AIDS Trestment News
Viral Resistance Testing: Practical Issues and Future Opportunities
Interview with Thomas Merigan, M.D.by John S. James
When treating bacterial infections with antibiotics, physicians have long had tests available to tell them which drugs should be avoided for a particular patient, because the bacteria had become resistant to that drug. It is much harder to develop such tests for viruses, but today two different kinds of tests for HIV resistance to antiretrovirals are in experimental use. These tests are expensive at this time, and not yet approved by the FDA, but physicians can use them. Recently two clinical trials -- GART,(1) which was mentioned above, and the VIRADAPT study(2) in France -- have provided clear evidence that viral resistance testing, when properly used, can improve the effectiveness of HIV treatment in certain cases.
The two kinds of tests are called genotypic and phenotypic viral resistance testing. Genotypic tests look for mutations in the virus which are known to be associated with viral resistance to particular drugs. Phenotypic tests grow the virus in the laboratory to see how well the drugs work to stop it; these tests are time-consuming and expensive, in part because virus from patients generally does not grow well in the laboratory, so genes from the patient's virus must be transplanted into a laboratory-adapted virus before the drug tests can be run. In HIV infection, a single variant of the virus is usually transmitted, but in the patient, this HIV evolves into millions of different genetic variations. The resistance tests currently available cannot detect minor populations. If a patient is being treated with an antiretroviral and resistance develops, and then the patient stops the drug, the resistant virus can over time become a minor population temporarily (since non-resistant virus is generally more fit and reproduces more rapidly, as viruses usually must pay a price for drug resistance). The resistant virus would then be missed by the test -- but can come back very quickly if the drug is started again. Therefore, a patient whose treatment is failing, and who is being tested to determine which of the drugs they are taking have become ineffective for him or her, should best be on the regimen when their virus is tested for resistance.
Interview with Dr. Merigan
AIDS Treatment News: What do people need to know now about viral resistance testing?
Merigan: There are three settings where HIV resistance testing might be used clinically:
(1) In case of exposure such as needlestick or possible maternal transmission, the virus from the contact may be tested, to make sure that this virus is not already resistant to the drugs being used in hope of preventing infection. Of course treatment will often need to start empirically before the results of the resistance test are available.
(2) Resistance testing might also be used before starting a person's first antiretroviral treatment -- especially if they are likely to have been infected with a virus already resistant to antiretrovirals.
(3) The third situation is when an antiretroviral drug regimen has clearly failed, and the doctor believes that the drugs are all being taken and the most likely cause of the drug failure is antiretroviral resistance.
So resistance testing can be used either to realign existing therapy, or to help pick the best initial therapy for the patient.
ATN: And when trying to analyze which drugs in a regimen are not working, it is important to still be on the regimen when the sample is taken for resistance testing, to prevent "wild type" virus from growing back and hiding the resistant virus from the test?
Merigan: That's true. But also, the regimen will usually be partially active for the patient -- another reason the doctor may not want to stop that treatment until a new regimen has been chosen to replace it.
Genotypic Vs. Phenotypic Resistance Tests
ATN: How should our readers understand the difference between genotypic and phenotypic testing? The general impression in the community is that the phenotypic test is best, or at least easiest to interpret, but also that this test is more expensive and takes a longer time before the results are available.
Merigan: It is important to know that any interpretation of a genotypic result must be based on phenotypic testing of that drug done sometime in the past [not with the same patient, usually]. Every time I interpret a genotypic assay [test], and say that this patient's virus is resistant to drugs X, Y, and Z, it means that somebody had already taken that kind of virus, with those mutations, and tested that virus in a phenotypic assay. So the genotypic test is basically a shortcut, based on knowing that the given amino acid change in the reverse transcriptase gene, or in the protease gene, results in phenotypic resistance to that drug.
It is important to help people understand that the genotypic information, when interpreted properly, is also giving you something equivalent to a phenotypic assay. An exception is that if you are encountering a new kind of virus for the first time, then you would have to do the phenotypic assay to know what you're up against. Our laboratory has been doing this kind of work for several years now; we have discovered the multi-nucleoside and the multi-drug resistance pathways. We look carefully at new patterns of amino acid changes if they develop during antiretroviral treatment -- especially if we can associate them with rising viral load.
You need to educate the public that no genotypic result stands alone; it depends on phenotypic verification being done at some time. That is why we can make a projection of resistance with a genotypic result. On the other hand, doing a phenotypic assay on every person's virus is like going back to first principles -- proving against each drug tested that you have resistance or sensitivity.
There are complications; for example, combinations of drugs can have actions in the body that are not seen in laboratory tests. You need to know the pharmacology of the drugs in patients to know that a given level is associated with resistance or sensitivity. Even if you measure resistance directly for each patient, a given number does not necessarily imply that the drug will fail clinically; that may depend, for example, on whether or not drug levels in the blood go below certain thresholds. And in the future, there may be drugs that are so active that they are effective even against virus which might have been judged resistant by other standards.
ATN: If a company is offering a test for viral resistance to particular drugs, wouldn't they be able to provide adequate guidance on how to interpret the results?
Merigan: They try to, but our understanding can change.
In drug development, you have to look at the pharmacology, as well as resistance patterns from genotypic or phenotypic tests. And sometimes companies do not do all of the necessary pharmacology, especially during the first few years in the drug's development.
In AIDS we are pushing the envelope in developing these drugs. And sometimes we would need data that has not yet been obtained, to come to firm conclusions.
ATN: How much of a problem do doctors have at this time in deciding which genotypic or phenotypic lab to use?
Merigan: The only phenotypic group now doing work on patient-submitted specimens is VIRCO in Belgium; they are working through LabCorp in the U.S. But there are many laboratories doing genotypic testing.
Because there have never been head-to-head trials of the two assays, comparing genotypic and phenotypic testing directly against each other, we do no know which niche applications might be better for one test or the other. It is likely that both of them give almost identical information for many, many uses -- that would be my guess. There may be specific cases where one would have advantages over the other, but this would have to be proven; it cannot just be hypothesized. We need that head-to-head test.
Our group is beginning work on designing one now. But to do the trial, we will need two test manufacturers who are willing to go head to head. That's like finding two drug manufacturers who are willing to put their drugs in trial against each other -- hard to do. We are working on it.
ATN: Especially with genotypic testing, it would help greatly if physicians could get expert assistance in interpreting the results. The GART(1) study showed a big difference between physicians who followed the advice of expert virologists and those who did not -- and these physicians were all HIV experts. Where are we now and in the near future on feasible ways to make such help widely available?
Merigan: Many companies doing these tests are already handing out tables showing the relationship between amino acid changes and drug resistance. Also, some of them have experts for doctors to call to discuss individual cases.
For the future, we should have expert meetings once or twice a year, which publish guidelines that summarize the best advice. But that best advice will always have to be tempered by the individual patients' side effects, drug history, and of course the possibility of drug interactions. No one can completely codify these; they need to be translated by a thoughtful physician who knows the full story of the drugs being used, the viral-resistance results, and the patient.
ATN: What about artificial-intelligence approaches for guiding physicians in choices of therapy?
Merigan: People have various software approaches. But none of them are either licensed or widely distributed. And there are fears about legal responsibility if the system fails to work in some case; what if you left out a fact that made it predictable that it would not work? I am not sure how we are going to handle this issue. It is easy to look at what the genotype means from a phenotypic standpoint; but once you start bringing in all the other factors, the decision approaches the usual complexities of the practice of medicine, where the most important thing is for the patient and the doctor to have a good understanding of what they are up against, and share the issues. And it means you have to take a risk; there will always be some unknowns.
ATN: Even with consensus medications, most doctors even in HIV practices will not have time to keep up with the intricacies of all the different mutations.
Merigan: That is why at least converting the mutations into generally accepted phenotypic results is a logical thing to do; this is happening already, and will improve with time.
Reimbursement for Viral Resistance Tests
ATN: What about reimbursement for these tests by private or public insurance?
Merigan: Policies for reimbursement seem to come rapidly in HIV. I don't believe there will be major gaps. Studies like GART(1) and the French VIRADAPT(2) have been presented at conferences; when these are fully published it will be easier to get reimbursement. Both third-party carriers and government agencies are already paying for these tests for some patients.
ATN: Could you summarize the GART study?
Merigan: It was a randomized trial to examine the usefulness of genotypic testing, plus expert advice on the results, when the volunteers needed to change their treatment regimen. Everyone in the trial was tested for HIV resistance mutations, but for 16 weeks, volunteers were randomly assigned to have their doctors receive the resistance-test results or not; at the end of the 16-week study period, everyone was given the test results.
ATN: I understand you were one of the three virologists who provided expert advice to the physicians.
Merigan: The others were John Baxter at Rutgers, and Doug Mayers from Henry Ford Hospital in Detroit.
ATN: And on the whole, there was about a half-log [3-fold] greater reduction in viral load when physicians received the results -- and that approached a one-log [10-fold] improvement at those institutions where doctors tended to follow the expert advice?
Merigan: That is correct. Remember that we only did this study for 16 weeks [since patients would be reluctant to volunteer for a long study where test results which might help them were being withheld].
ATN: And the advice was to use an average of about four drugs; without the test results or the advice, the physicians used an average of about three?
Merigan: The principle advantage of GART availability was that it allows selection of the best four drugs -- not just four drugs, but ones which were likely to work.
Viral Resistance and Developing Better Drugs
ATN: You mentioned that your laboratory is working toward the design of new protease inhibitors which specifically target viruses resistant to the current drugs. Explain how this approach could help everyone, even patients starting therapy, not only those already resistant to the protease inhibitors currently in use.
Merigan: Ten years ago, when everybody knew that viral protease was an important target, they all made the same three-dimensional structure of the protease molecule, and tried to fit compounds into it. As a result, there is such a close relationship between all the HIV protease inhibitors that have been developed, that it is not surprising that we are out of options. If we could inhibit the virus by targeting viral protease which has become drug resistant, maybe we could use standard protease inhibitors more rationally, and make them last much longer.
New drugs developed this way could be very good candidates for combination treatment; they might be as different from conventional protease inhibitors as non-nucleosides [efavirenz, delavirdine, nevirapine] are from nucleoside analog drugs [AZT, ddI, d4T, abacavir, etc.]. Why not let what the virus has done drive us in new directions? Especially since we are not moving forward very well with targeting the other genes of HIV.
ATN: Two weeks ago in San Francisco you mentioned that you had to go to an X-ray crystallographer in an academic institution, rather than to a pharmaceutical company, to pursue this research approach. Why have the companies been slow to move?
Merigan: It is a departure for the pharmaceutical companies, because they would rather focus on first-line therapy. We are starting with the most troublesome virus, and trying to extend it backwards some day to first-line therapy as well. But the first question is, can we come up with antiretrovirals which are tailored for third-line use, for heavily treated patients who are otherwise out of options?
ATN: So this is an important research front that might lead to better treatment for everyone?
Merigan: It has that broader potential. And when you do science, if it's done very well, it surprises you. It is not too much to hope for a pleasant surprise.
ATN: Where do you think viral resistance testing will fit in clinical care in the future?
Merigan: I believe these tests are a new phase, like viral load, in the rational treatment of patients with HIV. There are unknowns, but to me it seems clear that we should push ahead, and that patients need the advantage of this approach.
1. Baxter J.D., Mayers D.L., Wentworth D.N., Neaton J.D., and Merigan T.C. A pilot study of the short-term effects of antiretroviral management based on plasma genotypic antiretroviral resistance testing (GART) in patients failing antiretroviral therapy. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract LB8].
2. Durant J, Clevenbergh P, Halfon P, and others. Can HIV genotype determination be useful for individualized adaptions of antiretroviral therapy: The VIRADAPT French study [abstract OP 7.1]. Abstracts of the Fourth International Congress on Drug Therapy in HIV Infection, Glasgow, Scotland. AIDS. 1998; volume 12, supplement 4, S16.
Medicare Recipients -- New Income Limits Can Increase Cash, Medical Benefits
"People with AIDS with SSDI and other income under $947 monthly will see the $45.50 Medicare Part B premium that's being deducted restored to their checks once the Specified Low Income Medicare Beneficiary (SLIMB) and Qualified Individual (I) programs begin paying it for them.
"Those with SSDI and other income under $707.00 per month will not only get the premium paid for them and have the $45.50 restored to their SSDI checks -- the Qualified Medicare Beneficiary (QMB) program will also pay the $768 hospital admission deductible, the $100 annual doctor bill deductible, and the 20% of doctor and outpatient bills that Medicare doesn't cover."
[From the introduction to "Program Offers Extra $45.50 in Social Security Check Plus Medical Bill Help to PWAs on Medicare," by benefits expert Thomas P. McCormack. You need to apply for these programs, they are not automatic; see the full article for other essential information. McCormack's article is being published in HIV ALIVE; for a copy, contact Jennifer at 202-543-6777x12 or at firstname.lastname@example.org. If you have questions after reading the article, contact Tom McCormack at 202-479-2543.]
Federal Employees -- New Life Insurance Option April 1 - May 31 Only
Under certain conditions, these policies can be taken into retirement, sold to viatical companies, or converted to private life insurance. Spouses and children of the employees can also be eligible under this program.
Much more information is available in an article by benefits expert Thomas P. McCormack, now being published in the HIV Alive newsletter. For a copy of the article, contact Jennifer at 202-543-6777x12 or at email@example.com. If you have questions after reading the article, contact Tom McCormack at 202-479-2543.
Vaccine and Microbicide Tax Credit Legislation Introduced in Congress
From a summary of the bill by Congresswoman Pelosi:
"I. Tax Credit
"Provides a tax credit for qualified research and development costs associated with research on vaccines for malaria, tuberculosis, or HIV. Investments in vaccines for other infectious diseases (of a single etiology) that cause over 1 million deaths per year would also qualify. The credit would also apply to R&D costs for microbicides to prevent these diseases.
"The tax credit equals 30% of total annual qualified R&D investments. This is a 'flat' credit on all qualifying expenditures in a given year. Like the Research and Experimentation Tax Credit (R&E Credit), this tax credit could be carried forward 15 years and backward three years. The credit would be 'transferable' so that a company could use the unclaimed tax credits of a company it acquires. Smaller companies could choose to waive the credit and pass it on to their equity investors who finance R&D on one of the priority vaccines.
"'Qualified research' is the same as in the R&E Credit and includes wages, salaries, supplies, certain time-sharing costs for use of computers, and 75% of contract research performed by research organizations. Buildings, overhead, and fringe benefits are not qualified expenses. To be claimed under the credit, R&D costs must be incurred in the United States, except for human clinical trials abroad since trials of these vaccines will be required in many countries.
"Companies that use the credit and develop a licensed product would be obligated to establish a good-faith plan for the widest possible global access to the vaccine. Companies would not waive any rights to pricing, patent ownership, or proprietary information.
"Expresses the Sense of Congress that the President and federal agencies, including the Department of State, the Department of Health and Human Services, and the Department of the Treasury, should work together in support of the creation and funding of multi-lateral international efforts, such as a vaccine purchase fund, to accelerate the introduction of priority vaccines into the poorest countries of the world. Further, the bill expresses the Sense of Congress that tiered or differential pricing for vaccines, providing lowered tiered prices for the poorest countries, is one of several valid strategies to accelerate the introduction of vaccines in developing countries."
This bill is modeled on the highly successful Research and Experimentation tax credit. But instead of applying only to increases in research spending, the Lifesaving Vaccine Technology Act of 1999 applies to all spending for qualified purposes. It essentially contributes 30% public funding to match 70% private funding for these projects.
The market failure and need for incentives is shown by a 1998 survey by PhRMA (Pharmaceutical Research and Manufacturers of America) of new medicines being developed for infectious diseases. Of the 43 vaccine projects listed, none were for HIV, malaria, or tuberculosis -- the three infectious diseases which cause the most deaths by far.
This bill will probably face little opposition. But it will need attention, since most of the bills introduced in Congress do not become law. And the public does not fully realize the linkage between global and domestic threats of emerging and drug-resistant infectious diseases, in a world of increasing population, increasing travel, and increasing risk of biological warfare.
For More Information
The Lifesaving Vaccine Technology Act of 1999 -- the full text, and Congressional actions -- is in Thomas, http://thomas.loc.gov/, the Library of Congress Web site which tracks current Federal legislation; search for 'vaccine' (or for the bill number, 'H.R. 1274').
AIDSWatch Federal Lobby Days, May 2-4 in D.C.
The agenda will focus on federal appropriations for research, care and treatment, housing, and prevention -- and for the first time this year, some education on international AIDS issues.
For more information, contact Jean-Michel Brevelle of the National Association of People with AIDS, 202-898-0414 x103, firstname.lastname@example.org -- or register through the Web at http://www.napwa.org. The Web site also includes a list of regional coordinators, and fundraising tips on raising money for your trip.
Washington: Demonstration on Africa Trade Bills and AIDS Drug Access, April 21
Besides ACT UP/Philadelphia, sponsors include the Health GAP Coalition (see AIDS Treatment News #315), labor unions, fair-trade activists, and environmentalists. Bus or other transportation is being organized for Philadelphia, New York City, Baltimore, Chicago, Richmond, Wilmington, North Carolina, and the West Coast.
For more information, contact ACT UP/Philadelphia; phone 215-731-1844, or email Julie Davids, email@example.com.
Copyright 1999 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.