Page 67 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 2 of 7 Opinion Paper

Rilpivirine for the management of suppression at 48 weeks compared to efavirenz (EFV)/TDF/
HIV infection: Efficacy and tolerability FTC (both administered as a single tablet regimen [STR]) in
people living with HIV who were virologically suppressed
The efficacy and tolerability of rilpivirine compared to on a NNRTI-based regimen prior to randomisation. In
efavirenz in antiretroviral-naïve individuals was explored in the SALIF study, there were more discontinuations and
6
a phase 2b dose-finding study, in the phase 3 ECHO and treatment-limiting adverse events in the rilpivirine arm. This
4,5
THRIVE studies (data from these two registrational studies most likely reflects the effect of being switched to a new
7
were pooled for analysis at weeks 48 and 96) 8,9,10,11 and the rilpivirine-containing regimen, as opposed to continuing
single-tablet regimen (STaR) study. In all of these studies, on an efavirenz-based regimen (randomisation ensured a
12
with the exception of the phase 2b dose-finding study, balance of participants who were previously on nevirapine
rilpivirine was associated with fewer adverse events leading regimen across both arms, approximately 45%). 16
to treatment discontinuation than efavirenz (including
neuropsychiatric events, rash and dyslipidaemia). Observational data from the Swiss HIV cohort followed up
patients who were initiated on or switched to the RPV/TDF/
The phase 2b study explored three different doses of FTC STR for two years. The main reasons for switches were for
rilpivirine compared to efavirenz 600 mg. The rilpivirine regimen simplification or efavirenz-related neuropsychiatric
doses explored were 25 mg, 75 mg and 150 mg, and the study adverse events. The study population were mainly
was powered to detect a dose response across the arms at a antiretroviral-experienced and virologically suppressed. At
5% significance level. The study was extended to follow 24 months, 96% of treatment-experienced and 100% of
5
participants out to 192 weeks from 96 weeks and found treatment-naïve patients remained virologically suppressed.
similar viral suppression and immunological efficacy across Among those who were switched because of neuropsychiatric
the rilpivirine and efavirenz arms, and the rilpivirine 25 mg adverse events, 78.3% experienced improvement at 12
17
dose was taken forward into phase 3. months. These results were similar to those of other
observational cohorts assessing switches to the STR. 18,19,20
The ECHO and THRIVE studies demonstrated non-inferior
efficacy of rilpivirine compared to efavirenz overall. In summary, rilpivirine has lower efficacy than efavirenz in
However, in these studies, which compared rilpivirine patients with high viral loads at ART initiation. This limits
25 mg with efavirenz 600 mg, both in combination with two the usefulness of rilpivirine-based regimens in first-line ART
nucleoside reverse transcriptase inhibitors (NRTIs), rates of in resource-constrained settings. Most large programmes in
virological failure and emergence of viral resistance lower- and middle-income countries do not routinely
were higher in individuals with high baseline viral loads quantify viral load at baseline, and adding this test in large
(> 100 000 copies/mL) receiving rilpivirine than efavirenz at programmes would add considerable treatment costs.
10
13
both 48 and 96 weeks. In the ECHO and THRIVE studies, However, switch studies of virologically suppressed patients
23/686 (3%) of participants taking rilpivirine discontinued have shown good efficacy of rilpivirine in maintaining
because of an adverse event, versus 52/682 (8%) taking suppression. 16,17,18,19,20,21 Rilpivirine may therefore be a useful
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efavirenz. In a systematic review of randomised clinical option for patients needing to switch for tolerability issues,
trials, comparing safety and neuropsychiatric adverse events especially those relating to neuropsychiatric adverse events.
of efavirenz with other agents, participants had double the
risk of discontinuation because of adverse drug reactions Rilpivirine for the management of
with efavirenz-containing ART regimens than with HIV infection: Other important
rilpivirine-containing regimens (RR: 2.0, 95% confidence
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interval [CI]: 1.0 to 3.8; RD: 4.1, 95% CI: 1.3 to 6.8). Side considerations for programmatic
effects of rilpivirine were uncommon; the two most common settings
side effects were headache in 2% and insomnia in 2% of Drug interactions
participants. 15
Rilpivirine is mainly metabolised by cytochrome P450 3A4,
In the STaR study, both rilpivirine and efavirenz were rendering it vulnerable to the effects of drugs that are
administered in combination with tenofovir disoproxil cytochrome P450 3A4 inhibitors or inducers. Its solubility
fumarate (TDF) and emtricitabine (FTC) as single-tablet and therefore absorption are pH dependent, requiring a low
regimens. STaR stratified participants at randomisation pH. Because of this, rilpivirine cannot be co-administered
according to their baseline viral load (≤ or > 100 000 copies/ with proton pump inhibitors, and when prescribed with
mL) and demonstrated superiority of the rilpivirine arm at histamine-2 receptor antagonists and antacids, doses need to
weeks 48 and 96 overall at viral loads below 100 000 copies/ be separated to allow rilpivirine absorption. 22
mL (for higher viral loads, the rilpivirine arm was non-
inferior). 12,15 Rilpivirine cannot be administered with rifampicin-containing
regimens, which are still the mainstay of tuberculosis
The switching at low HIV-1 RNA into fixed-dose combinations management in many lower- and middle-income countries
(SALIF) study demonstrated non-inferior efficacy of where the burden of tuberculosis is the highest. Rifampicin may
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rilpivirine (RPV)/TDF/FTC in maintaining virological reduce the rilpivirine concentrations substantially, putting
http://www.sajhivmed.org.za 60 Open Access