Rilpivirine better tolerated, less toxic and more durable than efavirenz in first-line ART

Rilpivirine is better tolerated, less toxic and more durable than efavirenz when used as part of a first-line antiretroviral regimen, investigators from Italy report in HIV Medicine.

Although the two drugs showed similar virological efficacy, people treated with efavirenz were significantly more likely than individuals taking rilpivirine to stop taking a drug because of toxicity, intolerance or to make a proactive treatment switch in the first two years after antiretroviral therapy (ART) initiation.

“The main finding of this work is a significantly higher durability of RPV [rilpivirine]-based regimens compared with EFV [efavirenz], in absence of significant differences in the chances of achieving HIV RNA load suppression or in the estimated rates of virological failure in patients treated with the two different NNRTI [non-nucleoside reverse transcriptase inhibitor]-based regimens,” comment the authors. “These findings have high clinical relevance.”


first-line therapy

The regimen used when starting treatment for the first time.



reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

Both efavirenz and rilpivirine belong to the NNRTI class of antiretrovirals and are available as single-tablet regimens co-formulated with emtricitabine and tenofovir (efavirenz/emtricitabine/tenofovir: Atripla; rilpivirine/emtricitabine/tenofovir disoproxil (Eviplera) or rilpivirine/emtricitabine/tenofovir alafenamide  (Odefsey). Efavirenz and rilpivirine are options for first-line ART for people with a viral load below 100,000 copies/ml.

Little is known about the comparative long-term durability of these two NNRTIs in real-life cohorts. Two phase III drug registration studies showed higher rates of adverse events in people who received efavirenz. Italian investigators, therefore, designed a study examining incidence and causes of treatment discontinuation (any cause; toxicity; intolerance; pro-active; failure) among antiretroviral-naïve patients initiating a regimen based on either drug. The analysis is especially timely as efavirenz is now available in cheaper generic formulations, making the drug an attractive cost-saving option.

The study had an observational design with data collected prospectively. However, analysis of the rates and causes of treatment discontinuation was conducted retrospectively.

The study population consisted of 1490 people, of whom 704 started first-line ART with efavirenz and 786 with rilpivirine. Efavirenz and rilpivirine were used in combination with emtricitabine/tenofovir. Approximately a third of people taking efavirenz immediately started Atripla, the others switching to this single-tablet regimen within six months of treatment initiation. Almost all (99.2%) of the people receiving rilpivirine initiated therapy with Odefsey.

Overall, 83% of the participants were male, 17% had a history of injecting drug use and 51% were in the men who have sex with men risk-group. Median follow-up was 40 months for people initiating efavirenz and 17 months for those starting rilpivirine.

There were significant baseline differences between the two treatment groups. People taking efavirenz were older (36 vs 33 years, p < 0.001), were more likely to have symptomatic HIV disease (3% vs 1%, p = 0.024), had lower current and nadir CD4 cell counts (p < 0.001) and a higher viral load (p < 0.001) than people starting rilpivirine. The median calendar year of ART initiation also differed (efavirenz = 2011; rilpivirine = 2014) as did the interval between HIV diagnosis and starting treatment (efavirenz = 19 months; rilpivirine= 13 months).

A total of 343 people discontinued their first-line regimen, with 218 of these people doing so within two years of initiating therapy. Just under a quarter of people starting efavirenz discontinued their regimen within two years compared to 10% of those initiating rilpivirine.

Treatment was discontinued because of intolerance in 34% of cases. Overall, 14% of people taking efavirenz discontinued for this reason compared to 2% of those taking rilpivirine. Toxicity was responsible for 21% of discontinuations, with 8% of people taking efavirenz stopping for this reason compared to 2% of those treated with rilpivirine. Treatment was changed pro-actively in 10% of people, including 4% of all people taking efavirenz and 0.5% of individuals starting rilpivirine.

Virological failure was recorded as the cause of discontinuation in 2% of people starting efavirenz and 2% of those initiating rilpivirine. After two years, almost all the participants in the rilpivirine group had a viral load below 50 copies/ml compared to 97% of individuals who started efavirenz. Two people died during follow-up, both of whom were in the rilpivirine group.

After taking into account potential confounders (age, gender, HIV disease, CD4 cell count, viral load and year of starting ART), people starting efavirenz were more likely to discontinue their regimen for any cause (RH = 4.09; 95% CI, 2.89-5.80), because of toxicity (RH = 2.23; 95% CI, 1.05-4.73) and due to intolerance (RH = 5.17; 95% CI, 2.66-10.07) than those initiating rilpivirine.

People starting efavirenz were almost eleven times more likely to have a pro-active treatment change during the first two years of therapy than people starting rilpivirine (RH = 10.96; 95% CI, 3.17-37.87).

The risk of virological failure did not differ between the regimens.

“RPV was better tolerated, was less toxic and showed greater durability than EFV, without significant differences in the rates of virological failure or discontinuation because of failure,” conclude the authors. “This observation should encourage modelling work to evaluate the cost-effectiveness of initiating EFV instead of RPV as first-line treatment.”


Taramasso L et al. First-line antiretroviral therapy with efavirenz plus tenofovir disoproxil fumarate/emtricitabine or rilpivirine plus tenofovir disoproxil fumarate/emtricitabine: a durability comparison. HIV Medicine, online edition, DOI: 10.1111/hiv.12628, 2018.