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RAL+TDF/FTC

Overview

RAL + TDF/FTC* is a regimen containing two NRTIs, an INSTI. It is a recommended regimen for treatment-naïve patients by both the DHHS and the IAS guidelines, but is not explicitly discussed for treatment-experienced patients. However, this type of regimen (1 INSTI + 2 NRTIs) may be considered in specific circumstances for some virally suppressed patients and patients who are experiencing virologic failure.

*There is evidence from bioequivalence or relative bioavailability studies that TAF can be substituted for TDF without loss of efficacy and with an improved side effect profile, particularly less impact on kidney function and on bone loss[1]. As such, TAF, an oral prodrug of TDF, is now included (since 2016) as a component of several recommended regimens and first line therapy in both DHHS and IAS guidance. TAF is FDA approved for use in patients with estimated CrCl as low as 30mL/min.

Recommendations for treatment-naïve patients

DHHS: RAL + TDF/FTC is a recommended regimen for treatment-naive patients.

IAS:  RAL + TDF/FTC is a recommended regimen for treatment-naive patients.

Recommendations for treatment-experienced patients

DHHS: In virally suppressed patients, within-class switches to RAL are not discussed. Between-class switches that can be considered include replacing an NNRTI or boosted PI with an INSTI, but this particular regimen is not discussed.

In cases of confirmed virologic failure, the DHHS does not discuss switching to any 2 NRTIs + 1 INSTI regimens specifically, but recommends considering a switch to a non-PI-based regimen with more than two fully active agents in cases of poor tolerability or interactions that result in the virologic failure of a PI-based regimen.

IAS: This regimen is not discussed for use in virally suppressed patients, but switching from an older regimen to a simpler regimen may be considered as long as the patient has no resistance or mutations that would result in virologic failure.

In cases of virologic failure, the IAS does not have any specific recommendations and does not discuss this regimen, but notes that in treatment-experienced patients, DTG was found to be superior to RAL and EVG was found to be noninferior to RAL.

Other Considerations

RAL

  • Must be taken twice daily, although a once daily dose has shown similar efficacy in a recent trial, but there is not enough data to recommend this[2].
  • Should not be taken with polyvalent cations, which may be found in antacids, laxatives, and mineral supplements
  • Possible side effects include creatine kinase elevation, myositis, rhabdomyolysis, and (rarely) severe skin reactions and systemic hypersensitivity reactions

TDF

  • Can lead to renal and bone toxic effects due to high plasma tenofovir concentrations
  • High daily dose (as compared to TAF)
  • Similar rates of HIV suppression, resistance with virologic failure, and increases in CD4 cell count as TAF

 

Efficacy in Clinical Trials

Trial Name

Drugs Compared

Participants

Study Results

SPRING-2

ABC/3TC+RAL vs. TDF/FTC+RAL

164 tx-naive, 24% with VL ≥100,000

After 96 weeks, there was no difference in virologic response between the ABC/3TC and TDF/FTC groups when RAL was given as the third drug [3][4].

SAILING

2 NRTIS + DTG or RAL

715 tx-experienced

 At week 48, 71% of patients on the DTG-based regimen were virally suppressed as comparted to 64% of patients on the RAL-based regimen. Fewer patients experienced virological failure in the DTG group. DTG, taken once daily, was well-tolerated and more effective than twice daily RAL[5].

SPRING-2

2 NRTIs plus DTG or RAL

822 tx-naive

At 48 and 96 weeks, once-daily DTG was non-inferior to twice-daily RAL (88% vs 85% viral suppression at 48 weeks, and 81% vs 76% at 96 weeks), with a similar safety profile[6] [2]

STARTMRK

TDF/FTC plus EFV or RAL

566 tx-naive

At 48 weeks, RAL was noninferior to EFV. At 4 and 5 years, RAL was superior to EFV, in part because of more frequent discontinuations due to adverse events in the EFV group [7][8][9].

ONCEMRK

RAL 1200mg QD vs RAL 400mg BID

802 tx-naive

      In a clinical trial of patients receiving RAL either 1200 mg once daily (QD) or 400 mg twice daily (BID) the once daily regimen was found to be noninferior at 48 weeks. 89% of patients receiving QD RAL and 88% of patients receiving BID RAL achieved viral suppression, and there were numerically higher rates of serious adverse events and discontinuations in patients receiving BID[bib]250[bib].