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Antiretroviral Therapy
(Part XXV)

Clinical Implications of Resistance To Antiretroviral Drugs

November 21, 1997

VA Medical Center, San Francisco

Resistance Patterns

Nucleoside Analogues

Decreased susceptibility to AZT in clinical isolates of HIV variants were first reported in 1989. This was followed in subsequent years by reports of resistance to other compounds of the same class. In general, advanced-stage disease, low baseline CD4-cell count, and HIV RNA plasma level strongly predicted the development of resistance. For AZT, resistance appears to be the consequence of a stepwise accumulation of mutations at codons 215, 70, 41, 67, and 219. (The same phenomenon has been seen with some of the protease inhibitors.) For other drugs, such as didanosine and zalcitabine, the mechanisms and the molecular correlates of resistance are less clear, although a number of mutations responsible for a reduced susceptibility have been identified.

The clinical significance of resistance to some dideoxynucleosides is still not completely defined. HIgh-level resistance to didanosine, stavudine, or zalcitabine is very difficult to document. However, cross-resistance has been reported between AZT and other azido-nucleosides, ddC and ddI/3TC (with the 65 and 184 mutations involved), ddI and ddC (codon 74), d4T and ddI/ddC (codon 75), and between 3TC and ddI/ddC (codon 184). Multiple resistance to nucleoside analogues has also been observed after long-term combination therapy using these agents. The mutations mainly responsible for multiple resistance to AZT, ddI, ddC, and D4T include codons 75, 77, 116, 62, and in particular, 151.

During treatment with lamivudine (3TC), resistance occurs rapidly in vivo, and is associated with a single substitution at codon 184. Although this mutation leads to high-level resistance to 3TC and to some cross-resistance to didanosine and zalcitabine, this codon change may antagonize AZT resistance mutations, leading to a restored phenotypic sensitivity to AZT. This mechanism, however, does not seem to be effective in all cases; dual AZT/3TC resistance has also been observed. Concerns have also been raised about the use of 3TC-containing regimens as first-line therapy because of the limitations it may place on subsequent nucleoside options, particularly ddI.

A new nucleoside analogue (1592U89), with antiretroviral potency that is apparently superior to that of other available compounds, is currently under clinical development. Although data are still scarce, the main mutations associated with decreased susceptibility to this compound seem to be associated with codons 184, 65, 74, and 115. No cross-resistance to AZT or d4T is induced. However, AZT/3TC-resistant viruses are also highly resistant to 1592U89. In general, for antiretroviral-experienced patients, the virological response to this new agent varies widely with the type of antiretroviral combinations previously used by the patient, suggesting that this promising new compound might perform better as first-line therapy than as salvage therapy.


The very rapid development of resistance to non-nucleoside reverse transcriptase inhibitors, whether used in monotherapy or in double combination, suggested, until a few months ago, only a limited clinical utility for this class of compounds. However, the results of two trials (INCAS and ISS-047 studies) in which the NNRTI nevirapine was used in triple-combination regimens with nucleoside analogues, have shown that resistance to NNRTIs can be significantly delayed if viral load suppression is obtained and sustained. This is important for two reasons. One, it gives rise to the possibility that NNRTIs may be incorporated into clinical practice, adding a new class of agents to the clinical armamentarium. Two, these trial results confirm with a class of compounds other than protease inhibitors, the concept that resistance occurs as a direct consequence of viral replication.

Despite this, it is worth noting that NNRTIs are often associated by a common pattern of resistance, which may in some cases limit their sequential use. In general, although cross- resistance is a more common phenomenon among NNRTIs, with in vitro studies indicating several mutations shared by difference compounds, some new NNRTIs (DNP-266 and MKC-442) show distinct resistance profiles that may make them suitable candidates for effective subsequent therapeutic regimens. Moreover, mutually counteracting mutations have also been detected among NNRTIs; the clinical correlates of these observations are being investigated.

Protease Inhibitors

Reduced sensitivity has been reported for all tested protease inhibitors. The patterns of mutations, however, appear to be more complex than for reverse transcriptase inhibitors, with a high natural polymorphism, a larger number of sites involved, and greater variability in the temporal patterns and in the combinations of mutations leading to "phenotypic" resistance.

Mechanisms conferring resistance to protease inhibitors are an exemplary model of the Darwinian dynamics of HIV resistance. Resistance patterns may evolve from mutations that reduce inhibitor-enzyme binding to mutations with "compensatory" activity, i.e., mutations that improve the "fitness" of the virus by compensating for the disadvantageous changes in the functionality of the protease enzyme. The compensatory mutations may include new changes in the protease enzyme, mutations that drive the increased production of the "less fit" enzyme, or even mutations that modify the protein cleavage sites.

As far as the individual protease inhibitors are concerned, the codon 82 mutation is the leading one in reducing sensitivity to indinavir, although high-level resistance to indinavir develops only as a consequence of multiple codon changes. Resistance to ritonavir also seems to occur as a consequence of the accumulation of different mutations, the most relevant being 82, 46, and 84, which are also common to indinavir, confirming the cross-resistance between these two compounds. Cross-resistance has also been reported between indinavir and saquinavir. Saquinavir may have a partially different resistance profile (the main mutations being at codons 48 and 90). However, results of a recent controlled trial seem to suggest that the virological response to indinavir is rather weak in patients switched to indinavir after treatment with saquinavir.

Because we have learned we should probably avoid changing from ritonavir to indinavir or vice versa, and avoid changing from long- term saquinavir to indinavir, it appears that the emergence of broad cross-resistance between protease inhibitors, which has been feared, is indeed becoming a problem, and is complicating the design of correct sequencing of protease inhibitors in case of therapeutic failure.

Nelfinavir seems to be characterized by a distinct genetic pattern of mutations, with codons 30, 35, 36, 46, 71, 77, and 88 most frequently involved. Because 60% of viral isolates from indinavir- or ritonavir-treated patients seem also to be resistant to nelfinavir, but, conversely, nelfinavir-resistant strains seem to retain sensitivity to other protease inhibitors, nelfinavir may be a candidate for first-line use in antiretroviral-naive patients. Changing from ritonavir or indinavir to nelfinavir should therefore be avoided, whereas change from nelfinavir to ritonavir might be acceptable.

Another compound under clinical development, 141W94, also seems to be characterized by a partially different resistance profile (codons 10, 46, 47, 50, 84), although data are mainly from in vitro experiments.

A final issue -- hypothetical and still unproven -- is the possibility of increasing efficacy by using protease/protease combination regimens that would induce mutually counteracting, drug-induced mutations. This might convert the unavoidable selection of mutant viruses into an at least partially favorable phenomenon. This possibility is currently addressed by the development of a new compound (ABT-378) designed to act on ritonavir-resistant viruses.

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