American Foundation for AIDS Research, July 2001
Jeff Getty

Clinical experience, the art of treating AIDS

Clinical experience, the art of treating AIDS learned through years of trial and error, along with recent research findings about unfit virus, have converged to create today’s model for treating patients with moderate to high levels of multidrug-resistant HIV. Unless HIV patients insist otherwise or the side effects are overwhelming, they are likely to remain on antiviral therapies – even when the drugs have failed to keep viral levels low. Though no new government guidelines have been issued regarding this patient population, doctors now tend to keep patients on anti-HIV drugs even after apparent treatment failure. Their hope is that multidrug-resistant HIV will be less "fit” – i.e., reproduce less efficiently and abundantly. Less fit HIV might be less virulent than the natural nonresistant wild-type HIV, which would reemerge should a patient stop treatment.

In the past two years, treatment interruption strategies became popular. In these, patients go on and off drugs to allow drug toxicities to clear up and, possibly, create a new, more rigorous immune response through controlled transient exposure to HIV. But individual results plus the data from two small studies at the University of California San Francisco (UCSF) are now discouraging treatment cessation in favor of continuous drug therapy. One study followed 23 HIV patients. Of 16 initial patients studied, 11 chose to stop taking antiretrovirals and five continued on with therapy. Seven additional patients who stopped medication were studied at the same time. All patients had multidrug- and protease-resistant HIV. They also had substantial HIV viral loads and measurable CD4 counts.

The researchers, led by UCSF’s Steven Deeks, compared nontreated to treated groups after 12 weeks and found remarkable differences. Patients who had chosen to stop therapy had large increases in viral load and significant decreases in CD4 count (mean declines of over 80 cells/mm³). Patients who remained on therapy showed little change in either viral load or CD4 count. "In terms of T-cells [CD4 count], the differences were dramatic." said Deeks. "One of the treating patients developed lymphoma while three of the non-treating patients had significant adverse clinical events. [But] we were unable to demonstrate clinical significance in such a small group of patients."

A second study recently published by a related group of investigators indicated that protease inhibitor-resistant HIV was deemed less destructive to the thymus, the organ that produces new CD4 cells. In this study, the lead scientist, Cheryl Stoddart, and her research team inoculated drug-susceptible, wild-type and drug-resistant HIV into human thymus, which was then implanted into mice. Weeks later, the drug susceptible virus grew substantially and began depleting the human thymus cells. Drug-resistant HIV, on the other hand, barely replicated and did not tamper with the thymus cells. "The difference in the way the thymus grew could not be more extreme," Stoddart said.

In another experiment, researchers added virus directly to human thymus cell cultures. Viral replication was measured and results indicated that, whereas many cells were infected by the drug-susceptible HIV, far fewer were infected by the drug-resistant strains. In actual virus isolates taken from patients, 12 times fewer thymus cells became infected with drug-resistant HIV than with wild type.

Finally, researchers scanned 14 persons with HIV to see how their thymuses were holding up. Many patients with protease-resistant virus had more abundant thymus than would have been expected in people their age. But the researchers did not find that patients with drug- resistant virus were guaranteed a functional thymus.

UCSF immunologist Michael McCune, co-author of the second paper, stated, "The studies that we have done with variant molecular clones (that are either wild type or have resistance to protease inhibitors) indicate that very small differences in the HIV genome can have significant impact on the ability of the virus to replicate in and to destroy the thymus. The UCSF observations suggest that HIV might normally interact with a thymus cell-specific protein as part of its life cycle. If so, a greater understanding of such an interaction might teach us more about how the virus causes disease; reciprocally, the interaction might itself constitute a target for drug action."

But what combinations of drug resistance mutations lead to the least virulent HIV infection? McCune said, "We do not know which ‘unfit’ virus is the best to have around (or, put another way, which combination of drugs is best to have on board). We only know that the phenomenon of impaired replication in the thymus can be associated with resistance to protease inhibitors. We do know that ‘structured treatment interruption’ carries risks: thus, cessation of therapy in patients with protease-resistant virus was found to be associated with the outgrowth of wild-type virus, higher viral loads, and plummeting CD4 T cell counts.”

Community Doctors Opt for Continuous Therapy

All this is not news to prominent San Francisco HIV specialists like Drs. Mary Romayne, Bill Owen and Virginia Cafaro. They have long suspected that maintaining resistant virus was better than having patients go off drugs altogether. "I urge my patients to stay on maximal therapy even in the presence of high viral loads. I am delighted to see Dr. McCune now showing proof of what those of us in the trenches have been sure of,” said Romayne.

Cafaro said, "Yes, I keep them on ART [antiretroviral therapy], if they don’t seem to be getting toxic – e.g., their [liver function tests] are okay, they can maintain their weight and energy, etc. I think that there is benefit to being on the drugs even if the numbers don’t reflect it, and this is something we were seeing pre-protease. Some patients may opt for time off in hopes of getting some killing power when they resume drugs. I’m not sure how effective that is overall, but I do think it can decrease toxicity.”

Bill Owen concurred and also mentioned that toxicities played a major role. He said, "I am encouraging my treatment-experienced patients to remain on some combination of previously well tolerated recycled drugs. Unfortunately, I have a few patients who are so intolerant of most antiretroviral agents that I have had to recommend treatment interruption.”

Jeff Gustavson, an HIV patient and treatment activist, thinks that the community is getting a mixed message about stopping or staying on drugs. "On the one hand, studies have shown that drug-resistant virus may not be as pathogenic as wild strain. On the other hand if the goal is still to reach undetectable virus levels, then the treatment interruption approach may still make sense,” he said. Gustavson was in the first UCSF study mentioned above, and he experienced virologic and CD4-count improvement following a second treatment interruption. He still holds out hope that pulsing therapies may turn out to be a viable treatment option. As for unfit virus he said, "It might be true, but staying on your medicine means possible troubles with accumulating toxicities.”

Gustavson recently was forced to stop taking combination therapy due to increasingly abnormal liver function tests. "I’ve been off all drugs for over two weeks and my liver enzymes are still dangerously high,” he said. He is wondering which medicines he will now be able to tolerate and if he will ever achieve undetectable HIV levels again.

High and unresponsive viral loads present a continuous therapy challenge to both patient and doctor. There is little published data or guidelines to help steer a course. Some fret that these situations are generating overtreatment as doctors thrash about with drugs to find the ultimate combination. "I suspect that with the continual panic that patients and care providers feel about high viral loads, prescriptions change so often that most of the medication dispensed never gets ingested.” said Donald Northfelt, M.D., an AIDS practitioner from southern California.

Like many patients, Northfelt is suspicious. He nevertheless agreed with the current treatment pattern: "I believe that it is important to keep the virus in the mutated [drug-resistant] state because all of the scientific findings suggest that highly mutated viruses are less damaging to the immune system. It has also been shown that when drug therapy is stopped, the wild-type virus rapidly regains predominance, and this is associated with immunologic deterioration. In summary, I like patients with resistant virus to stay on therapy to maintain that state of affairs.”

The Patients' Perspective

Indeed, many members of Survive AIDS (a San Francisco group whose participants include many long-term AIDS survivors) report a buildup of unused medications in their medicine cabinets. Such drug stockpiles are so prevalent that local activists now send these drugs to Third World countries, which desperately need them. [quote]

The idea that one should stop and wait for new therapies to come along when one's treatments all fail does not apply to today's typical AIDS and HIV patient. Survive AIDS members, many of whom took the lead on strategic treatment interruption a year ago, describe how they became convinced to stay on drugs. In a typical scenario, a patient with a high viral load may opt for new drug combinations and then finally total drug cessation. Eventually, the doctor seems to go along with stopping drugs altogether. The doctor holds a wait-and-see attitude while the patient experiences a break from toxicities and rigid dosing schedules.

Often, after a month or two, the patient returns to the doctor to learn that his or her viral load has jumped up and, perhaps, CD4 count fallen. This bad news is combined with a thoughtful discussion about wild-type HIV versus unfit virus. And soon the patient is sent home with a new prescription for recycled anti-HIV medications. He or she may also be placed on the list for some experimental drug distributed through a compassionate use program. All in all, the pressure to stay on drugs is inescapable. Unless toxicities are alarming or dangerous, the patient's role is to learn to cope.

An Assay in Search of a Treatment Model

Though the latest trend toward continuous treatment may seem wise at this point, doctors and activists alike worry that corporate interests from drug manufacturers and ViroLogic, an up-and-coming biotech with an HIV fitness assay, are influencing treatment decisions in favor of constant therapy and drug recycling.

While researchers have been looking into unfit virus, ViroLogic has been betting on it. Along with phenotypic and genotypic assays to detect drug-resistant HIV, ViroLogic is developing its new technology for quickly gauging a particular HIV's replication capacity. The company was able to slightly modify its HIV resistance assay to create the fitness assay as part of its worldwide competition for resistance testing sales with dominant Belgian rival Virco.

The ViroLogic test can tell patients how fit, or able to replicate, their HIV has become after exposure to antiretroviral therapy. As ViroLogic develops this HIV fitness test, it is also funding the science to validate the assay's use. The company was involved in both studies mentioned above and has a continuing relationship with the UCSF scientists.

ViroLogic's clinical director, Nick Hellman, M.D., freely admits that the need to learn about unfit virus comes both from doctors' quest for information and from ViroLogic's desire to sell the fitness assay. More studies are on the way: "We currently have a study lasting one year with 250 patients in it. We are in the process of looking at viral fitness and clinical outcomes," said Hellman. "We will be educating physicians about these results. Just as we are doing with resistance testing right now." It would seem that Hellman and ViroLogic expect their upcoming study results to be favorable.

Hellman's concept of utilizing treatment to weaken HIV's fitness is similar to that of other doctors and researchers. There is one difference, however: Unless doctors use an assay such as ViroLogic's fitness test, they will not know to what degree a patient's virus has become unfit. Running a drug-resistance assay would not be enough. The fitness assay is essential to fine-tuning treatment if the goal is to force the patient's HIV to reach minimal fitness as it evolves drug resistance.

This research/marketing strategy does not sit so well with Northfelt. In an e-mail, he pointedly commented; "I don't mind being on the record about the lack of attention being paid to the concept of managing drug-resistant virus without resorting to multiple medication changes, multiple pointless genotype and phenotype [resistance] analyses, etc." Northfelt fears that corporate concerns underlie the new continued treatment paradigm for multidrug-resistant HIV. He warned, "All of the economic incentives for pharmaceutical companies, clinical laboratory services (like Virco and ViroLogic), and 'expert' clinical trialists in the ACTG [the National Institutes of Health-sponsored AIDS Clinical Trials Group] and elsewhere are lined up to favor frequent changes in antiretroviral therapy."

So is unfit virus for real, or are we hearing all this because ViroLogic wants to sell us new assays? It is remarkable that so many doctors agree on a treatment strategy based upon such a new and unverified hypothesis as the reduced disease progression from HIV that is deemed less "fit." Perhaps clinical experience and patient survival can pragmatically teach us the best way to proceed in the absence of substantial confirmed study results.

ViroLogic claims that the emerging goal of treating to achieve drug-resistant but less fit virus requires new, expensive lab tests. It is troubling that this same testing technology is also helping to elaborate the new treatment model. Such influence did not occur in implementing the CD4 count assay early in the epidemic. On the other hand, there was some scientific research and at least one large study conducted by the viral load assay companies. This work helped pave the way for acceptance and use of viral load testing, but the increasing reliance on the companies to validate the scientific basis for their own products was never examined. Indeed, that tendency seems to be intensifying.

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