1 EI + 1 PI + 1 NNRTI

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

Overview

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 NNRTI 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 NNRTI, INSTI or PI 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, NNRTI + PI may have been included as part of that OBR, based on treatment history and resistance testing. Our assessment of regimens containing EI + NNRTI + PI 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 NNRTI + MVC as part of salvage regimens. Testing for CCR5 tropism is recommended each time when considering MVC.

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. There is relatively limited data on the OBR components when using an NNRTI as part of salvage regimens with IBA. However, in the primary clinical trials leading to FDA approval, 67% of individuals in the trial (18 out of 27) had inclusion of Darunavir (PI) as part of their OBR (personal communication). In heavily treatment-experienced patients with MDR HIV-1, IBA was effective in combination with Darunavir (DRV). Furthermore, safety and efficacy of IBA observed at Week 25 were maintained through 96 weeks.

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

DHHS (Dec. 2019):  In general, NNRTI-based regimens are not recommended for persons with HIV-2. The combination of MVC and PI and NNRTI in treatment-naïve patients is not specifically discussed in the guidelines. MVC in combination with 1 PI is not discussed as initial therapy. MVC 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 a PI (or INSTI 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. The combination of MVC+ NNRTI + PI is not discussed as initial therapy.

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. MVC in combination with 1 PI is not discussed for treatment of naïve patients and is not listed as one of the preferred options in patients with other treatment options. In a rare circumstance in which MVC might be included in initial therapy, initiation should not occur before confirmation of CCR5 tropism.

Recommendations for MVC+ 1 NNRTI + 1 PI 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 NNRTI, INSTI 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. MVC appears to be active against some HIV-2 isolates, however, there are no FDA-approved assays that can determine HIV-2 co-receptor tropism, and HIV-2 is known to use many other minor co-receptors in addition to CCR5 and CXCR4. In a randomized controlled trial, patients with virologic suppression who were on a regimen of two NRTIs plus a boosted PI and who had only CCR5-tropic HIV (as detected by proviral DNA testing) were randomized to continue their current regimen switch was associated with higher rates of virologic failure and treatment of discontinuation than the other two regimens. Based on these results, a regimen consisting of a boosted PI and MVC cannot be recommended.

IAS-USA (2018): 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 an NNRTI and PI in treatment-experienced patients is not specifically discussed.

Recommendations for IBA + 1 NNRTI + 1 PI 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 and requires IV therapy. In general, NNRTI-based regimens are not recommended for persons with HIV-2. The combination of IBA and NNRTI and PI 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. This regimen is not discussed in the IAS-USA guidelines for treatment-naïve patients.

Recommendations for IBA + 1 NNRTI + 1 PI 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 discuss an NNRTI or PI to pair with IBA.

IAS-USA (2018): IBA, 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 discuss an NNRTI and PI to pair with IBA.

Other Considerations

MVC

• 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 

IBA

• 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

Atazanavir

• Potent, once-daily anchor agent when given with a pharmacokinetic enhancer
• Causes indirect hyperbilirubinemia that can lead to jaundice
• May cause nephrolithiasis and gallstones
• Concomitant use of certain acid suppressive agents can decrease absorption
• Can be given with or without a pharmacokinetic booster (recommended to combine with pharmacokinetic enhancer)

Atazanavir-Cobicistat

• Fixed-dose one-pill combination
• May cause indirect hyperbilirubinemia, kidney stones and gallstones
• Typically causes benign small increase in serum creatinine
• Can cause significant drug interactions

Darunavir (DRV)

• Must be combined with pharmacokinetic booster (cobicistat or ritonavir)
• Retains activity following development of drug resistance with most other PIs

Darunavir-Cobicistat

• Fixed-dose combination pill consisting of a PI and pharmacologic booster
• Option for initial ART and as a component of salvage regiments for tx-experienced if once-daily dosing is indicated
• Similar tolerability to once-daily darunavir plus ritonavir
• High potency and barrier to resistance as anchor drug
• Gastrointestinal side effects and drug interactions
• Has sulfonamide moiety (use with caution for patients with sulfonamide allergy)

Fosamprenavir

• Prodrug of amprenavir (discontinued PI)
• Replaced by newer ART anchor drugs that involve fewer pills and side effects
• For tx-naïve, can be administered unboosted 2x daily, boosted by ritonavir once daily, or boosted by ritonavir twice daily
• For PI-experienced, 2x daily dosing with ritonavir boosting is recommended
• Virologic failure can lead to resistance mutations that decrease efficacy of darunavir
• Contains sulfonamide moiety so use caution in patients with sulfonamide allergy
• Clinicians should change fosamprenavir to a currently recommended anchor drug to lower risk of adverse events and pill burden

Indinavir

• No longer used as ART because of toxicity
• Frequently causes kidney stones (advise patients to drink 1.5 liters of water per day)
• Requires more frequent dosing than currently recommended agents, has strict food requirements, associated with cosmetically disturbing lipoaccumulation
• Patients should switch to a safer and currently recommended agent

Lopinavir-Ritonavir

• Fixed-dose combination of PI (lopinavir) and booster (ritonavir)
• Widely used for pregnant women with HIV and PrEP
• Rarely used in U.S. because of newer anchor drugs with lower pill burden and lower adverse effects
• May be dosed once-daily for tx-naive and some tx-experienced individuals
• Only twice-daily dosing recommended for the following patients: with 3 or more lopinavir-associated resistance mutations, taking certain other ART medications that interact with lopinavir, and if pregnant
• Common drug interactions, gastrointestinal side effects, and metabolic adverse effects (e.g. hyperlipidemia)

Nelfinavir

• Replaced in clinical practice with newer, more portent, better-tolerated medications
• Administered without pharmacokinetic booster
• Relatively low potency, low genetic barrier to resistance
• If patient develops drug resistance to nelfinavir, they usually respond to newer PI
• Not recommended for use in ART regimens: patient should switch to current recommendation

Saquinavir

• Different formulations: hard-gel capsule, soft-gel capsule (discontinued), tablet
• Not recommended for use in ART regimens: patient should switch to current recommendation

Tipranavir

• Developed as salvage therapy for patients with resistance mutations to other PIs (also studied as component of initial therapy)
• Unique resistance profile
• FDA black box warning: fatal and nonfatal intracranial hemorrhage, severe hepatoxicity
• Requires 2x daily dosing with ritonavir boosting
• Required dosing is higher than with other PIs
• Tipranavir + ritonavir causes frequent GI side effects and drug interactions

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

IBA

MVC 

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.