Minor protease inhibitor (PI) mutations are very common among treatment-naïve patients infected with HIV-1 but their impact on treatment outcome is poorly understood. The prevalence of different minor PI mutations among treatment-naïve patients varies largely and is highly dependent on the HIV-1 subtype. Some minor PI mutations occur as natural polymorphisms whereas others do not occur in the absence of PI therapy.
Minor PI mutations do not lead to high level resistance when occurring alone but they either improve the viral fitness or increase the drug resistance level in the presence of major PI mutations. Minor PI mutations are therefore also called secondary or accessory mutations.
It was assumed that minor PI mutations among treatment-naïve patients might facilitate the emergence of major PI mutations and therefore lead to a worse therapeutic response to PIs. Other studies analyzing this issue were quite controversial. Perno et al. found evidence that the presence of minor PI mutations, particularly at position 10 and 36, lead to early treatment failure and to a higher number of acquired major PI mutations at the time of treatment failure. Other studies found no evidence for an impaired treatment outcome. All these studies are limited by a rather small sample size and mainly focus on response to unboosted PI therapy which is no longer recommended.
Therefore, we aimed studying the impact of minor PI mutations on virological outcome in first-line antiretroviral therapy (ART) using the dataset of the Swiss HIV Cohort Study (SHCS).
Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential.
To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs.
We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0–1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5–1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome.
The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals.