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1 INSTI 1 NNRTI

ARVs: 

This is a generic educational information sheet for 1 INSTI + 1 NNRTI regimens.

Overview

This regimen consists of 1 INSTI paired with 1 NNRTI. This combination of drugs is more often used in tandem with either 2 NRTIs or a single NRTI.  This combination is discussed in the 2017 DHHS, under the section of simplification strategies. . DTG/RPV now comes coformulated (Juluca) as a one pill/once daily regimen

Recommendations in treatment-naïve patients

DHHS: This type of regimen is not discussed as an option for initial treatment in the guidelines. However, both INSTI-based and NNRTI-based regimens are recommended for initial treatment for most people or in certain clinical situations when combined with 2NRTI's. 

IAS: This type of regimen is not discussed in the IAS guidelines. However, both INSTI-based and NNRTI-based regimens are recommended for initial treatment.

Recommendations in treatment-experienced patients

DHHS: This type of regimen is not discussed in the guidelines for treatment-experienced patients in cases of virologic failure.  However, DTG+RPV is now discussed as a 2drug simplification strategy in patients that are virally suppressed. DHHS guidelines now state that, "DTG plus RPV can be a reasonable option when the use of NRTIs is not desirable and when resistance to either DTG or RPV is not expected."

  • In an open label cohort study switching virologically suppressed patients with multiple previous treatment failures to once daily DTG/RPV was found to be safe and effective through week 48. CD4 cell count remained stable after the switch, and the regimen was associated with improved liver function tests, improved lipid profile, and stable kidney function at 48 weeks[1].
  • There are two ongoing phase III RCTS (SWORD1 and SWORD 2) evaluating the strategy of switching from stable ARV regimens (2NRTIs + etiher PI, INSTI or NNRTI) to DTG plus RPV.  Preliminary results were presented at CROI 2017 and suggested that of 513 patients switched from a 3 or 4 drug regimen, 95% maintained virus at undetectable levels, compared to 96% of 511 patients who remained on their original treatment regimen.
  • In an observational cohort at eight centers in Italy, 132 subjects were followed for median of 24 months on DTG + RPV.  Most were switched to this regimen for simplification (53%) or toxicity (35%), and nearly half had RT mutations and nearly half had PI mutations, and majority were virally suppressed at time of starting on to DTG +RPV.  At 24 weeks, all but one individual appeared virally suppressed[2]
  • In an open label multicenter study of 104 participants (80% suppressed) that switched to DTG/RPV, mostly for reasons of prior toxicity or convenience, 88.4% were virally suppressed at 24 weeks (97% per protocol analysis)[3]

 

IAS: The IAS guidelines do not specifically recommend any regimens for treatment-experienced patients in both cases of virologic failure or suppression. This type of regimen is not discussed in the guidelines.

Other Considerations: DTG/RPV is now available coformulated.

NNRTI           

  • Lower rates of causing lipodystrophy than PI-based regimens; should consider switching to NNRTI-based regimen if experiencing PI-induced lipodystrophy

RPV

  • Smallest tablet among the single-pill regimens
  • Approved for use in patients with pre-treatment viral loads <100,000 copies/mL and CD4 count >200 cells/mm3
  • Must be taken with a high-calorie meal (at least 390 kcal)
  • Interacts with many other drugs
  • Contraindicated with PPIs, use with caution with H2 antagonists or antacids
  • Can prolong the QTc
  • Lowest risk of rash among NNRTI-based therapies, and low risk of metabolic adverse effects
  • Possible side effects include depressive disorders and suicidality

 

DTG

  • Lowest risk of resistance with virological failure among INSTIs
  • Relatively few drug interactions
  • Can be taken with or without food (but not with polyvalent ions, which may be found in antacids, laxatives, and mineral supplements)
  • May raise serum creatinine 
  • Largest tablet among co-formulated single-pill regimens 
  • Possible side effects include insomnia, headache, and (rarely) hypersensitivity reaction
  • 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. [4]

Efficacy in Clinical Trials

Trial

Regimen

Population

Result

N/A

PI and/or NRTI-based regimens vs RAL + ETR

25 tx-experienced

In a prospective cohort study, virologically suppressed patients on PI or NRTI regimens who expressed concerns due to unwanted side effects were switched to an RAL+ETR regimen. The regimen was wel- tolerated and maintained viral suppression at 48 weeks and the regimen can be considered a well-tolerated potential regimen in certain patients who had difficulty with both PI and NRTI therapy [5].

SWORD 1 and 2

DTG/RPV vs prior combination ART

1024 participants virally suppressed and no history of treatment failure

Virologic suppression was maintained in ~95% of participants in both arms at 48 weeks. 

     
  • In an observational cohort at eight centers in Italy, 132 subjects were followed for median of 24 months on DTG + RPV.  Most were switched to this regimen for simplification (53%) or toxicity (35%), and nearly half had RT mutations and nearly half had PI mutations, and majority were virally suppressed at time of starting on to DTG +RPV.  At 24 weeks, all but one individual appeared virally suppressed[2]. .
  Open label study of DTG/RPV 38 Heavily experienced with history of treatment failure Three patients discontinued the new regimen due to gastrointestinal toxicity, DDI with omeprazole, and physician’s decision, one case each. There were no virological failures: HIV-RNA remained below 37copies/mL in 100% (38/38) at week 4 and 100% (35/35) at week 48. CD4 count remained stable after switching: median 707.7 cells/mm3 at week 48 (95%CI 591.7-823.6, P=0.99). We observed a statistically improvement in total cholesterol and triglycerides with no changes in HDL and LDL-cholesterol. All total bilirubin, ALT, AST, GGT and alkaline phosphatase decreased (P<0.05). CKD-EPI eGFR decreased from 85 to 76 mL/min/1.73m² (95% CI 5.1-16.6, P=0.0002) at week 4 and maintained stable until week 48.[1].
DORIVIR DTG/RPV 104 participants treatment experienced A total of 104 participants were included, who switched for the following reasons: toxicity/intolerance (42.3%), convenience (27.8%), and drug interactions (17.3%). 82 (78.8%) with virologic suppression and 22 (21.1%) without virologic suppression (8 virologic failure and 14 restarting ART).Prior regimens are protease inhibitor (56.7%), integrase strand transfer inhibitor (26.9%), and non-nucleoside reverse transcriptase inhibitor (16.3%). Efficacy at 24 weeks was 88.4% (intention to treat) and 96.8% (per protocol).  No patient discontinued due to adverse events.[3]

 

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