing therapy.
"Resistance is not inevitable. Be careful when selecting drugs and follow suppression carefully. In patients who have never been on therapy, single and double mutations [changes in the virus that help it beat the meds] are likely to pre-exist. A 10-fold reduced susceptibility to therapy has been seen in acute [new] infection [because of infection with resistant virus]. Also, time to first treatment failure [usually defined as detectable viral load] is shortened in those with resistance.
"Incomplete suppression occurs because of limited drug potency or PK [pharmacokinetics, how a drug interacts with other substances], incomplete adherence -- which most likely occurs because of intolerance (side effects) -- or prior drug resistance. Even modest evolution [low but detectable viral load] evolves into resistance.
"In a HCSUS study (HIV Cost and Services Utilization Study), 63% of people after their first two years of HAART (highly active antiretroviral therapy) had greater than 500 copies viral load. Risk factors for resistance included having advanced AIDS or inexperienced doctors, and low CD4 count when starting treatment. Greater access to treatment was the greatest risk for resistance. [HIV mutates most when antivirals are thrown at it.]
"Treatment failure that occurs within weeks or months limits future options. Progression should be anticipated if there is persistent viremia [detectable viral load]! Avoid blind switches. Test for resistance in people with more than 1,000 copies viral load. [You cannot run a resistance test with less than 1,000 copies.] Avoid impotent regimens or those that have a high pill burden and frequent dosing."
Dr. Robert Gallo, one of the first people to isolate HIV, talked about the search for a vaccine. Finding the body's reservoirs of HIV (its hiding spots) identify targets that are important to vaccine development, he said.
"Targeting extracellular [outside of the cell] factors which promote HIV replication or a diminished immune response is crucial," Gallo said. He said dysregulative cytokines, a type of protein in the body, are an example of this. "We have to identify and find mechanisms of action for each HIV suppressive factor and exploit this information," he said. In poor countries, a TAT vaccine such as the one his lab is looking at would be welcome because it can be taken as a shot two or three times a year.
Gallo criticized the idea that ethics demands triple therapy for the Third World. Instead, he believes that something is better than nothing. Therapeutic vaccines can help control disease progression in people living with HIV.
He said that when looking at reports on vaccines, look for the words "neutralizing antibodies," not just "antibodies." Antibodies are one of the targets of vaccines. [They help fight HIV and other invaders in the human body.]
Gallo said the discovery of the CCR5 co-receptor in 1995 was an important finding. CCR5 helps HIV enter the body. People without this gene, or with a defective one, have higher immunity to HIV infection. They also have higher resistance to disease if they do get infected. "Targeting CCR5 is major today. CCR5 is dispensible, so it's an important target [for vaccines and medications]. People can be born without it and do fine." In other words, toxicity to the targeted CCR5 co-receptor is less of a concern.
Discovery of the gp120 receptor for HIV, which allows the virus to target the CD4 T-cells, was another important discovery. All together, there's a "triple complex" of membrane fusion (entering the cell), virus-cell infection or cell-cell infection.
Another target is gp140, and peptides that can block this HIV co-receptor have been discovered. Overall, Gallo said a vaccine is critical, especially to counter the toxicity of current therapies and overcome the problems of drug resistance. (See "An AIDS Vaccine" in this issue.)
That was the title of a talk by Dr. Michael S. Saag of the University of Alabama at Birmingham. Saag talked about when to start HIV therapy, what to start with, when and how to change therapy, Strategic Treatment Interruptions (STIs) and the benefits of therapy.
Appropriately enough, the Journal of the American Medical Association (JAMA) had that day published the new HIV treatment guidelines of the International AIDS Society-USA (IAS-USA), of which Saag was an author. [See "New Treatment Guidelines" in this issue.] Saag called CD4 cells "a moving target."
The latently infected CD4+ lymphocytes -- those that are not yet activated -- lay around until one day they are activated, and then they too infect cells. It is these cells, which do not die off in two days as previously thought, but instead take six months to decay, that create the 60-plus years of treatment estimated for HIV eradication.
In Saag's clinic, half of the patients looked at in one report did not stay on their first therapy for more than two years. For people with greater T-cell counts, toxicity was the biggest issue. For those with less T-cells, viral load rebound (increases) was the primary problem.
When and how to change, he said, depends on the definition of treatment failure. Generally, viral load rebound to detectable levels within 16 to 24 weeks of treatment is considered failure. Something should be done quickly to prevent the development of drug resistance. However, in subsequent regimens, the prevention of T-cell decline is more important than the concern for drug resistance. Nevertheless, he said, the definition of treatment failure needs to be individualized, as stated in the IAS-USA guidelines.
With STIs, research has shown a conversion to wildtype virus -- which is good, but there's also concern about a steep drop in CD4 cell count. The guidelines say more data is needed. Study 506 designed to look at STIs is "now up and running."
As for benefits, Saag said the question is, How have benefits been derived? In New York City, there was a more rapid progression to death between 1990 and 1995 than there was in the HAART era post-1995. Moreover, New Yorkers were able to survive five years after PCP (pneumocystis carinii pneumonia, formerly the biggest killer of people with AIDS, and a quick killer at that).
A cost-benefit analysis from Saag's clinic showed an average cost of $18,000 a year to treat a patient with HIV. However, the figure was $34,000 for people with advanced disease, and $14,000 for the people with more than 350 T-cells. "There's a direct cost benefit to keeping people healthy," he said.
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