Darunavir/ritonavir most durable boosted protease inhibitor in European patients, especially those switching treatment for any reason

Darunavir/ritonavir (DRV/r) is the most durable boosted protease inhibitor for antiretroviral therapy (ART)-experienced people, investigators from the EuroSIDA cohort report in HIV Medicine. People switching treatment to a DRV/r-containing regimen had a significantly lower risk of virological failure and/or treatment discontinuation compared to people 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. “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 people, 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.

Glossary

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

salvage therapy

Any treatment regimen used after a number of earlier regimens have failed. People with HIV who have experienced side-effects and/or developed resistance to many HIV drugs receive salvage therapy, sometimes consisting of a large number of medications.

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

Investigators from the EuroSIDA study wanted to determine the long-term durability of combinations containing these drugs. They, therefore, designed a study involving 5678 people 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 participants 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 individuals 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 people taking DRV/r compared to those 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%). People in this sub-group were followed for a median of 40 months, with 16% experiencing virological failure and 51% meeting the composite end-point. The PI/r was discontinued in 82% of people meeting the composite end-point. The median time to virological failure was significantly longer for individuals taking DRV/r compared to the other regimens. Over three years, 6% of people taking DRV/r experienced virological failure, compared to 14% of individuals taking ATZ/r and 21% of people 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. Participants had previously taken a median of two PI-containing regimens. Virological failure was observed in 34% of people 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). People 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 people. “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.”

References

Santos JR et al. Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe. HIV Medicine, online edition. DOI: 10.1111/hiv.12581 (2018).