Doctors in South Africa have reported the first case of Kaletra (lopinavir/ritonavir) failure in a protease inhibitor-naïve individual to be associated with a pattern of protease resistance mutations that confer cross-resistance to other protease inhibitors, despite apparently excellent adherence. The case is reported in a letter featured in the latest issue of the journal AIDS.
Kaletra’s dominance of the HIV marketplace over the past few years has stemmed from excellent trial and real-life results regarding its control of HIV as first-line therapy. In fact, so few people have failed first-line Kaletra that researchers have been unable to identify any HIV mutation patterns that are unique to lopinavir.
Just over three years ago, a 25-year-old woman accessed Kaletra as part of her initial HAART regimen through Abbott’s Early Access Programme. She had previously received two weeks of d4T/ddI boosted with hydroxyurea, which she stopped due to skin problems. Her baseline CD4 cell count in June 2000 was 282 cells/mm3 and her viral load was 325,000 copies/ml. She began Kaletra, AZT and 3TC in November 2000, and after 16 weeks her viral load was below 50 copies/ml.
A year later, her viral load was still undetectable, and her CD4 count had risen to 395 cells/mm3. After two years, however, even though her CD4 count had risen further to 451 cells/mm3, her viral load was 908 copies/ml. No drug interactions were found, and the woman was given intensified adherence counselling, despite self-reported adherence of greater than 95%. After five months, her viral load had increased to 16,200 copies/ml and her CD4 count remained stable at 451 cells/mm3. Her lymph nodes were enlarged and tender (generalised lymphadenopathy) although no pathogen was found. A month later, her viral load was 12,800 copies/ml even though the woman claimed to have been completely adherent in the previous month. The lymphedenopathy was then assessed as having been caused by her raised viral load.
After resistance testing was performed, the woman changed to nevirapine-based HAART, although the doctors do not report how successful this therapy was in controlling viral load. There is evidence that HIV with reduced susceptibility to lopinavir shows high level cross-resistance with indinavir and ritonavir, intermediate-level cross resistance to amprenavir and susceptibility to saquinavir.
Samples from November 2000 and July 2003 (when the woman was still on her failing regimen) underwent genotype testing using Truegene in South Africa. The initial sample showed M36I and L63P mutations, which are naturally occurring mutations (polymorphisms) in HIV-1 subtype C, with which this woman was infected. The sample on-treatment included the following protease mutations: M36I, I54V, L63P and V82A. The first three are considered to be minor Kaletra mutations, although the latter confers resistance to all protease inhibitors (PIs).
The PI sequences were then sent to the Stanford database for drug resistance, which identified an additional mutation prior to therapy, I93L, a common polymorphism associated with PI resistance in the presence of other mutations. Additional mutations identified in the on-treatment sample included L33F as well as the I93L seen in the pre-treatment sample. L33F is selected during treatment with ritonavir, amprenavir, lopinavir and the lipid-lowering drug atorvastatin, but its effect on PI sensitivity is unknown.
In addition, M184V – associated with 3TC resistance – was seen in the failing regimen.
The authors conclude that “this appears to be a failure of Kaletra therapy as a result of the accumulation of multiple PI and the M184V mutation.” They add that the naturally-occurring polymorphisms found in the woman's HIV may have contributed to this, although poor adherence cannot be discounted.
This case report suggests that prior to starting therapy, resistance testing may be useful even when acquired resistance is not suspected, in order to rule out any naturally occurring polymorphisms that may reduce sensitivity to HAART regimens. This, of course, is only likely to be possible in well-resourced settings.
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Conradie F et al. Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient. AIDS 18 (7), 1084-5, 2004.