Rare case of lopinavir resistance in first line treatment reported

A rare case of resistance to the protease inhibitor lopinavir has been published in a case report in the September 24^th edition of AIDS. Even though the patient developed high-level resistance to lopinavir, this did not confer extensive cross resistance to other protease inhibitors.

The case involved a 43-year-old African American was diagnosed with HIV after developing cryptococcal meningitis. At the time of HIV diagnosis, the individual had a CD4 cell count of 10 cells/mm³ and a viral load of over 65,000 copies/ml. A highly active antiretroviral therapy (HAART) regimen comprising efavirenz (Sustiva), tenofovir (Viread), AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir) was started. A genotypic resistance test before the commencement of HIV therapy found no major or minor HIV resistance mutations.

After complaining of visual hallucinations, the patient swapped efavirenz for Kaletra (lopinavir/ritonavir). At the time of this treatment change the patient had an undetectable viral load.

For unknown reasons, the patient stopped taking all his anti-HIV drugs except Kaletra. This resulted in an increase in his viral load and this led doctors to perform resistance testing.

Initially, genotypic testing revealed the presence of the V82A mutation. A repeat genotype test a month later showed that the V82A mutation was no longer present, but that V321, M46M/I, and I47A mutations had developed.

A phenotypic assay at this time found high-level phenotypic resistance to lopinavir. However, there was no resistance to ritonavir, the patient was hypersusceptible to saquinavir, and he also remained sensitive to all other protease inhibitors. The investigators also found that his HIV had a low replicative capacity.

The I47A mutation has previously been seen in laboratory studies after exposure to lopinavir and is associated with the emergence of p7/p1 (A43IV) and p1/p6 (L449F) mutation cleavage sites in gag. Although this patient did not have either A43IV or L449F mutations, he did have R429G and S45IN mutations and changes to the PTAPP domain.

A search of a database of over 70,000 samples for this resistance pattern found three examples with high-level lopinavir resistance and amprenavir (Agenerase) resistance with increased saquinavir susceptibility.

The investigators conclude that although resistance to lopinavir is difficult to generate during treatment, it is not impossible. The preferred pathway for lopinavir resistance may involve mutations at codons 47 and 32. However, this pathway appears to preserve other protease inhibitor treatment options.