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Darunavir/ritonavir for ART-experienced patients

Darunavir/ritonavir is the most durable boosted protease inhibitor for antiretroviral (ART)-experienced patients, investigators from the EuroSIDA cohort report. Patients switching treatment to a darunavir/ritonavir (DRV/r)-containing regimen had a significantly lower risk of virological failure and/or treatment discontinuation compared to patients changing to combinations including either atazanavir/ritonavir (ATZ/r) or lopinavir/ritonavir (LPV/r).

“When we examined endpoints that counted PI/r [protease inhibitor/ritonavir] discontinuation as treatment failure, there was a clear superiority of DRV/r over LPV/r and ATZ/r,” write the authors led by JR Santos at the Fight Against AIDS Foundation, Germans Trias i Pujol University Hospital, Barcelona, Spain. “Although the risk of VF (virological failure) was similar for DRV/r, ATZ/r and LPV/r in ART-naïve patients, the risk of PI/r discontinuation for any reason was lowest for DRV/r. In treatment-experienced patients who initiated PI/r either as a result of a switching strategy with a suppressed VL [viral load] or as a salvage treatment, the percentage of patients who experienced VF and the risk of VF or PI/r discontinuation were lower for DRV/r compared with both LPV/r and ATZ/r.”

The ritonavir-boosted protease inhibitors atazanavir, darunavir and lopinavir remain important treatment options for HIV-positive patients, especially as alternative regimens and as second-line therapy. Darunavir/ritonavir is the only boosted protease inhibitor recommended as a preferred option for first-line antiretroviral treatment in the European AIDS Clinical Society (EACS) 2017 treatment guidelines.

Investigators from the EuroSIDA study wanted to determine the long-term durability of combinations containing these drugs. They, therefore, designed a study involving 5678 patients who initiated treatment based on ATZ/r, DRV/r or LPV/r between 2000 and 2013.

End-points were time to virological failure (two consecutive viral loads above 200 copies/ml) and virological failure/treatment discontinuation. Data were also gathered on CD4 cell response.

The patients were divided into three groups according to their HIV treatment history: ART naïve (8%); ART switching with viral suppression (44%); ART switch with detectable viral load (48%).

Analysis of the ART-naïve patients showed that 51% started a LPV/r containing regimen, 28% a ATZ/r-containing combination and 21% a DRV/r-based regimen. These patients were followed for a median of 28 months, and during this time 18% experienced virological failure, with 43% meeting the end point of virological failure/treatment discontinuation. Boosted protease inhibitor treatment was discontinued in 80% of these individuals. The time to virological failure was longer in patients taking DRV/r compared to patients taking the other two regimens (p = 0.004). However, there was no difference between the regimens for virological failure/discontinuation. CD4 cell response did not differ between the combinations.

LPV/r was the most widely used drug in the switch group (41%), followed by ATZ/r (33%) and DRV/r (26%). Patients in this sub-group were followed for a median of 40 months, with 16% experiencing virological failure and 51% met the composite end-point. The PI/r was discontinued in 82% of patients meeting the composite end-point. The median time to virological failure was significantly longer for patients taking DRV/r compared to the other regimens. Over three years, 6% of DRV/r patients experienced virological failure, compared to 14% of individuals taking ATZ/r and 21% of patients treated with LPV/r. Switches to LPV/r (HR = 2.56; 95% CI, 1.62-4.05, p < 0.001) or ATZ/r (HR = 1.98; 95% CI, 1.27-3.08, p < 0.001) were each associated with a higher risk of virological failure than DRV/r. Other predictors of virological failure included higher baseline viral load. The CD4 response was similar across the three combinations.

In the salvage sub-group, 69% started LPV/r, 22% ATZ/r and 9% DRV/r. Median follow-up was for 35 months. Patients had previously taken a median of two PI-containing regimens. Virological failure was observed in 34% of patients and 66% reached the composite end-point (70% treatment discontinuation). Median time to virological failure was significantly longer in the DRV/r group (p < 0.001). Patients taking this drug had a 14% risk of virological failure over three years, compared to 21% for ATZ/r and 38% for LPV/r. When the investigators examined the composite end-point, starting LPV/r or ATZ/r-based therapy was associated with a higher risk of virological failure/discontinuation than DRV/r (both comparisons, p < 0.001). CD4 cell changes did not differ between the three regimens, though immune recovery was associated with a higher nadir CD4 cell count, a lower viral load and resistance testing. The investigators believe their results show the superiority of DRV/r in treatment-experienced patients. “Consistently, our results show a lower risk of VF and treatment discontinuation for any reason or because of toxicity in patients starting DRV/r compared with those initiating ATZ/r or LPV/r, reflecting the well-known better efficacy and safety profile of DRV/r and of ATZ/r compared with LPV/r-based regimens,” they comment. But they also acknowledge that “confounding by indication for switching cannot be ruled out.”

Objectives: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens.
Methods: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches.
Results: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART.
Conclusions: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

JR Santos, A Cozzi-Lepri, A Phillips, S De Wit, C Pedersen, P Reiss, A Blaxhult, A Lazzarin, M Sluzhynska, C Orkin, C Duvivier, J Bogner, P Gargalianos-Kakolyris, P Schmid, G Hassoun, I Khromova, M Beniowski, V Hadziosmanovic, D Sedlacek, R Paredes, JD Lundgren


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