Equivalent efficacy with lower dose darunavir

1 December 2014. Related: Antiretrovirals, PK and drug interactions.

Polly Clayden, HIV i-Base

A reduced dose of darunavir boosted with ritonavir was effective in two reports from Italy and Spain. [1, 2]

Dose optimisation strategies aim to reduce the cost and possibly the toxicity of antiretroviral treatment (ART) while maintaining its efficacy. [3]

In a letter to the Journal of Antimicrobial Chemotherapy – published as an advance access article on 8 October 2014 – Massimiliano Lanzafame and colleagues described the efficacy of 600 mg darunavir boosted with 100 mg ritonavir (DRV/r 600/100 mg) once daily in a cohort of 26 HIV positive adults.

Twelve of the cohort were women and the remaining 14 men; their age ranged from 21 to 53 years. Twelve participants were treatment-naive (Group 1) and received DRV/r 600/100 mg once daily in regimens with tenofovir/FTC (n=9) or abacavir/3TC (n=3). Seven had been virologically suppressed on a previous regimen but due to reasons other than virological failure had switched to DRV/r 600/100 mg once daily (Group 2) plus tenofovir/FTC (n = 2), abacavir/3TC (n=2), nevirapine (n=1) or AZT/3TC (n=1), and one participant received DRV/r 600/100 mg monotherapy once daily. Seven were treatment experienced (Group 3) with a detectable viral load, that had switched to DRV/r 600/100 mg once daily plus tenofovir/FTC (n=5), abacavir/3TC (n=1) or raltegravir (n=1).

Group 1 had a mean baseline viral load of 134,024 copies/mL (range 4526-397,932); after a mean follow-up of 27.4 months (range 12-33), 11/12 had undetectable viral load (<20 copies/mL). The mean pharmacokinetic (PK) DRV trough level in this group was 2920 ng/mL (range 1268-4562).

PK samples were collected 24 hours after the last dose of DRV/r. The researchers noted that one participant had virological failure after 14 months (39,300 copies/mL) but no DRV-associated resistance was detected. His viral load was suppressed again following a dose adjustment to DRV/r 600/100mg twice daily.

Group 2 participants were virologically suppressed for a mean of 32.8 months (range 21-54). A PK trough level was only available for one participant (3442 ng/mL).

Group 3 participants had mean baseline viral load of 24,167 copies/mL (range 112-111,426), five were suppressed for a mean of 46.2 months (range 31-67), one participant interrupted ART for 3 months, then restarted and achieved viral load 628 copies/mL after 5 weeks of treatment. The researchers noted that this participant had the I47V mutation. Another participant from Group 3 failed after 42 months (3930 copies/mL) and re-suppressed after the dose was adjusted to DRV/r 600/100 mg twice-daily.

PK trough levels were available for three participants from Group 3 and these were a mean of 2502 ng/mL (range 844-4518).

The researchers wrote: “In our clinical experience of 26 patients, the use of darunavir/ritonavir at a dose of 600/100 mg once-daily led to sustained HIV RNA suppression in 23 patients with acceptable pharmacokinetic exposures to darunavir”.

Results from the related DRV600 study were presented at the 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy in May 2014.

This study, authored by José Moltó and colleagues, compared the efficacy and safety of a reduced dose with the standard dose of DRV in 100 virologically suppressed (<50 copies/mL) participants. It was a multicentre, randomised, open-label clinical trial.

Study participants were on stable DRV/r 800/100mg once-daily plus two NRTIs. DRV resistance, or prior virologic failure while receiving protease inhibitor-based ART, were exclusion criteria.

The participants were randomised to continue on the standard DRV/r 800/100mg once-daily dose or to switch to 600/100 mg once-daily. Two consecutive viral load tests >50 copies/mL or discontinuation of treatment by week 48 was defined as failure.

Across both study arms, 81% of participants were men, they were approximately 45 years of age, and 20% were co-infected with HCV. Their mean CD4 count at baseline was 562 cells/mm3 (SD 303). Approximately 65% received DRV/r plus tenofovir/FTC and 35% abacavir/3TC.

Two participants in the DRV/r 800/100mg arm and three from the DRV/r 600/100mg arm developed virologic failure by week 48. One participant from each arm was lost to follow-up and one from the DRV/r 600/100mg arm died of septic shock.

In intent-to-treat analysis, the proportion of patients with viral load<50 copies/mL at week 48 in was 90% in the DRV/r 600/10 mg and 94% in the DRV/r 800/100mg arm, difference -4% (90% CI -12.9 to 4.9), p=0.46). This met protocol defined non-inferiority: 95% CI for delta less than -15% (80% power).

CD4 cell counts remained stable during follow-up in both arms and were similar, p=0.415. DRV trough levels were comparable between the two arms, p=0.776.

Adverse events occurred in 12 participants receiving DRV/r 800/100 mg and 7 receiving 600/100 mg. These were gastrointestinal, dyslipidaemia and other (<5%), occurring in 6 and 4, 5 and none, and 1 and 3 participants, in the DRV/r 800/100 mg and 600/100 mg arms respectively. There was a modest difference in total cholesterol and triglycerides (both slightly lower in the 600/100 mg arm) but neither was significant: respectively p=0.284 and p=0.157.

The study investigators calculated that lower dose of DRV could represent an approximate saving of 1000 Euros per patient per year according to Spanish antiretroviral prices. They noted that four patients on DRV/r 600/100 once daily = one free compared to dosing 800/100 mg once daily.

Comment

In two pivotal trials of DRV/r (ODIN and TITAN), there was evidence of negative PK/PD, that is, people with higher concentrations of DRV have significantly lower overall efficacy. [4, 5] These correlations have been seen for the 800/100 once-daily and 600/100 mg twice-daily doses.

Although the numbers in the second study were small and did not reach statistical significance, it is possible that there might be an improvement in tolerability with the lower dose with a larger sample size. DRV/r has shown worse overall safety than dolutegravir in the head-to-head Flamingo study, suggesting that there is the potential to improve its safety profile. [6]

The two reports described above (as well as suggestions from the early DRV/r trials) add weight to the argument that optimised DRV/r dosing needs to be thoroughly investigated, particularly for low-income countries, where cost savings could be considerable.

Various plans are being discussed to look at DRV/r 400/100 mg once daily, with the aim to develop a simplified one pill, once-daily second-line treatment (co-formulated with dolutegravir) for people failing the current recommended first-line regimen.

Donors need to ensure that the research to generate the data to inform this development programme is done sooner rather than later.

References:

1. Lanzafame M et al. Efficacy of a reduced dose of darunavir/ritonavir in a cohort of antiretroviral naive and experienced HIV-infected patients: a medium-term follow-up. J. Antimicrob. Chemother. 8 October 2014. doi: 10.1093/jac/dku390.
   http://jac.oxfordjournals.org/content/early/2014/10/07/jac.dku390.extract
2. Moltó J et al. Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients. 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. 19-21 May 2014. Washington DC. Oral abstract_02.
   http://regist2.virology-education.com/2014/15HIVHEP_PK/3_Molto.pdf (PDF)
   http://regist2.virology-education.com/abstractbook/2014_4.pdf (PDF)
3. Clayden P. Fit for purpose: treatment optimisation. i-Base/TAG Pipeline Report. 19 July 2014.
   https://i-base.info/htb/26960
4. Cahn P et al. Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS. 24 April 2011;25(7):929-39.
5. Bánhegyi et al. Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN. Curr HIV Res. March 2012;10(2):171-81.
6. Clotet B et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. The Lancet. 28 June 2014; 383(9936): 2222 – 2231.
7. Clayden P. Pill A, Pill B: simplified second-line treatment for low-income countries. HTB. 1 August 2014.
   https://i-base.info/htb/27169