July 14, 2004
Resistance to NNRTIs and PIs is known to develop at different rates because of what is referred to as the resistance threshold for resistance development. It is also known that for NNRTIs, high-level, drug- and class-specific resistance can develop with just a single mutation (such as K103N). With PIs, on the other hand, it usually takes the accumulation of several mutations (except with nelfinavir [NFV, Viracept] and the development of the D30N mutation) to develop high-level resistance.
Bangsberg's group followed 108 marginally housed patients for this study. Adherence was quantified by monthly, random pill counts that were performed wherever patients were known to be staying over the course of 1 year. Genotypic resistance testing was performed. For those with detectable viral loads, resistance was defined as the identification of one or more primary resistance codons. Patients with undetectable levels of viral load were considered to have sensitive virus. Of the 108 patients on treatment, half were on NNRTIs and half were on PIs. The mean age was 44 years, 85% were male, 60% were nonwhite, the mean CD4+ cell count was 214 cells/mm3, and patients had on average 20 months of prior antiretroviral exposure. Two thirds of the NNRTI patients were receiving nevirapine (NVP, Viramune), and two thirds of the PI patients were receiving nelfinavir. None of the patients were receiving a boosted PI.
In general, a greater proportion of the patients on NNRTIs had undetectable viral loads compared to those on PIs, even when adherence was <80%. However, among patients with detectable viral loads, the prevalence of NNRTI mutations was significantly higher than that of PI mutations (67% vs. 21%) in patients who had the lowest adherence rates (0%-55%), which was also highly correlated with lower adherence to NNRTIs.
These findings are somewhat surprising, though not unexpected. NNRTIs are usually administered once daily and have relatively long half-lives. Patients would be expected to be more adherent to once-daily dosing regimens because of simplicity. PI-containing regimens usually have more complex twice-daily dosing schedules, and are therefore expected to be adhered to less.
The difference between NNRTIs and PIs in terms of the number of patients with undetectable viral load levels may also be a reflection of the PIs that were used. Ritonavir (RTV, Norvir)-boosted PI regimens might be expected to be better at achieving undetectable viral loads and decreasing the possibility of developing resistance as long as high adherence rates were maintained, but these boosted regimens were not used in this study.
It is unclear whether the outcome would have been different in patients who were treatment naive and just starting treatment, compared to patients with extensive prior treatment history. One could also argue that studying adherence and resistance development in marginally housed patients does not simulate other clinic-based patients who are housed. However, Bangsberg's group has also previously reported that homeless or marginally housed patients do not differ in their rates of adherence or prevalence of resistance compared to patients who are housed. This study emphasizes the importance of maintaining the highest level of adherence that is practical for a given patient, in order to prevent the development of resistance to HIV medications, specifically NNRTIs.
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