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DTG+MVC+DRV/c

Overview

DTG+MVC+DRV/c+ is a regimen containing  an INSTI, a PK enhanced PI, and a CCR5 inhibitor. It is not routinely used and is only considered in specific circumstances for treatment-naïve and treatment-experienced patients. The DHHS and IAS guidelines do not discuss this regimen for treatment-naïve patients, but  this regimen may be considered based on clinical trial data from similar regimens of INSTI +PI. Addition of MVC to such a regimen may allow for 3 active component drugs.

+DRV/c was found to be bioequivalent to DRV/r in healthy volunteers[1]. Based on the results of the study, efficacy of DRV/c has been extrapolated from DRV/r data. Therefore, many experts may consider use of DRV/c despite the limited supporting data from clinical trials due to the reduced pill burden. Use of DRV/c is discussed in both the DHHS and IAS guidelines for use in treatment-naïve and treatment-experienced patients. Cobicistat inhibits active tubular secretion of creatinine, which can increase serum creatinine without an effect on renal glomerular function.

Recommendations in treatment-naive patients

DHHS: DRV+DTG+MVC is not discussed or recommended.  However, a different 1 INSTI + 1 PI regimen, DRV/r+RAL, is recommended as a regimen for consideration in some treatment-naïve patients when an NRTI cannot be used. Based on trial data, the DHHS acknowledges that a regimen of DRV/r+RAL has some potential disadvantages and may be less effective with patients who have high viral loads or low CD4 counts[2].

IAS:DRV/c+DTG is not discussed in the IAS guidelines. However, a different regimen of 1PI+1INSTI, DRV/r+RAL, is recommended for consideration in situations where patients cannot take ABC, TAF, or TDF.  It is acknowledged that DRV/c+RAL may be less effective in patients with CD4 cell counts below 200µ/L or HIV RNA levels above 100,000 copies/mL.

 Recommendations in treatment-experienced patients

DHHS: For treatment of virally suppressed, this regimen is not discussed in the DHHS guidelines, but the guidelines mention a similar regimen, DRV+EVG/c/TAF/FTC, for patients who have resistance to at least 2 ARV drug classes without INSTI resistance, given promising results[3].  Other 2 drug simplification regimens utilizing DRV/c and/or DTG appears to be effective, suggesting that a regimen of DRV/c+DTG+MVC is likely to be effective at maintaining virologic supression if all drugs are fully active.  Maraviroc has been studied as part of 2 drug combinations with RAL for simplification and has not shown favorable efficacy.[4] [5].  

 In cases of virologic failure, the DHHS does not specifically discuss this regimen, but recommends that patients start a regimen with at least 2 to 3 active agents. In cases where there is resistance to RAL or EVG/c, a regimen containing newer generation INSTI's, such as DTG, in cobmination with a boosted PI can be considered.  Addition of MVC is likely to strengthen such regimens.  The MOTIVATE 1 and 2 trials [6][7] have suggested that MVC in combination with an optimized background regimen have significantly higher rates of viral suppression and increases in CD4 compared to placebo.  

IAS: This regimen is not discussed in the IAS guidelines for treatment-experienced patients. However, the IAS recommends using a boosted PI in second line regimens because of the high barrier to resistance.

 Other Considerations

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

DTG

  • DTG has the lowest risk of resistance with virological failure among INSTIs
  • Relatively few drug interactions
  • Can be taken with or without food (but not at the same time as polyvalent cations, which may be found in antacids, laxatives, and mineral supplements; give DTG at least 2 hours before or at least 6 hours after antacids containing polyvalent cations). 
  • DTG may raise serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function
  • Use caution in women of child bearing age, based on limited reports of neural tube defects. DHHS recommends documenting negative pregnancy test prior to initiation. Women should be counseled about switching to alternatives if pregnant and within 8 weeks since LMP. [8]

DRV

  • Must be taken with food
  • Low risk of virologic failure, even with intermittent use
  • PI boosters (cobicistat or ritonavir) interact with many other drugs 
  • Cobicistat inhibits active tubular secretion of creatinine, which can increase serum creatinine without an effect on renal glomerular function
  • Possible side effects include diarrhea, nausea, and headache

 

Efficacy in Clinical Trials

DTG

Trial Name

Drugs Compared

Participants

Results

SINGLE

ABC/3TC/DTG vs. TDF/FTC/EFV

833 tx-naive

At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the ABC/3TC/DTG group than in the TDF/FTC/EVF group (88% vs. 81%).  Was due primarily to discontinuations because of adverse events (2% in the ABC/3TC/DTG group and 10% in the TDF/FTC/EVF group). At week 144, ABC/3TC/DTG remained superior (71% vs 63% viral suppression) [9] [10] [11]

ARIA

ABC/3TC/DTG vs. TDF/FTC+ATV/r

495 tx-naive women

At 48 weeks, ABC/3TC/DTG was superior in terms of virologic suppression (82% vs 71%). There were fewer virological nonresponses and fewer discontinuations due to adverse events in the ABC/3TC/DTG arm [12]

FLAMINGO

2 NRTIs plus DTG or DRV/r

484 tx-naive

At 48 weeks, DTG outperformed DRV/r (viral suppression 90% vs 83%). Discontinuation due to adverse effects was higher in the DRV/r group than the DTG group (2% vs 4%, respectively), which contributed to the difference in the response rate. DTG continued to outperform DRV/r at 96 weeks (viral suppression 80% vs 66%) [13][14]

SPRING-2

2 NRTIs plus DTG or RAL

822 tx-naive

At 48 and 96 weeks, DTG was non-inferior to RAL (88% vs 85% viral suppression at 48 weeks, and 81% vs 76% at 96 weeks), with a similar safety profile[15] [16]

 

DRV

TRIAL

REGIMEN

Study Participants

Study Results

N/A

ABC/3TC+DRV/r (single arm)

67, 48% tx-naive

At 48 weeks, 79% achieved viral suppression [17].

ARTEMIS

TDF/FTC plus DRV/r or LPV/r 

689 tx-naive

At 92 weeks, DRV/r was superior to LPV/r with respect to virological response. Among participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm [18].

FLAMINGO

2 NRTIs plus DRV/r or DTG

488 tx-naive

At week 96, virologic suppression was significantly greater among those who received DTG. The excess failure observed in the DRV/r group was related to a higher rate of virologic failure among those with a viral load >100,000 copies/mL and more drug discontinuations in the DRV/r group [14].

ACTG A5257

TDF/FTC plus DRV/r, ATV/r, or RAL

1809 tx-naive

At 96 weeks, RAL and DRV/r were found to be equally tolerable, while ATV/r was found to be less tolerable, leading to more discontinuation by patients on ATV/r-based regimens. RAL was superior to both PIs in combined virologic efficacy and tolerability, while DRV/r was superior to ATV/r. RAL has a more favorable lipid profile (lower increases in total cholesterol, triglycerides, and LDLc)  as compared to ATV/r and DRV/r, but the long-term clinical significance of the results need to be further evaluated [19][20].

 

N/A

2 NRTIs + DRV/c (single arm)

313, 95% tx-naive

At week 48, 81% achieved viral suppression, while 5% discontinued treatment because of adverse events [21].

Study 115

DRV/c vs.DRV/r

62 tx-naive

DRV/c is bioequivalent to DRV/r in healthy volunteers [1].

 

PI+INSTI

Trial

Drugs Compared

Population

Result

Tivista

DRV/r+DTG (1 arm)

113 tx-experienced

At week 48, the combination of DTG and DRV/r provided a high rate of viral suppression (98.1%), with only one dropout due to drug toxicity [22].

PROGRESS

TDF/FTC + LPV/r vs. LPV/r + RAL

206 tx-naive

Viral suppression at 48 weeks 83% in RAL group vs 85% in TDF/FTC+LPV/r group (non-inferior)[23]

SPARTAN

RAL + ATV vs TDF/FTC+ATV/r

94 tx-naive

Similar rates of viral suppression at 24 weeks, but higher incidence of hyperbilirubinemia and RAL resistance development[24]

ACTG A5262

DRV/r + RAL

112 tx-naive

26% virologic failure by 48 weeks, with integrase resistance in 5 participants, particularly in those with baseline viral load >100,000[25]

RADAR

DRV/r+ RAL vs TDF/FTC+DRV/r

68 tx-naive

62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175)[26]

ANRS143/NEAT 100

DRV/r+RAL vs

TDF/FTC+DRV/r

805 tx-naive

DRV/r+RAL was noninferior for the primary endpoint of time to treatment failure (17.8%vs 13.8% at 96 weeks); planned subgroup analysis showed RAL arm was inferior for those with CD4 <200.[2]

SECOND-LINE

LPV/r + NRTI backbone vs LPV/r + RAL

541 tx-experienced

At 48 weeks, a regimen of LPV/r+RAL was found to be noninferior to a regimen of LPV/r+2 NRTIs, given that 223 (83%) of patients in the LPV/r + RAL group and 213 (81%) of patients in the control group were virally suppressed[27].

EARNEST

PI monotherapy vs 2 NRTI+LPV/r vs LPV/r + RAL

1277 tx-experienced

PI+INSTI regimen had 64% viral suppression and was noninferior to a 2NRTI+PI regimen that had 60% viral suppression[28]

KITE

LPV/r + RAL vs sHAART

60 tx-experienced

At week 48, both arms of the study were found to have similar levels of sustained viral suppression; 92% of the LPV/r + RAL patients and 88% of the sHAART patients[29].

N/A

ATV/r+RAL vs ATV/r+TDF/FTC

109 tx-experienced

At 24 weeks 94.6% of patients on the ATV/r+TDF/FTC regimen maintained viral suppression, while 80.6% of patients on the ATV/r+RAL regimen maintained suppression. At 48 weeks, 86.5% of ATV/r+TDF/FTC and 69.4% of ATV/r+RAL patients maintained virologic suppression. The ATV/r+RAL group was noted to have lower adherence and higher treatment discontinuation along with a higher virologic rebound rate as compared to ATV/r+TDF/FTC[30]

 

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References

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