Kaletra therapy fails woman with subtype C virus with multiple mutations

Graham McKerrow, HIV i-Base

The importance of studying pattern of natural polymorhisms and development of resistance in response to treatment in non-B subtypes was highlighted in a case report of a South African patients with dominant subtype C virus using a lopinavir/r (Kaletra)-based combination.

Francesca Conradie and colleagues in Johannesburg report in the 30 April issue of AIDS on the failure of Kaletra in a 25-year-old woman. The failure, they write, appears to be the result of an accumulation of multiple PI mutations and a single reverse transcriptase mutation. Kaletra is a potent antiretroviral drug with a high resistance barrier, and primary failure has not previously been described in an antiretroviral naïve patient.

This patient received treatment (stavudine, didanosine and hydroxyurea) for two weeks in June 2000 but the treatment was stopped when she developed eosinophillic folliculitis. She had a baseline CD4 count of 282 cells/mm3 and her viral load was 325,000 copies/mL. In November 2000, she was started on Kaletra, AZT (zidovudine, ZDV) and 3TC (lamivudine), and by week 16 her viral load was less than 50 copies/mL.

At one year, her viral load was undetectable and her CD4 count was 395 cells/mm3. At 2 years, her viral load had rebounded to 908 copies/mL although her CD4 count had increased to 451 cells/mm3. Self-reported adherence was greater than 95% but adherence counselling was intensified. Five months later, her viral load had increased to 16,200, and her CD4 count was still 451 cells/mm3. She had generalised lymphadenopathy with a large node in her armpit. One month later the viral load was 12,800 copies/mL. The patient said she was completely adherent in the previous month. Lymphadenopathy persisted.

After resistance studies, the regimen was changed to AZT, abacavir and nevirapine.

Viral genotyping on a stored sample from before November 2000, showed M361 and L63P mutations, which are naturally occurring polymorphisms in subtype C viruses, in the protease gene.

Viral genotyping on a sample taken on the failing regimen, showed the only reverse transcriptase mutation was M184V. The PI mutations identified were M36I, I54V, L63P and V82A. The PI sequences were sent to the Stanford database for drug resistance, which found several more mutations associated with PI treatment.

Conradie and colleagues write: “Mutations in the protease gene that are known polymorphisms but are also secondary mutations associated with PI resistance were present before starting treatment and may have made the accumulation of additional mutations more likely. In addition, poor adherence with suboptimal lopinavir levels may have contributed to the development of resistance. This observation supports the hypothesis that resistance to lopinavir requires the accumulation of a series of mutations, and demonstrates that well-described PI resistance mutations can accumulate when on lopinavir-ritonavir therapy and can contribute to virological failure. A signature mutation for lopinavir resistance was not identified.”


It is important to note that this patient primarily responded to therapy despite high viral load.

The interesting news is that mutation pattern leading to lopinavir resistance may be different in genotype C patients.

It seems strange however, that the patient did not acquire NRTI mutations beyond M184V which are usually more rapidly acquired than PI mutations in the presence of replicating virus.


Conradie F, Sanne I, Venter W et al. Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient. AIDS: Volume 18(7) 30 April 2004 pp 1084-1085

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