The latest antiretroviral drug against HIV-1 infection, rilpivirine, is a safe and effective alternative to the widely used efavirenz in combination with standard background therapy, in patients beginning HIV treatment for the first time. Furthermore, the rilpivirine regimen is better tolerated with fewer side effects. The conclusions of two large international randomised trials published in a special HIV issue of The Lancet suggest that once-daily rilpivirine will be a valuable additional treatment for patients with HIV who have not yet started antiretroviral therapy.
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine, in combination with nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), are two of the most commonly used drugs for initial treatment of HIV infection. Although equally effective at suppressing the virus, both drugs can cause severe side effects, highlighting the need for other first-line NNRTIs with a more favourable safety profile. In a phase 2 trial, the NNRTI rilpivirine showed long-term efficacy and tolerability in patients starting HIV treatment for the first time, with similar response rates to efavirenz.
The THRIVE and ECHO phase 3 trials were independently conducted to assess whether rilpivirine is as effective as efavirenz when given in combination with different NRTI background regimens.
The THRIVE trial randomly allocated treatment-naïve patients to rilpivirine (25mg once daily) or efavirenz (600mg once daily) and two NRTIs (emtricitabine/tenofovir, abacavir/lamivudine, or zidovudine/lamivudine). In ECHO, patients were randomly assigned to receive rilpivirine (25mg once daily) or efavirenz (600mg once daily), each combined with emtricitabine/tenofovir. In both studies, the primary endpoint was defined as the proportion of patients with HIV viral levels below 50 copies per mL at week 48.
Both studies showed that rilpivirine was non-inferior to efavirenz and had a better side-effect profile, despite an increased incidence of virological failures (returning to detectable levels of the virus).
The THRIVE trial, which included 678 patients from 98 hospitals and medical centres in 21 countries, found that the rilpivirine regimen suppressed the virus to undetectable levels (below 50 copies per mL) in more patients than the efavirenz regimen at week 48 (86% vs 82%). Additionally, patients taking rilpivirine experienced fewer treatment-related side effects such as rash and central nervous system adverse reactions including abnormal dreams/nightmares, somnolence and dizziness. Patients taking rilpivirine were also less likely to discontinue treatment due to side effects (4% vs 7%).
The ECHO trial included 690 patients from 112 sites across 21 countries. After 48 weeks of treatment, 83% of patients from both groups achieved undetectable levels of HIV. However, rilpivirine was better tolerated and moderate to (very) severe side effects were less common in patients taking rilpivirine than efavirenz (16% vs 31%). Discontinuations due to adverse events were more frequent among patients taking efavirenz (8% vs 2%).
Importantly, in both studies patients taking rilpivirine had an increased risk of virological failure. In ECHO, 11% of patients in the rilpivirine group had virological failure during the study compared with 4% in the efavirenz group. In THRIVE, the proportions of virological failures were 7% and 5%, respectively.
The authors say: "In contrast to the use of efavirenz, rilpivirine might be suitable for use in women of child-bearing age [because of the potential of efavirenz to cause physical abnormalities in the unborn fetus] and patients with certain pre-existing psychiatric disorders."*
On the basis of the findings of these two studies, rilpivirine has been approved in the USA in combination with other antiretroviral drugs for the first-line treatment of HIV.
In a Comment, Zeger Debyser and colleagues from Katholieke Universiteit Leuven, Leuven, Belgium remark: "Rilpivirine should be embraced as an example of the continuous effort to generate patient-tailored drugs that are highly convenient, have minimal side effects, and are sufficiently efficacious."
However, they caution: "Although apparently non-inferior, rilpivirine should be started cautiously as patients with a baseline plasma viral load of more than 100 000 copies per mL were more prone to virological failure (and development of resistance). Additional studies explaining the increase in virological failure with rilpivirine and studies about resistance or cross resistance are warranted."
THRIVE trial contact: Dr Calvin Cohen, Community Research Initiative of New England, Boston, USA. T) +161 7803 5928 (mobile) E) ccohen@crine.org
ECHO trial contact: Dr Jean-Michel Molina, Saint-Louis Hospital and University of Paris Diderot, Paris, France. T) +33 1424 99066 or +33 683 437 924 (mobile) E) jean-michel.molina@sls.aphp.fr
Comment contact: Dr Zeger Debyser, Katholieke Universiteit Leuven, Leuven, Belgium. T) +32 1633 2183 E) zeger.debyser@med.kuleuven.be
Notes to Editors: *Quote direct from authors and cannot be found in text of articles.
Journal
The Lancet