I have a 53-year-old male patient diagnosed HIV+ in 1993. He has been previously treated with multiple agents. The patient presented to me on nevirapine, nelfinavir, saquinavir and ddC. Viral load was 285,000 copies/mL; CD4 count was 5 cells/µL. Genotyping was done and showed resistance to all components of this regimen. The patient’s virus had no mutations associated with resistance to 3TC, d4T, adefovir, amprenavir or lopinavir, but had mutations associated with resistance to all other drugs. The patient was placed on d4T, 3TC, and lopinavir. Repeat labs 3 weeks after change of therapy found viral load of 63,647 and CD4 count of 26 cells/µL. Repeat labs 6 weeks after change shows viral load >500,000, CD4 count of 47 cells/µL. Any thoughts?
Dr. Brian Conway responds: This is a difficult, but unfortunately all too typical case. This individual has been treated with multiple agents and regimens in the past, and has likely acquired a range of mutations conferring resistance to NRTIs, NNRTIs and PIs. One point to be made about the genotypic resistance test result obtained while on nevirapine, nelfinavir, saquinavir and ddC is that the absence of resistance mutations to a drug such as 3TC must be interpreted cautiously. If the patient previously received 3TC, it may be that the M184V mutation is present as a minority species in the circulation, and is not currently being detected due to the absence of drug pressure. It would quickly re-emerge once appropriate drug pressure was applied (i.e., 3TC therapy was re-initiated). Thus, resistance tests are most valuable in evaluating susceptibility to the drugs included in the current regimen.
The issue of lopinavir is also interesting (and will be covered in detail in an upcoming article on HIVresistanceWeb). Briefly, there is no single primary mutation that confers resistance to this agent. Rather, it appears that as mutations accumulate in the protease gene, lopinavir susceptibility is decreased in rough proportion to the number of mutations that are present. Lopinavir may still be active as long as the "mutation score" does not exceed 7 or so.
Now, back to the patient at hand. I do not think there is a clear, single answer. I would favor a triple class regimen, with the goal of therapy being to reduce plasma viral load as much as possible ("undetectable" may be unrealistic) and to achieve some degree of immune reconstitution. As NRTIs, I would use 3TC (if only to ensure that the M184V mutation persists, as some have argued this may be beneficial) along with another agent, such as abacavir. I would add the NNRTI efavirenz, as the patient is naive to this agent and some nevirapine-resistant isolates remain sensitive to it. Further, it appears that isolates with many NRTI resistance mutations may be hypersusceptible to NNRTIs, at least in vitro. As a PI, I would select lopinavir, at a dose of 4 capsules twice daily, to maximize drug levels, especially in the presence of efavirenz, which reduces lopinavir trough levels by 30% or more. I would emphasize to the patient that compliance with this regimen is key in order to maximize the chances of success. Good luck!!! (3/12/2001)
