ABSTRACT:
One of the major problems associated with the non-nucleoside reverse transcriptase inhibitors (NRTIs) is the ability of HIV-1 to develop rapid resistance to this inhibitor class, both in vitro and in vivo. The extent and nature of the numerous NNRTI resistance mutations that occur in RT have been well documented. In general, it appears that many of these single mutations cause broad class cross-resistance. We were interested in determining the nature of NNRTI mutations and spectrum of phenotypic cross-resistance in clinical samples recently obtained for routine testing from patients in the US. In a survey of over 5000 samples using ABI sequencing, the most common NNRTI mutations were as follows: 103N (20%), 181C (14%) and 190A (7%). Of interest, significant numbers of samples with NNRTI resistance had multiple NNRTI mutations (26).
The most common double combination was 103N plus 181C plus 190A. Patterns of phenotypic cross-resistance to nevirapine, delavirdine and efavirenz were determined by recombinant virus assay in samples containing single and multiple NNRTI mutations. Of 71 NNRTI-resistant samples, 56% were resistant to all three drugs, 34% to two and 10% were resistant to a single drug. All efavirenz-resistant samples were co-resistant to nevirapine. However, there were many examples of nevirapine resistance in the absence of delavirdine or efavirenz resistance. Specific genotypes associated with resistance to nevirapine alone included 98G or 108I. Broad class cross-resistance required the accumulation of multiple NNRTI mutations, typically 103N plus 181C plus 190A and many other combinations. Thus, it is clear that distinctions occur in resistance patterns to different NNRTIs and high-level, broad cross-resistance requires multiple mutations. This is reminiscent of the mechanism of protease inhibitor broad cross-resistance.
