1 EI + 1 INSTI + 1 NNRTI

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


There are multiple Entry Inhibitors (EIs), including Maraviroc (MVC), Ibalizumab (IBA), Enfuvirtide (T-20), and Fostemsavir (BMS-663068; not FDA approved). While considered together here, each has a different mechanism of action, requirement for usage and mode of delivery. In general, regimens containing an EI and INSTI are not routinely used for treatment-naïve or treatment-experienced patients, but they can be considered in specific circumstances for treatment-experienced patients with significant resistance profiles. Most ART regimens have historically included 3 active drugs including an INSTI, PI or NNRTI as an anchor, and 2 NRTI’s as a backbone. Most studies evaluating inclusion of an EI have done so in the context of an optimized background regimen (OBR); in some situations, INSTI and NNRTI have been included as part of that OBR, based on treatment history and resistance testing. Our assessment of regimens containing EI + INSTI + NNRTI are largely extrapolated from such studies, which contain limited data explicitly studying the effectiveness of these particular combinations.

MVC is the only CCR5 antagonist currently approved by the FDA.  Importantly, it can only be used to treat CCR5-tropic virus, and a co-receptor tropism assay—either phenotypic or genotypic—must be performed prior to MVC initiation and in cases of suspected virologic failure on MVC.  There is greater evidence available for the use of phenotypic assays, making them the preferred test to determine tropism; however, genotypic assays, which are less expensive and less time-intensive than their phenotypic counterparts, are also available. There is limited data on the OBR components when using INSTI and NNRTI as part of salvage regimens.

IBA is a CD4 post-attachment inhibitor that has been studied in combination with at least one other active antiretroviral medication in treatment-experienced individuals with extensive resistance. IBA is not affected by resistance to other classes of antiretroviral medications, nor it is impacted by HIV tropism status (CCR5 versus CXCR4), or renal insufficiency, and there are no significant drug interactions. This medication requires administration via intravenous infusion. It is given as an initial loading dose, followed by a 15-30 minute intravenous infusion every 14 days. Based on the need to give IBA via an intravenous infusion, the use of this agent will likely be reserved for rare instances in which an adult has developed multiclass antiretroviral drug resistance and for whom a complete regimen cannot be crafted using other available options. In clinical trial, phenotypic and genotypic test results revealed no evidence of cross-resistance between IBA and any of the approved classes of anti-retroviral drugs, including INSTI and NNRTI. Specifically for NNRTI, the primary clinical trials leading to FDA approval (personal communication), 65% of individuals in the trial (26 out of 40) had inclusion of DTG as part of their OBR. IBA was effective in combination with Dolutegravir (DTG). However, there is relatively limited data on the OBR components when using INSTI and NNRTI in combination as part of salvage regimens with IBA.

Recommendations for MVC + 1 INSTI + 1 NNRTI in treatment-naive patients

DHHS (Dec. 2019): MVC in combination with 1 INSTI and 1 NRTI is not discussed as initial therapy. MVC (with NRTI backbone) is not recommended due to a lack of virologic benefit of MVC when compared to other available drug classes (PIs, NNRTIs, or INSTIs), as well as its requirements for CCR5 tropism testing and twice-daily dosing. Mostly recommended initial regimens include an INSTI (or PI or NNRTI) as an anchor along with 2 NRTIs as a backbone; only in exceptional circumstances should substitution of these other classes with a CCR5 inhibitor be considered in ART-naïve patients. It could be considered if all other ARV classes are contra-indicated, but such situations would be rare. In general, NNRTI-based regimens are not recommended for persons with HIV-2.

IAS-USA (2018): Initial NNRTI-based regimens should not be used without baseline resistance data because of possible presence of transmitted NNRTI-resistant virus. In the rare circumstance in which MVC might be included in initial therapy, initiation should not occur before confirmation of CCR5 tropism. The combination of MVC and an NNRTI in treatment-naïve patients is not specifically discussed in the guidelines. Similarly, MVC in combination with 1 INSTI is not discussed for treatment of naïve patients and is not listed as one of the preferred options in patients with other treatment options.

Recommendations for MVC+ 1 INSTI + 1 NNRTI in treatment-experienced patients

DHHS (Dec. 2019): In virally suppressed patients, there may be situations in which a between-class switch is considered.  Between-class switches involving the replacement of an INSTI, NNRTI or boosted PI with MVC are discussed as an option but should not be attempted if there is any doubt about the activity of the other agents (e.g., NRTI backbone) in the regimen. Switching to MVC should only be attempted in individuals that are R5 tropic; determining tropism in a suppressed patient can be difficult.  When switching to MVC, co-receptor usage in virologically suppressed patients can be determined from pro-viral DNA obtained from peripheral blood mononuclear cells[1, 2]. This strategy was used successfully in a randomized trial that switched virologically suppressed individuals from a regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a boosted PI to two NRTIs plus MVC[3].

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 PIs, NNRTIs, or INSTIS, MVC can be considered as a replacement. The MOTIVATE 1 and 2 trials[4, 5] have suggested that MVC in combination with an optimized background regimen has significantly higher rates of viral suppression and increases in CD4 compared to placebo.  

IAS-USA (2018): In a nonrandomized pilot study, patients with virologic suppression were switched from their prescribed regimen to MVC plus Raltegravir (RAL). This combination led to virologic relapse in five out of 44 patients. Based on these study results, use of MVC plus RAL is not recommended. For virologic failure with more complex treatment history, therapy with at least 2 fully active drugs from different antiretroviral classes, perhaps including MVC in the setting of CCR5-tropic virus, is recommended. The combination of MVC and INSTI and NNRTI in treatment-experienced patients is not specifically discussed.

Recommendations for IBA + 1 INSTI + 1 NNRTI in treatment-naïve patients

DHHS (Dec. 2019): IBA in treatment-naïve patients is not recommended, as it has only been studied in a very small number of patients with virologic failure, requires IV therapy. Similarly, NNRTI-based regimens are not recommended for persons with HIV-2. The combination of IBA and INSTI and NNRTI in treatment-naïve patients is not specifically discussed in the guidelines.

IAS-USA (2018)Initial NNRTI-based regimens should not be used without baseline resistance data because of possible presence of transmitted NNRTI-resistant virus. The combination of IBA and INSTI and NNRTI in treatment-naïve patients is not discussed in the IAS-USA guidelines. 

Recommendations for IBA + 1 INSTI + 1 NNRTI in treatment-experienced patients

DHHS (Dec. 2019): IBA, in combination with at least one or two additional active antiretroviral agent(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen. Guidelines do not specifically state an INSTI or NNRTI to pair with IBA.

IAS-USA (2018): Ibalizumab, an anti-CD4 monoclonal antibody that inhibits HIV cell entry via CD4 binding, is active against CCR5- and C-X-C chemokine receptor 4 (CXCR4)–tropic HIV isolates and may be useful as a fully active agent for patients with multiclass-resistant virus (evidence rating BII). Almost 50% of adults with virologic failure from multi-drug resistant HIV achieved undetectable HIV RNA levels at 24 weeks after receipt of biweekly intravenous ibalizumab (800 mg) with at least 1 other active drug. In trial [6] subjects received a loading dose of IBA, followed 7 days later by the initiation of an OBR including at least one agent to which the subject’s virus was susceptible. Two weeks after loading dose, another dose was administered IBA, continuing every 2 weeks through week 25. Guidelines do not specifically state an INSTI to pair with IBA, however, the trial specifically reports on DTG as part of the OBR (personal communication), and guidelines do not specifically discuss an NNRTI to combine.

Other Considerations


  • Requires performing an HIV tropism assay prior to use and is ineffective in patients who do not have pure R5-tropic HIV
  • Generally well-tolerated with few long-term side effects 
  • Twice daily dosing 
  • Generally reserved for salvage therapy; however, often not an option for treatment-experienced patients with advanced disease, as the likelihood of X4-tropic HIV increases as patients develop more advanced immunosuppression
  • Possible side effects include upper respiratory tract symptoms, diarrhea, stomach upset, insomnia, rash 


  • Risk of infusion-related adverse events
  • Can cause Immune Reconstitution Inflammatory Syndrome
  • Intravenous infusion (do not administer as intravenous push or bolus) every 2 weeks
  • Not affected by resistance to other classes of antiretroviral medications or HIV tropism status (CC45 versus CXCR4), or renal insufficiency
  • Recommended in heavily treatment-experienced patients who are failing current ART

Dolutegravir (DTG)

  • High potency against susceptible virus
  • High genetic  barrier to drug resistance
  • Excellent tolerability for most patients
  • No food requirements
  • Few significant drug interactions
  • Dosage adjustment required if certain integrase mutations are present or if certain interacting drugs are given concurrently

Raltegravir (RAL)

  • Relatively good tolerability
  • No food requirements
  • Few drug interactions
  • Limited metabolic adverse effects
  • Originally approved only for twice daily dosing (400 mg twice daily dosing)
  • Recently approved by FDA for once daily dosing with 1200 mg (two 600 mg tablets)
  • Failure of regimen with raltegravir often results in drug resistance mutations that confer resistance to raltegravir and elvitegravir
  • Cross-resistance to dolutegravir may also be present with more extensive raltegravir resistance
  • Recommended for individuals who are already pregnant

Cabotegravir (investigational; not approved by FDA)

  • Dose once daily
  • Potent anti-HIV activity
  • Few bothersome adverse effects
  • Does not have high barrier to resistance
  • Being studied in oral form (half-life 40 hours) and long-acting injectable nanosuspension (half-life 21-50 days)
  • Potential risk for drug resistance to cabotegravir if person discontinues injectable cabotragevir abruptly or misses doses (upon discontinuation, may need standard oral antiretroviral therapy to prevent development of resistance)

Doravirine (DOR)

  • Well-tolerated and dosed once-daily with or without food
  • Indicated for adults with no prior ART history, or to replace current ART in those who have suppressed (HIV-1 RNA <50 copies per mL) on stable AT regimen with no history of tx failure and no known substitutions associated with resistance to doravirine
  • Reverse transcriptase mutations that cause >100-fold reduced susceptibility of HIV to doravirine: (1) Y188L alone or in combination with K103N or V106I, (2) V106A in combination with G190A and F227L, or (3) E138K in combination with Y181C and M230L
  • Tx failure can result in emergence of resistance-associated substitutions that may confer cross-resistance to efavirenz, etravirine, nevirapine, and rilpivirine
  • No CD4 count or HIV RNA level restriction for use
  • No restrictions for use in combination with proton pump inhibitors
  • Only single-tablet coformulation with doravirine includes the NRRI backbone tenofovir DF-lamivudine (limited utility as single-tablet regimen)
  • Will likely be used more often for antiretroviral-experienced individuals, especially those with resistance to NNRTIs

Efavirenz (EFV)

  • Has been replaced by newer agents that are more tolerable
  • Risk of neuropsychiatric adverse effects (e.g. depression and suicidality)
  • Frequently causes sleep disturbances, vivid dreams, grogginess, and disorientation
  • May cause unfavorable changes in lipid parameters and reductions in vitamin D levels
  • No longer U.S. designated as a recommended option for initial ART
  • Potential teratogenicity in pregnancy (unconfirmed risk)
  • Relatively low barrier to resistance; common mutations carry less cross-resistance with other NNRTI’s as compared to the typical rilpivirine mutations
  • Combination tablet includes tenofovir DF, as opposed to tenofovir alafenamide

Etravirine (ETR)

  • Later generation NNRTI that usually retains some activity in the setting of common NNRTI resistance-associated mutations
  • Typically used as part of salvage therapy (not initial)
  • Well tolerated
  • Recommended dosing requires twice daily administration, after meal
  • Important drug interactions with other ART medications (i.e. dolutegravir with ritonavir-boosted atazanavir)
  • Second-line effectiveness can be compromised by high-level resistance to etravirine in persons who have virologic failure with earlier generation NNRTI
  • Degree of resistance depends on the number and specific mutations that develop
  • Dissolves in water and can be taken immediately after dispersion in water (useful for those with difficulty or an inability to swallow pills)

Nevirapine (NVP)

  • No longer widely used in U.S. because of safer and more effective ARTs
  • Can cause severe rash and hepatitis, including immune-mediated, life-threatening hypersensitivity reactions (more likely in those who start tx with CD4 count >240 cells/mm3 in women and >400 cells/mm3 in men
  •  Most people switch to newer first-line agent though some have continued nevirapine as part of combination therapy
  • Low barrier to resistance, and resistance-associated mutations, if they occur, generally result in a high degree of cross-resistance to other NNRTIs, especially with prolonged nevirapine failure
  • Available as a once-daily extended release formulation, twice-daily immediate-release formulation, and oral suspension (all available as generic formulations)
  • Often included for treatment of infants at high-risk of HIV acquisition

Rilpivirine (RPV)

  • Generally well-tolerated and less effect on serum lipid markers as compared to older
  • Not recommended as initial therapy for individuals with an HIV RNA level >100,000 copies/mL or a CD4 count less than 200 cells/mm3 due to inferior virologic response rates in those groups
  • Must be taken with a meal
  • Contraindicated for individuals who take a proton pump inhibitor
  • Relatively low barrier to resistance
  • Emergence of resistance-associated mutations while taking rilpivirine frequently results in cross-resistance to other NNRTIs
  • Combination tablet (rilpivirine-dolutegravir) approved for maintenance therapy for individuals who have a suppressed HIV RNA on stable antiretroviral therapy for at least 6 months with no past virologic failure and no resistance to the component

Efficacy in Clinical Trials


Trial Name

Drugs Compared




IBA + optimized background regimen (OBR) (single arm)

40 tx-experienced with MDR HIV-1 

All participants were monitored on their failing antiretroviral therapy for 7 days, then received a loading dose of ibalizumab (2,000 mg by IV infusion) and were monitored for another 7 days, then their background regimen was optimized (including at least one other active ARV), and then they continued this optimized background regimen along with ibalizumab 800 mg by IV infusion every 2 weeks. At 7 days after the loading dose of ibalizumab, the proportion of participants with at least a 0.5 log drop in HIV RNA level was 83% (the primary outcome) and the proportion with at least a 1 log drop was 60%. After 24 weeks, the mean viral load decrease from baseline was 1.6 log, 24% achieved an undetectable viral load, and 50% achieved a viral load below 200 copies/mL. There was only one drug-related adverse event leading to treatment discontinuation[7].

TMB-311(open-label extension of TMB-301)


27 tx-experienced with MDR HIV-1

Twenty-seven individuals completed TMB-301 and enrolled in an open-label extension and continued ibalizumab infusions every 2 weeks plus optimized background regimen until completing 48 weeks of therapy. By that time point, 3 had discontinued for nondrug-related reasons, 59% achieved an undetectable HIV RNA level, and 63% achieved an HIV RNA level below 200 copies/mL[6].



Trial Name

Drugs Compared




MVC qd + OBT vs. MVC bid + OBT vs. placebo + OBT 

1,049 tx-experienced 

At 48 weeks, 55% of participants receiving MVC once daily and 60% of participants receiving the drug twice daily achieved a viral load less than 400 copies/mL compared with 26% of those taking placebo with optimized background therapy (OBT, consisting of 3-6 drugs based on treatment history and resistance testing); about 44% of the once-daily and 45% of the twice-daily MVC group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4+ count of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group[4, 5].


MVC qd+AZT+3TC vs. MVC bid +AZT+3TC vs.  EFV+AZT+3TC 

916 tx-naive 

Once daily MVC was discontinued for not meeting pre-specified non-inferiority criteria. At 48 weeks, twice daily MVC was non-inferior to EFV for <400 copies/mL (70.6% vs. 73.1%) but not for <50 copies/mL (65.3% vs. 69.3%) at a threshold of -10%[8].


MVC+RAL (single arm) 

44 tx-experienced 

In long-term experienced patients, MVC+RAL therapy lacks virologic robustness despite a benefit in lipid profile and bone density. Among 44 patients, seven failed MVC+RAL therapy, including five with virologic failure and two with serious adverse events. Upon DSMB recommendation, the study was prematurely discontinued[9].


MVC + 2 NRTIs vs. 

PI/r + 2 NRTIs

238 tx-experienced 

At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms[3].


MVC-based regimen vs. NNRTI- or PI/r-based regimen 

30 tx-experienced

Switching to maraviroc was well tolerated and associated with small, but statistically significant, declines in total, high-density lipoprotein and low-density lipoprotein cholesterol. Switching the third drug (either an NNRTI or PI/r) to maraviroc was safe, efficacious and improved lipid parameters[2].


MVC-containing regimen (single arm) 

20 tx-experienced 

Switching suppressive ART to a MVC-CR based upon genotypic tropism prediction from proviral DNA improves tolerability. Over median 7.5 months of follow-up, 3/20 patients discontinued MVC due to severe headache, fatigue and VL rebound. A significant reduction in soluble CD30 levels in MVC-treated patients was observed during follow-up at both 2 (p = 0.027) and 6 months (p = 0.001)[1].

1.         Vitiello P, Brudney D, MacCartney M, Garcia A, Smith C, Marshall N, et al. Responses to switching to maraviroc-based antiretroviral therapy in treated patients with suppressed plasma HIV-1-RNA load. Intervirology. 2012;55(2):172-8.

2.         Bonjoch A, Pou C, Perez-Alvarez N, Bellido R, Casadella M, Puig J, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial. J Antimicrob Chemother. 2013;68(6):1382-7.

3.         Pett SL, Amin J, Horban A, Andrade-Villanueva J, Losso M, Porteiro N, et al. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study. HIV Med. 2018;19(1):65-71.

4.         Hardy WD, Gulick RM, Mayer H, Fatkenheuer G, Nelson M, Heera J, et al. Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J Acquir Immune Defic Syndr. 2010;55(5):558-64.

5.         Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359(14):1429-41.

6.         Ibalizumab Plus Optimized Background Regimen in Treatment-Experienced Patients With Multi-Drug-Resistant HIV-1. [Internet]. Google Scholar. 2018.

7.         Emu B, Fessel J, Schrader S, Kumar P, Richmond G, Win S, et al. Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1. N Engl J Med. 2018;379(7):645-54.

8.         Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201(6):803-13.

9.         Katlama C, Assoumou L, Valantin MA, Soulie C, Duvivier C, Chablais L, et al. Maraviroc plus raltegravir failed to maintain virological suppression in HIV-infected patients with lipohypertrophy: results from the ROCnRAL ANRS 157 study. J Antimicrob Chemother. 2014;69(6):1648-52.