Research Initiative Treatment Action (RITA!); Vol 5, No. 4 October 1999
L. Joel Martinez
Background. Pharmaceutical companies have made many claims regarding the virtues of their protease inhibitors and with time some of these claims have either been validated or discredited with patient experience. The answer to whether one drug is "stronger," more "tolerable," or more "durable" than another will come with experience. In the interim the optimal sequencing and combination of drugs needs desperately to be sorted out and for the moment the patient is left to make decisions utilizing limited clinical research data and some incremental hints of science and research.
The expectation tied to the use of highly active antiretroviral therapy (HAART), especially when the regimen contains a protease inhibitor, is that HIV will be maximally suppressed. The hope of eradication having faded, patients and physicians are left ruminating about that span of time required to declare victory over HIV. Absent a major therapeutic development the only reasonable expectation is that HAART will have to work for an indefinite period, that is, for the life of the patient. Given the degree of adherence required to maintain virologic suppression, the chemotherapeutic nature and the unknown long-term side effects of protease inhibitors, long-term success with a first regimen may be in doubt for many patients.
Scarier still, is that in clinical practice this period of maximal suppression is indeed short or absent altogether for a majority of patients. Recent data published in the Archives of Internal Medicine (159, pp.1771-1776, 1999) indicate that more than 50% of patients treated in a university-affiliated clinical setting experience virologic breakthrough (viral load greater than 400 copies) in less than a year when treated with a protease-containing HAART regimen.
In this real world context it is important to consider the likelihood of virologic breakthrough; but equally important may be the consideration of the consequences of virologic breakthrough. Astute patients will ask not only about their chances of long term success with a certain regimen, but also what options are available should they become resistant to the regimen.
In a recent study published in The Journal of Virology (73, p. 3744, 1999), Richard D'Aquila, MD, et al., examined the consequences of virological breakthrough and the activity of the resultant protease inhibitor mutants. He concludes that the virus that evolves as a result of developing resistance to a protease inhibitor can differ from one protease inhibitor to the next and that these differences of evolution may have clinical implications.
The mechanics of resistance. One of the major problems with the use of protease inhibitors has been the prevalence of broad cross-resistance between drugs. In simplest terms cross-resistance is this: patient takes drug A and develops resistance to drug A and to drug B without ever having taken drug B. The consequence of cross-resistance is to narrow quickly the number of drugs a patient can take and expect to have a potent antiviral effect. Experiencing virologic breakthrough with a drug with broad cross-resistance will have consequences that reach beyond the utility of that particular drug.
Resistance to a protease inhibitor develops in stages. The first mutation selected is usually near the active site of the protease. With the exception of the overlap of the primary mutation that develops with ritonavir (Norvir) and indinavir (Crixivan), in most cases the primary viral mutations generally differ from protease to protease. If primary mutations were the only change and no further mutations developed there would be little cross-resistance between protease inhibitors. The problem arises when additional—the so-called "secondary"—mutations develop. Primary mutations have a direct effect on the efficacy of the drug. Secondary mutations often do not have effect on the level of resistance, but instead are thought to improve protease's overall function and fitness. See Figure.
Unlike primary mutations, secondary mutations overlap considerably between the different protease inhibitors. This large overlap of secondary mutations is what accounts for the broad cross-resistance that is generally seen with protease inhibitors. This broad cross-resistance was confirmed using phenotypic tests in a study reported by Hertogs, et al. at the 12th World AIDS Conference in Geneva (Abstract 230, 1998). In that study viral isolates that were at least ten fold resistant to one protease showed high levels of cross-resistance to other protease inhibitors.
A breakthrough is a breakthrough is a breakthrough. Unlike Shakespeare's rose (which by any other name would smell as sweet), virologic breakthroughs appear to differ one from the other. As an example, persons who experience virologic breakthrough on a nelfinavir (Viracept)-based regimen appear to have more success controlling viral replication with subsequent regimens than persons who experience breakthrough on other protease inhibitors.
Tebas, et al.1 reported on a study of 26 patients who had experienced virologic breakthrough on a nelfinavir-based regimen and were subsequently switched to a regimen containing ritonavir and saquinavir (Fortovase). The median viral load at enrollment of the study was 46,674 copies and the median CD4 T cell count was 222 cells. At a median follow-up of 60.9 weeks over 58% of the patients had a viral load of less than 500 copies.
This is in sharp contrast to other studies that illustrate the difficulty of suppressing virus after breakthrough on other protease inhibitor-based therapies.2 There have been a few studies that report success with subsequent ritonavir/saquinavir combinations when the patient has had a virologic breakthrough on other protease inhibitors. These studies appear to succeed when the switch is made early in the course of virologic breakthrough, when the viral load is still low. Or when the change in drugs is guided by the results of phenotypic resistance assays and the patients have been able to add new nucleoside drugs to the subsequent regimens. The successes depend on careful monitoring and in some cases on the use of phenotypic tests which are available commercially but expensive and currently not widely used.
Protease inhibitor resistant mutants. D'Aquila speculated that the successful rescue of patients who had experienced virologic breakthrough with nelfinavir might have to do with the mutant virus that results when HIV develops resistance to the drug. Experience with zidovudine (Retrovir) has shown that resistance to the drug was accompanied by a certain loss of viral fitness that was later regained with the appearance of secondary mutations.
In experiments designed to measure the fitness of nelfinavir resistant virus, D'Aquila designed unique assays that allowed two strains of HIV to grow in the same cell culture. In one experiment D'Aquila combined 20% wild-type virus and 80% nelfinavir-resistant virus.3 At days seven and 14 the proportion of nelfinavir-resistant virus had decreased sharply in comparison to the wild-type virus and the proportion of wild-type had correspondingly increased. Such a disparity in growth, according to D'Aquila, indicates a degree of impairment of the nelfinavir-resistant mutants.
The impairment of saquinavir-resistant mutants was also measured in D'Aquila's study. The results indicated that while saquinavir-resistant virus with the L90M primary mutation was also less fit that wild-type virus, it was still more fit than nelfinavir resistant virus. D'Aquila estimated that while nelfinavir-resistant virus was more than 30% impaired, saquinavir-resistant virus was only 10% impaired.
Another resistance mutation, namely L63P was added into the picture. This mutation is not associated with resistance but is common in about one half of patients prior to therapy and further, is commonly selected with patients on protease inhibitor therapy. When saquinavir-resistance viruses with L90M mutations were given the L63P mutation the mutant virus became just as fit as wild type. When the L63P mutation was added to the nelfinavir-resistant (D30N) virus the mutant virus was still impaired.
D'Aquila's hypothesis. What does this mean clinically? D'Aquila speculates that broad cross-resistance may be associated with the recovery of fitness of the mutant virus. It may be then that a nelfinavir-resistant mutant virus is impaired for a longer period of time if more compensatory mutations are required for it to acquire wild-type levels of fitness. And if this is so, mutant virus may take longer to acquire those compensatory mutations because it is replicating more slowly.
Clinical research appears to bear out D'Aquila's hypothesis. The key to changing successfully from one protease-based therapy to another protease-based therapy seems to lie in the timing (sooner is better than later) and the availability of other new agents to combine in the new regimen.
While not yet proven beyond challenge, recent clinical history and D'Aquila's scientific evidence seem to suggest that nelfinavir may provide an extra cushion of time to make a successful regimen change not provided by other protease inhibitors.
There are unanswered questions. How does this hypothesis apply to other protease inhibitors like amprenavir (Agenerase) that also seems to have viral mutants that are significantly impaired?4 Also, do patient variables come into play that might influence the resistance pattern? The true test of D'Aquila's assertions will require studies of the viruses of patients failing different protease inhibitors, with similar durations of viral load rebound. In such patient it will be possible to compare the number of different mutations and the resulting fitness of the mutants.
If D'Aquila's speculations hold true the relative fitness of protease inhibitor resistant mutants may have clinical implications for the sequencing of protease inhibitor usage. The less fit the resulting protease inhibitor mutants, the greater opportunity the patient may have to succeed with subsequent therapies.
1 6th Conference on Retroviruses and Opportunistic Infections, Abstract 392, 1999.
2 AIDS, 1998 Jul 9;12(10):F97-102; 37th ICAAC, Abstract I-201, 1997; 38th ICAAC, Abstract I-194, 1998; AIDS, 1999 Aug 20;13(12):1485-9.
3 The nelfinavir resistant virus had the D30N mutation—a common primary mutation for nelfinavir resistance.
4 Antiviral Therapy 1999; 4 (Supplement 1): 30, Abstract 44.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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