1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

MULTIPLE CONCURRENT RT AND PROTEASE MUTATIONS AND MULTIDRUG RESISTANCE IN HEAVILY TREATED HIV-1-INFECTED PATIENTS

Antiviral Therapy 1997;2 (Suppl 5):25 (abstract no. 39)

RW Shafer, MA Winters and TC Merigan
Center for AIDS Research, Stanford University, Stanford, California, USA

The success of highly active three-drug combinations in suppressing HIV-1 in previously untreated patients is due in part to the high genetic barrier to resistance imposed by these regimens. The benefits of combination therapy, however, are decreased in previously treated patients whose isolates often already have developed some drug-resistance mutations. We examined HIV-1 isolates of four patients who began anti-HIV therapy prior to the advent of potent three-drug combinations and were unable to achieve plasma HIV-1 suppression despite therapy with multiple different drug combinations. Dideoxynucleotide chain- termination sequencing was done on HIV-1 RT and protease sequence from three time points in three patients and from one time point in a fourth patient who died during the study. Drug susceptibility testing was done on isolates from three patients using a PBMC-based susceptibility assay. Triplicate tests were done with zidovudine, didanosine, lamivudine, stavudine, nevirapine, saquinavir, indinavir and nelfinavir. Ritonavir was not tested because isolates resistant to indinavir are usually also resistant to ritonavir.

The four patients received 4-9 years of anti-HIV drug therapy. Each patient received four or more nucleoside analogue RT inhibitors and three protease inhibitors (saquinavir, indinavir, ritonavir). None had received nelfinavir or a non-nucleoside RT inhibitor. Isolates from 4/4 patients shared six protease-resistance mutations (L10I, G48V, I54V/T, L63P/H/Q, A71V/L, V82A) and eight RT mutations (M41L, K43E/N, E44A/D, D67N, V118I, M184V, L210W, T215Y). This constellation of mutations was present at three separate time points in each of the three patients with multiple isolates. The shared mutations occurred despite a mean 6.4% protease and 5.6% RT sequence divergence between isolates from the four patients. Sequences of four biological clones from two patients confirmed the simultaneous presence of all 14 mutations in the same HIV-1 genomes. Susceptibility testing showed high-level resistance to zidovudine, lamivudine, saquinavir, indinavir and nelfinavir (100-1000-fold), low-level resistance to disanosine and stavudine (2-4-fold), and susceptibility to nevirapine.

Simultaneous resistance to nearly all available anti-HIV drugs (including four protease inhibitors) may occur. The frequency of this phenomenon is not known, though it may be particularly common in patients who began therapy prior to the availability of potent three-drug combinations. The striking concordance of mutations in these multi-drug-resistant HIV-1 isolates suggests that these sets of RT and protease mutations provide a selective advantage in a variety of genetic contexts and in the presence of multiple different drug combinations. New drugs and drug regimens that are active against isolates with these mutations should be developed.

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1997-06-25
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