Consider this situation. A patient who started on AZT monotherapy back in 1992, and was on it for several years (shortly after seroconverting). Approximately four years later 3TC was added (Combivir), and then 1 year later when the viral load was noted to be slightly over 500, nelfinavir was added. The patient remains NNRTI-naive. Medicine compliance has always been very good.
In Feb of 2000, full testing including resistances were done. CD4 count was 1400 (43%), CD8 count was 1350 (41%), ratio 1.0. Viral load was 128, and resistance mutations were L10V, K20R/M, and L63P for PIs and K70R and M184V for NRTIs. No mutations were noted for NNRTIs. At the time, given how stable he and his numbers are, we opted to follow him and retest in approx 6 months.
Ten months later, viral load was 425, CD4 was 1600 (48%), CD8 1225 (37%) with a ratio of 1.3. So what to do: the patient has yet to ever test with an undetectable viral load, which would really be the ultimate goal!
Does the M184V really "cancel out" the affects of the K70R, in which case one should leave him on AZT? But should one also leave him on 3TC to continue to select for M184V,or would it make more sense to just switch over to AZT in the hope that we might select for wild type, get rid of M184V, and reselect for genotypic sensitivity to the other NRTIs which technically the patient doesn't have with M184V.
My thoughts would be to change this patient to a regimen of AZT and nelifinavir but substitute efavirenz for 3TC. But I am truly unsure whether it makes more sense to attempt to "keep" M184V and just add efavirenz to the current regimen -- or to completely change the regimen around. Any suggestions on what would make the most sense from a resistance standpoint? Where do you think the increased viral load is coming from?
Dr. Mark Wainberg responds: My response is as follows on the issue of M184V:
There is a growing body of evidence that the M184V mutation can impact negatively on HIV fitness and simultaneously resensitize, at least in relative terms, to AZT and d4T. However, this latter effect may be of limited duration, and may be lost as other drug resistance-related mutations are accumulated.
It probably makes little sense to switch this patient back to AZT, as resistance was already apparent with this drug, and, it is well established that resistance-conferring mutations never disappear. In view of accumulating data on AZT/d4T cross-resistance, d4T should probably excluded from future therapy as well.
The increased viral load that your patient is experiencing does not seem to be unmanageable in regard to current situation. However, if viral load goes above 1000 and CD4s come substantially down, a change in therapy could be contemplated to include an NNRTI. Based on the above, you should certainly consider maintaining the 3TC, although, abacavir could also be contemplated, since it too can select for M184V yet simultaneously exert an anti-viral effect, as long as no substantial accumulation of nucleoside-associated mutations has occurred.(6/1/2001)
