The Body Covers: The 45th Interscience Conference on Antimicrobial Agents and Chemotherapy
Rare Case of PI Resistance After Failure of First-Line Boosted Fosamprenavir
December 17, 2005
Drug resistance is frequently a major obstacle to the long-term durability of combination treatments for HIV. The emergence of drug resistance is often accompanied by cross-resistance to other HIV drugs and the potential loss of future treatment options. Previous clinical studies of ritonavir (RTV, Norvir)-boosted protease inhibitors (PIs) -- such as lopinavir (LPV), indinavir (IDV, Crixivan), saquinavir (SQV, Fortovase, Invirase) and fosamprenavir (FPV, 908, Lexiva, Telzir) -- have strongly suggested that first-line boosted PIs offer distinct advantages over non-nukes and unboosted PIs in protecting patients from the emergence of drug resistance.
Among the relatively few patients who did experience treatment failure, only limited drug resistance was detected -- and only to the nucleoside components of treatment. Hence case reports of PI resistance emerging following failure of first-line boosted PIs have generated interest.
In recent months, cases of new PI resistance after failure of boosted lopinavir or boosted atazanavir (ATV, Reyataz) have been reported.
The current poster presentation by Paul Sax from Brigham and Women's Hospital in Boston, Mass., and collaborators from GlaxoSmithKline (GSK) describes the first case of PI resistance after failure of ritonavir-boosted fosamprenavir dosed once daily in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC, Ziagen) and lamivudine (3TC, Epivir), both dosed twice daily.
The patient had a very high initial viral load of nearly 400,000 and a CD4+ cell count of 162. Over the first 72 weeks of treatment, the patients viral load remained at undetectable (<50 copies/mL) levels and the patient's CD4+ cell count rose to over 600 cells.
Despite excellent adherence, the patients viral load increased to levels between 400 and 50 copies (well below the range necessary for resistance tests to be performed) over the next 72 weeks.
Finally, with a viral load just below 1,000 copies, a resistance test revealed the emergence of new drug resistance, including NRTI resistance mutations (M184V and L74V), PI resistance mutations (M36L, M46I and I50V) and phenotypic resistance to all three drugs in the regimen.
Retrospective special resistance testing (not available commercially) performed by the GSK virology team showed the telltales of resistance emerging earlier, with viral loads in the low hundreds. Of note, despite the emergence of virus and resistance, the patient was able to maintain his CD4+ cell count between 500 and 600 cells, over 400 cells higher than at baseline.
At 171 weeks, the patient switched to a new treatment regimen of zidovudine/lamivudine (AZT/3TC, Combivir) + tenofovir (TDF, Viread) + ritonavir-boosted atazanavir, which resulted in re-suppression of the patients viral load to undetectable levels.
How should patients and healthcare providers view this and other case reports of PI resistance after first-line boosted PIs? Does this mean that conclusions about the resistance differences of boosted PIs are incorrect?
As articulated by Trevor Hawkins of Santa Fes Southwest CARES clinic, the very fact that a single case like this one receives attention highlights just how rare these events are. With thousands of patients on first-line boosted PIs, the number of reported cases with PI resistance can still be counted on one hand.
Taken together, I believe that such cases illustrate how important it is to consider each HIV-infected person individually, and to monitor adherence and viral load data closely.
Persistent low-level viral loads should trigger consideration of the emergence of resistance and, when possible, drug resistance testing should be used to guide treatment decisions. I dont think that the extremely rare possibility of PI resistance after failure of first-line boosted PI treatment will fundamentally alter how I or my patients view their treatment options.
Authored by: PE Sax, F Xu, M Tisdale, R Elston
Affiliations: Brigham and Women's Hosp., Boston, MA, GlaxoSmithKline, Stevenage, United Kingdom
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