Can Sequencing Delay Resistance? -- More from ICAAC and Lisbon
Being Alive - December, 1999 Walt Senterfitt
Many people with HIV are doing very well on the first combination antiretroviral medication regimen they began, meaning their CD4 or T-cells have risen or stayed up and viral load has fallen or stayed low, perhaps undetectable on current tests. This happy circumstance is usually due to several factors: few or transient side effects, ability to adhere strictly to the prescribed regimen, and having escaped the burden of a lot of accumulated drug resistance from the days when therapies were not so effective or lasting.
Others are failed by their first drug regimen (or their second or third)--sometimes after a few months, sometimes after several years. Aside from adherence problems and resistance, failure may also be due to drug absorption or metabolic problems. This results in inadequate levels of the drug in the bloodstream to suppress HIV effectively. Recent developments in laboratory tests of drug levels in the blood may soon eliminate this cause of failure by allowing timely monitoring and dosage adjustments.
What Evidence on Cross-Resistance is Useful for Planning?
Several recent and earlier research findings are useful:
All non-nucleoside reverse transcriptase inhibitors (NNRTIs) have cross-resistance, meaning that resistance to one usually implies resistance to all other NNRTIs. This means we can only count on having one shot at using this class. The primary mutation responsible for this cross-resistance is at location k103n on the HIV reverse transcriptase (rt) gene, but it may also occur at v108 or y181.
Cross-resistance among protease inhibitors (pis) is the rule rather than the exception, but there are exceptions. In particular, early resistance to nelfinavir (Viracept) or amprenavir (Agenerase) is associated with one very specific mutation–at the locations on the protease gene of HIV known respectively as d30n or i150v. This characteristic may mean that starting with one of these pis leaves the option of later using another of the pis for which these mutations are irrelevant. On the other hand, primary resistance to saquinavir (Fortovase), indinavir (Crixivan) or ritonavir (Norvir) seems to confer resistance to all other pis. The picture is complicated by the fact that secondary mutations also occur over time. These secondary mutations may confer cross-resistance even if the primary ones do not.
Nucleoside reverse transcriptase inhibitors (NRTIs) resistance patterns are the most varied of the three classes. There is just one primary mutation identified as conferring cross-resistance: mutations at m184v of the reverse transcriptase gene cause resistance to both lamivudine (3TC or Epivir) and abacavir (Ziagen). There are also two mutation groups that cause resistance to the entire class of NRTIs, the q151m complex and the 69s "insertion complex." There is some evidence that any of the AZT resistance-causing mutations together with 184v can also cause resistance to the whole class.
What Strategies Best Preserve Later Options?
Okay, now that this spate of numbers has flown by, what does it mean? What should a person selecting his or her first therapy do? As usual, there is so far no clear, consistent and comprehensive answer. Here are some useful points of considerable (though not complete) consensus:
It is possible to begin effective combination antiviral therapy with an NNRTI and two NRTIs, thus saving pis for later (a "protease-sparing regimen"). The DuPont 006 study shows that regimens containing efavirenz (Sustiva) are the most potent such option, perhaps even more potent and long lasting that a regimen that contains a pi. Nevirapine (Viramune) regimens are somewhat less potent and durable, but may nevertheless be viable options.
It may be possible to start combination therapy with three NRTIs, sparing both NNRTIs and pis for later. An ongoing, randomized clinical trial known as the Atlantic Study is comparing one such regimen (ddI/d4T/3TC) to a three-drug regimen containing an NNRTI and one with a pi. After 48 weeks, it appeared that the 3-NRTI group was faring somewhat less well that the other two arms, although the differences were not statistically significant.
Two studies (by Haubrich and Tebas and colleagues) show that starting pis with nelfinavir may increase one's chances of benefiting from a different pi regimen later (one with indinavir, saquinavir and/or ritonavir). The same advantage may exist for amprenavir, though that has not yet been demonstrated in a clinical trial.
The best sequence of NRTIs to use in combinations is the subject of considerable debate, and conflicting laboratory studies. At least one clinical trial has shown that those starting with AZT/3TC had a failure rate of 45% when they switched to ddI/d4T, whereas those who started with ddI/d4T had a failure rate of 18% when they switched to AZT/3TC. These patients had been on nrti-only therapy from many months to several years and thus had accumulated multiple drug resistance mutations. The number of such mutations, however, was smaller in the group taking ddI/d4T first than in the group taking AZT/3TC first. These findings need to be confirmed in other and larger studies but point toward the possible benefit of starting with ddI/d4T and saving AZT/3TC for a later regimen if needed.
Many Questions Remain Unanswered
Among the more important unanswered questions are the degree to which initial selection can be improved by using resistance testing, the benefits and risks of a two-pi initial regimen and whether or not a regimen containing both a pi and an NNRTI is a superior first line therapy.
Other debates concern the best point at which to switch, when to switch just one or two rather than all drugs in a failing regimen and the role of "intensification" (adding more drugs or larger doses) as an alternative to changing drugs.
Summary
Even though we only know a fraction of what we'd like to know, think about backup regimens and discuss them with your provider. This is just one aspect of the choice, however. Tolerability and ability to meet the adherence requirements are at least as important. The first regimen is almost always the one we get most benefit from. Make the best choice you can.
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ÆGIS is made possible through unrestricted grants from Roxane Laboratories, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.
This information is designed to support, not replace, the relationship that exists between you and your doctor.