Next generation first-line NNRTI, rilpivirine (TMC278) potent; lowest dose better-tolerated than efavirenz at 96 weeks

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Tibotec’s next-generation NNRTI, rilpivirine (previously known as TMC278) continues to suppress viral load and increase CD4 counts in similar numbers of treatment-naïve patients to efavirenz (Sustiva) over 96 weeks according to Phase IIb study data presented to the recent XVII International AIDS Conference in Mexico City. When compared to efavirenz, however, rilpivirine appears to produce a lower incidence of rash, central nervous system disorders, and lipid abnormalities.

TMC278-C204 is a relatively small Phase IIb study with 368 participants, that compares three blinded, once-daily doses of rilpivirine (25mg, 75mg, or 150mg) with open-label once-daily efavirenz (600mg), in combination with either AZT/3TC (Combivir; 76%) or tenofovir/FTC (Truvada; 24%).

The study’s 48-week results, including details of study design and participant characteristics, were previously presented to the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles in February 2007.



A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).


A rash is an area of irritated or swollen skin, affecting its colour, appearance, or texture. It may be localised in one part of the body or affect all the skin. Rashes are usually caused by inflammation of the skin, which can have many causes, including an allergic reaction to a medicine.

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.


Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.


Term used to indicate how well a particular drug is tolerated when taken by people at the usual dosage. Good tolerability means that drug side-effects do not cause people to stop using the drug.

Results at 96 weeks show that rilpivirine continues to show staying power. In a time to loss of virological response (TLOVR) analysis, 73% of patients in all three rilpivirine arms combined achieved viral loads below 50 copies/ml, compared with 71% in the efavirenz arm.

When separated according to rilpivirine dose (25mg, 75mg, or 150mg) mean CD4 cell increases were 146, 172, and 159 cells/mm3 respectively, compared with 160 cells/mm3 in the efavirenz arm. However, numbers achieving sustained virological response at 96 weeks were highest in those receiving the 25mg dose (76%), compared with 72% of patients on the 75mg dose, and 71% on the 150mg dose.

The success of the 25mg dose appears to have been driven by a higher number of study discontinuations due to adverse events in the 75mg (12%) and 150mg (14%) dosing arms compared with the 25mg arm (9%) and the efavirenz arm (9%). However when asked, during the question and answer session that followed, what specific adverse events were seen on the higher doses of rilpivirine, Dr Mario Santoscoy, presenting, was unable to answer.

In fact, the adverse event data presented highlighted rilpivirine’s improved tolerability at all doses compared with efavirenz in terms of:

  • rash: 9% for combined rilpivirine arms vs 21% for efavirenz (p
  • nervous system disorders: 31% for combined rilpivirine arms vs 48% for efavirenz (p
  • psychiatric events: 16% for combined rilpivirine arms vs 21% for efavirenz (although this was not statistically significant, there were significantly fewer reports of abnormal dreams/nightmares: 3% for the combined rilpivirine arms vs 11% for efavirenz: p

In addition, increases in lipid parameters at 96 weeks were consistently lower on rilpivirine compared with efavirenz:

  • total cholesterol: 9mg/dl for the combined rilpivirine arms vs 35.4mg/dl for efavirenz (p
  • LDL cholesterol: 4.5 mg/dl for the combined rilpivirine arms vs 18.2mg/dl for efavirenz (p
  • HDL cholesterol: 6.2 mg/dl for the combined rilpivirine arms vs 11.3mg/dl for efavirenz (p
  • triglycerides: a reduction of 9.9mg/dl for the combined rilpivirine arms vs an increase of 29.2 mg/dl for efavirenz (p

Nevertheless, rates of grade three or four adverse events were higher for the combined rilpivirine arms (27%) versus efavirenz (21%) as were rates of grade three or four laboratory abnormalities, at 27% vs 24%, respectively.

No clinically relevant changes in adrenal, thyroid measurements were detected. In addition, heart rate interval measurement (QTc interval - the faster the heart rate, the shorter the QTc interval) found that:

  • QTc interval increases were observed up to Week 48 with all rilpivirine doses and efavirenz;
  • QTc interval stabilised from Week 48 to Week 96;
  • and the 25mg rilpivirine dose was associated with lowest increase in QTc interval.

Very few participants (6% on the rilpivirine arms combined vs 7% on efavirenz) experienced virological failure with resistance mutations and the emergence of NNRTI resistance mutations in participants with virological failure was broadly similar across the four arms:

  • rilpivirine 25mg: 56% (5/8);
  • rilpivirine 75mg: 60% (3/5);
  • rilpivirine 150 mg: 33% (1/3);
  • efavirenz: 60% (3/5).

During the question and answer session, Dr Santoscoy noted that Tibotec “cannot say with any certainty which, and how many, mutations can confer resistance” to rilpivirine. However, he added that, of the nine participants on rilpivirine with resistance mutations at virological failure, "most had 184V, and some had 138K."

The study has now been extended to five years, with all patients previously on the 150mg or 75mg dose now taking the 25mg dose. It is this lowest dose that has also been chosen for Phase III studies that are currently enrolling in Africa, Asia, Europe, and North and South America and which Tibotec hopes will position rilpivirine as a once-daily, first-line rival to efavirenz.


Santoscoy M et al. TMC278 (rilpivirine), a next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naïve patients: 96-week results of study C204. XVII International AIDS Conference, Mexico City, abstract TUAB0103, 2008.

Tibotec Press Release. Ninety-six week data on Tibotec investigational NNRTI, TMC278, presented at AIDS 2008. August 5th, 2008.