AIDS TREATMENT NEWS Issue #170, March 5, 1993
John S. James

What Is Convergent Combination Therapy?

Drug combinations have long been important for many diseases which are difficult to treat -- for example, cancer and tuberculosis -- and AIDS experts have long suspected that HIV treatment, too, will require more than one drug. But there are different theories guiding the selection of which drugs are likely to work well together.

The usual approach has been to combine drugs which work at different stages in the life cycle of the target organism. (One successful example of such a combination is called co- trimoxazole, best known by its brand names Septra or Bactrim, which is used for treating or preventing certain infections. It consists of two drugs, trimethoprim and sulfamethoxazole, combined in a fixed ratio, which block two different enzymes required by the target organisms.)

In AIDS, this conventional approach has called for combining drugs which work at different stages in the life cycle of HIV, in order to make more powerful treatments, and in particular to slow the development of drug resistance (since a mutant virus which happens to be resistant to one drug will, by chance alone, most likely be susceptible to the other; in that case, since the new virus still cannot grow, the dangerous mutation will be lost). Examples of this approach might be to combine AZT with a protease inhibitor, or with a tat inhibitor. Unfortunately this theory has had little practical test in AIDS, because all of the approved anti-HIV drugs, as well as many of the experimental ones now being tested in people, target only one point in the viral life cycle, the enzyme reverse transcriptase (which is essential for HIV reproduction, but not found at all in uninfected human cells).

The idea behind convergent combination therapy is that carefully chosen drugs against the same target, the reverse transcriptase enzyme, may work even better together than drugs against different targets. The theory is that reverse transcriptase must perform critical functions for HIV, and if it is changed too much (in order to evade various drugs), it may not work as well, and perhaps may not work at all.

For example, any HIV which is resistant to AZT has been found to have one (or more) of only five different mutations in the gene which codes for the reverse transcriptase enzyme -- at codons (positions in the gene) 41, 67, 70, 215, and 219; the one at 215 is the most serious cause of AZT resistance. Of course there might also be others which are currently unknown. But the point is that there are only a few different mutations which can block the effect of AZT and still allow the virus to reproduce at all. Other mutations can convey resistance to ddI or to other drugs.

The idea of convergent combination therapy is to find particular combinations of drugs, all targeted against the reverse transcriptase enzyme, such that there is no combination of mutations which could convey resistance to all the drugs without also making the reverse transcriptase unable to function. Then any variant of HIV would either be susceptible to one or more of the drugs, and stopped by it, or would be unable to reproduce because of the incompatible mutations required to provide the various drug resistances. If the theory works, therefore, there would be no evolutionary pathway for the virus to develop resistance to all of the drugs.

The reason this idea is fairly new is that it may be most applicable to viruses--not to other disease-causing organisms such as bacteria, which have much more complex genetic machinery than viruses, including various ways to disable drugs without necessarily affecting the function which the drugs are targeting.

History: The Harvard Experiments

According to a detailed news release dated February 16 from Massachusetts General Hospital, convergent combination therapy was first proposed by Yung-Kang Chow, an M.D.-Ph.D. student at Harvard Medical School, working under the supervision of Martin S. Hirsch, M.D., a noted AIDS researcher and Professor of Medicine at Harvard. Results of an early test of the idea, conducted at Massachusetts General Hospital, were presented at the VIII International Conference on AIDS in Amsterdam, in July 1992.(1) This poster reported that a genetically engineered virus, artificially given several mutations to confer simultaneous resistance to AZT, ddI, foscarnet, and pyridinone (an experimental antiviral being developed by Merck & Co., also known as "L661" or "the L-drug") was no longer able to reproduce.

A recent paper in Nature(2) led to the current public interest. It describes two different series of experiments. In one, viruses were artificially given various mutations, for example at positions 215 and 219 (AZT resistance), 74 (ddI resistance), and 103 (resistance to pyridinone and certain other experimental drugs with a similar mechanism of action, such as nevirapine). When all these mutations were combined in a single virus, the reverse transcriptase (RT) activity of that virus was undetectable, and the virus became non-infectious. But when only some of these mutations were combined (for example, the first three, giving resistance to AZT and ddI but not to pyridinone, etc.), then the virus was still infectious (although somewhat less so than the original virus with none of the mutations).

The second series of experiments detailed by Chow and others in the recent Nature paper tested combinations of two or more anti-HIV drugs, at concentrations which can be achieved in the body, to see whether they could prevent or stop an HIV infection in a laboratory culture of human cells. The combinations (1) AZT plus ddI; (2) AZT plus alpha interferon plus the Hoffmann-La Roche protease inhibitor Ro31-8959; (3) AZT plus alpha interferon plus soluble CD4; and (4) AZT plus pyridinone, all failed to do so (although AZT plus pyridinone almost worked). However, the three-drug combination AZT plus ddI plus pyridinone completely prevented the infection in the laboratory test. Even when the drugs were added at the peak of HIV infection, seven days after the virus was added, the three-drug combination of AZT plus ddI plus pyridinone stopped spread of infection in the laboratory cultures.

After 49 days of the three-drug treatment, the cells were placed in a drug-free medium for an additional 45 days, giving ideal conditions for HIV to grow. But after the 45 days, there was no evidence of the virus; nothing was found even with a PCR test so sensitive that it could detect a single copy of the HIV genetic information within DNA from 100,000 cells. This does not mean that the virus would similarly be reduced to such low levels in people -- for a number of reasons, some of which are discussed below. But it does suggest that certain combinations (for example, AZT plus ddI plus pyridinone) might work much better as antivirals than combinations now in use (for example, AZT plus ddI).

The virus used in this experiment was a clinical isolate (i.e., obtained from a patient), not a laboratory strain or a product of genetic engineering. The particular patient's virus was selected because previous research had suggested that it included a number of variants of HIV.

The Nature article mentioned two other three-drug combinations which stopped HIV infection in laboratory cultures: AZT plus ddI plus nevirapine (BI-RG-587); and AZT plus ddI plus foscarnet (an intravenous drug approved for anti-CMV use, which is also known to have some anti-HIV effect). No details were given, however; a manuscript on these results is in preparation. The success of these other combinations (in the laboratory) illustrates that "breakthrough suppression is not unique to a particular convergent combination. Regardless of the mechanism of breakthrough suppression, as reverse transcription is necessary to create HIV-1 variants, complete inhibition of this process using convergent combination regimens should prevent emergence of multiply resistant viruses as well as any immune escape mutant viruses." (page 652)

The work at Harvard/Massachusetts General Hospital was funded by three different units of the U.S. National Institutes of Health: the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the Medical Scientist Training Program.

Related Research

Some of the drug-resistance mutations in the reverse transcriptase enzyme are known to interact with each other, so that viruses containing certain combinations of mutations may behave differently than expected in laboratory experiments. For example, a mutation at position 74 which causes ddI resistance can also suppress the AZT resistance caused by certain other mutations.(3) This data suggested that AZT resistance and ddI resistance might not be able to co-exist in a single virus. But unfortunately, by the time of the VIII International Conference on AIDS in Amsterdam last July, some groups reported early data showing that virus resistant to both AZT and ddI could be found in some patients who had first received AZT treatment and then switched to ddI.(4,5)

Other experiments at the Wellcome Research Laboratories in Kent, U.K., found another mechanism by which HIV may be limited in its ability to develop multi-drug resistance to reverse-transcriptase inhibitors.(6) In these tests, a virus was constructed with mutations associated with resistance to AZT, ddI, and non-nucleoside reverse transcriptase inhibitors including pyridinone and nevirapine -- as was done by Chow and others in the Harvard group -- except that this virus was given a different mutation (at position 181) to confer resistance to the non-nucleoside drugs, and it did not contain one of the AZT resistance mutations (at position 219) that was present in the virus made by the Harvard group. Unlike the multiply-resistant virus in the Harvard study, the virus with these mutations could reproduce. However, the mutation at position 181 suppressed the effect of an AZT- resistance mutations, so that virus could be inhibited by AZT. Although at first this result would seem to weaken that of the Harvard group, in that virus with (different) mutations known to cause resistance to the same three drugs was able to reproduce, the practical result is the same, since that virus had become susceptible to AZT again, so the three-drug combination should be effective against it.

Confusion in the News

One widespread confusion among readers of the news-media reports of convergent combination therapy concerns the identity of the drugs being discussed (other than AZT and ddI). The media picked up the name pyridinone as the third drug used in the three-drug combination for most of the experiments in the recent Nature article. That name had not been widely known before the current publicity, and people have often not realized that it is another name for Merck's "L-drug," better known as L661 (or L697,661), as mentioned above.

Another confusion is that while the Nature article largely reported on AZT plus ddI plus pyridinone, the major clinical trial of convergent combination therapy, planned to start in a few months, will use a different convergent combination, AZT plus ddI plus nevirapine. Nevirapine (also known as BI- RG-587), an anti-HIV drug being developed by Boehringer Ingelheim Pharmaceuticals Inc., is similar to pyridinone in that both are non-nucleoside reverse-transcriptase inhibitors; and the drugs show cross resistance, meaning that virus which has become resistant to one will also be resistant to the other even before being exposed to it (suggesting that the mechanism of action of the two drugs is similar). The combination with nevirapine was tested by the Harvard group and found to work; this was reported in the Nature article, but few details were given. Another confusion stems from a short article in the current Business Week (March 8, page 37) which includes the statement that "The three-drug approach worked with only certain strains of HIV -- variations of the most common form, known as HIV-1 -- but it didn't work with other strains." We called the reporter, who told us that this statement referred only to the tests of whether a virus artificially given certain combinations of mutations could reproduce (not to the more direct and more important tests of whether a three-drug combination given to wild-type virus could stop its growth). However, the Harvard group only did this test on one kind of virus, and it did not have any failures (cases in which the virus could reproduce despite the mutations which conferred three-drug resistance).

While we could not definitively track down this confusion by press time, we suspect that the Business Week report may have referred to the Kent, U.K. results mentioned above. Here a virus remained able to reproduce despite having artificially- inserted mutations associated with resistance to the same three drugs that the Harvard group used. (Some of the mutations were different from those used at Harvard, however, so the different results concerning the viability of the virus are not contradictory.) But in practical terms, the mutant virus was still susceptible to the three-drug combination, because one of the mutations canceled out the resistance provided by another, making the virus become susceptible to AZT again. Therefore the three-drug convergent combination therapy should still work against the virus tested in Kent, since no known combination of mutations leaves it able to reproduce and also resistant to all three of the drugs.

Why Convergent Combination Therapy Might Not Work in People

To keep perspective on the potentially important but still unproven idea of convergent therapy, it is important to remember that most drugs and therapies which work well in the laboratory do not turn out to be useful in people. There are many reasons for this. Here are only some of the reasons why convergent combination therapy might not work: * In the body, HIV infects a number of different kinds of cells -- and drugs can work differently in different cells. For example, AZT works much better in T-helper cells than in macrophages, which also are infected with HIV. Before AZT can be effective, it must be chemically transformed to its triphosphate form after it enters the cell, and some cells are better than others at producing this chemical reaction. If any of the three or more drugs used together for convergent combination therapy fail to reach effective levels in certain kinds of cells, then the virus could still grow in those cells, and the therapy would not be completely effective.

* New, unknown mutations might enable HIV to become resistant to any particular combination therapy. The large viral burden now known to exist in the lymph nodes during HIV infection gives plenty of chances for such a mutation to develop, if one is biologically possible.

* Different combinations of known mutations, other than those which have been tested so far, might also be able to confer simultaneous resistance to drug combination without preventing the virus from reproducing.

* Reverse transcriptase inhibitors will not stop viral activity in cells which have already been infected. Even if convergent combination therapy prevents further spread of infection, the virus in chronically infected cells could continue to cause problems. These cells could stay in the body for a long time. (In the laboratory cell culture experiments, in contrast, infected cells die and stop producing virus -- meaning that eliminating the virus in cultures does not imply that the same drugs will eliminate it in the body.)

* Until drug combinations are tested in people, no one can be sure they will be safe -- a question which is especially critical with drugs which will have to be taken indefinitely. There could be drug interactions which are harmful, or which make one or more of the drugs ineffective.

In the press release from Massachusetts General Hospital on convergent combination therapy, repeated cautions about not misinterpreting the results are underlined or in bold type.

Clinical Trial Plans

The major clinical trial of convergent combination therapy, named ACTG 241, in expected to begin in a few months at sites throughout the U.S. -- hopefully starting enrollment by May. Volunteers will be randomly assigned to receive either AZT plus ddI plus nevirapine, or AZT plus ddI plus a placebo. The trial will last one year. Originally it was scheduled to recruit 200 volunteers, but that number has been increased to 400. Sixteen sites are expected to participate.

A small study now ongoing at the University of Alabama in Birmingham is testing the combination in eight volunteers. This study is giving nevirapine to three groups of volunteers: one of which had been taking AZT alone, another taking ddI alone, and the third taking the combination of those two; only this last group will serve as a test of the convergent combination when the nevirapine is added. The main goal of this trial is to check that the combinations are safe, as ddI plus nevirapine has not previously been given to patients. The study is also measuring p24 antigen levels and is doing viral cultures, in order to get a quick estimate of whether or not the convergent combination therapy is working.

Another study, which is recruiting now in Philadelphia, Pittsburgh, and Providence, may test a different convergent combination (with pyridinone, the Merck "L-drug," combined with AZT and ddI), but the decision to try all three drugs has not been made yet. For now, the study will only test two drugs, comparing AZT alone with AZT plus pyridinone. Merck recently decided to begin a pharmacokinetic study to show that ddI and pyridinone can safely be used together; if this study is successful, then ddI might be added later to both treatment groups, giving a comparison of AZT plus ddI with the three-drug convergent combination.

To be eligible for this trial, volunteers must have a T- helper count under 250. Volunteers do not need to have been on any antiretroviral therapy in the past; they can qualify whether or not they have used AZT, ddI, or ddC, but if they are currently using ddI or ddC, they will need to stop those drugs two weeks before entering the trial. (There might also be a two-week washout for AZT, and a four-week washout for d4T.) This trial will last 24 weeks, and weekly visits to the medical center will be required for the first eight weeks, then less frequent visits will be required. After the 24 weeks, L-661 should be available on an open label basis to participants, if the drug still looks promising at that time.

Forty volunteers are now being recruited at each site. For more information, call the University of Pennsylvania in Philadelphia, 215/662-2473; or the Pitt Treatment Evaluation Unit in Pittsburgh, 412/647-8125; or the Miriam Hospital/Brown University in Providence, 401/331-8500 x2928.

Comment: The Future

We are concerned that, no matter how well convergent combination therapy might turn out to work in people, there seem to be no plans or institutional means to get it to many patients for two years or more. The major trial may take several months to begin and then it will run for a year, with little chance of data being released before that year is up. Then it will likely take months for all the data to be collected from the trial sites, checked, analyzed, delivered to the FDA, and published. Then, if that trial shows that the treatment works well, nevirapine could probably be approved for marketing, a process likely to take several more months at least.

What about parallel track, or accelerated approval, as faster means to get the treatment to patients in the meantime? The problem is that, as far as we know, there are no plans to obtain the data needed to support either of these programs, until after the major trial is finished and analyzed. It is hard to believe that parallel track, let alone accelerated approval, could be based on only the eight patients now being studied in Birmingham. (The 120-patient trial discussed above may or may not decide to test the three-drug combination.)

What about the treatment underground? We have heard that a nevirapine underground will be difficult, because the published information on how to synthesize the drug would yield too expensive a product. Therefore, expert chemists would first need to develop a better synthesis procedure, and it seems unlikely that this substantial effort will come together underground when there is so little clinical evidence to prove that the treatment is useful. (We do not know how difficult it would be to synthesize pyridinone, if the combination including this drug should turn out to work.)

What should be done? Two different plans should be pursued. First, we need a rapid trial of convergent combination therapy with more than the eight patients in Birmingham but fewer than the several hundred in the major study now being planned. This proposed trial would look at safety, at markers of viral activity, and at T-helper count and other markers of immune or general health. It should run for several weeks and then release the data available at that time, while offering the patients ongoing treatment and collecting longer-term followup data. One central question this trial would ask would be whether patients who continue to deteriorate on other therapies are likely to improve when switched to this one. If so, the unapproved drug in the combination (probably nevirapine or pyridinone) could be given accelerated approval, or made available through parallel track if the company is willing to pay the expense. (If not, there is no legal way to allow patients to pay the cost of parallel-track distribution, and governments are very unlikely to pay, so patients will be deprived of the drug. It is rumored that there have been a number of cases in the past where the FDA has pleaded with a company to make its drug available under an early-access program but the company has refused; the information remains confidential, however, so the public does not know, and cannot bring pressure to obtain the drugs or to reform the system. The only way we know around this problem is to push for accelerated approval, which companies are very eager to cooperate with.)

Second, we should do more laboratory testing to find out whether combinations of reverse transcriptase inhibitors already approved or otherwise available (AZT, ddI, ddC, d4T, foscarnet) show promise as convergent combination therapy. If combinations of existing drugs work in the laboratory and then work in small human trials, physicians could start using them for patients with no alternatives, without waiting for official action to be completed.

Making the system work so that it does the right thing with convergent combination therapy could be an early task for the new "AIDS czar" (AIDS coordinator, or special assistant to the president) when one is appointed. (For news about possible candidates for this job, see story in The New York Times, February 28, 1993.)

References

1. Chow Y-K, Hirsch MS, Merrill DP, and others. Replication incompatible and replication compromising combinations of HIV-1 RT drug resistance mutations. VIII International Conference on AIDS, Amsterdam July 19-24 1992, abstract number PoA 2450.

2. Chow Y-K, Hirsch MS, Merrill DP, and others. Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature. February 18, 1993; volume 361, pages 650 to 653.

3. St. Claire MH, Martin JL, Tudor-Williams G and others. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1. Science. September 27, 1991; volume 253, pages 1557-1559.

4. Eron JJ, Chow Y-K, Bechtel LJ and others. Interactive effects of AZT- and ddI-selected HIV-1 reverse transcriptase (RT) mutations. VIII International Conference on AIDS, Amsterdam July 19-24 1992, abstract number PoB 3580.

5. McLeod G, Mayers D, McCutchan F, Sanders-Buell E, Hammer, S. Dideoxynucleoside resistance patterns in clinical isolates of HIV-1. VIII International Conference on AIDS, Amsterdam July 19-24 1992, abstract number ThA 1569.

6. Larder, BA. 3'-Azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrobial Agents and Chemotherapy. December 1992; volume 36, number 12, pages 2664-2669.

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