Date of last update: September 2013
For comprehensive information regarding the use of antiretroviral agents, see Antiretroviral Therapy. For up-to-date information on individual drugs, please refer to the AIDSinfo Drug Database.
Prescribers should consult with a clinician with extensive experience with antiretroviral therapy and management when constructing alternatives to first-line regimens for initial treatment and second- and later-line regimens for ART-experienced patients.
Integrase strand transfer inhibitors and CCR5 co-receptor antagonists should optimally be used as part of a regimen with at least two fully active agents plus the new agent.
Two new classes of antiretroviral agents have been approved by the FDA:
- Integrase strand transfer inhibitors (INSTIs): raltegravir, dolutegravir, and elvitegravir
- CCR5 co-receptor antagonists: maraviroc
Maraviroc, raltegravir, and dolutegravir are approved for use in both ART-experienced and ART-naïve patients. Stribild (elvitegravir/
II. INTEGRASE STRAND TRANSFER INHIBITORS (INSTIS)
A. Elvitegravir (currently approved only as a component of the combination pill Stribild)
Posted September 2013
Clinicians should calculate glomerular filtration rate before initiation of therapy, 1 month after initiation, and every 4 months thereafter for patients receiving Stribild.
The FDA has recently approved Stribild, a pill containing emtricitabine and tenofovir plus two new agents: elvitegravir (EVG), an integrase strand transfer inhibitor (INSTI); and cobicistat (COBI), a pharmacokinetic enhancer that prolongs the effectiveness of EVG. Stribild is prescribed as a once-daily fully potent regimen for ART-naïve patients (see Antiretroviral Therapy: Appendix A: Elvitegravir table).
At 96 weeks in two phase III trials, EVG/COBI/FTC/TDF was non-inferior to the following two regimens for the treatment of ART-naïve patients: 1) the combination formulation Atripla (EFV/FTC/TDF)1; and 2) ritonavir-boosted atazanavir plus the combination formulation Truvada (ATV/r + FTC/TDF).2 Viral suppression (<50 copies/mL) was achieved at rates of 84% and 83% for EVG/COBI/FTC/TDF vs. 82% for both EFV/FTC/TDF and ATV/r + FTC/TDF.
Although EVG is currently approved only as a component of Stribild for ART-naïve HIV-infected patients, the manufacturer is seeking FDA approval for EVG as a single agent to be prescribed with at least two fully active agents for ART-experienced patients.
- Dosing for Stribild: One tablet (EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg) PO once daily with food
- Should not be co-administered with:
- Other ART agents
- Drugs that are contraindicated or should be avoided in combination with any components of Stribild (for drug-drug interactions using EVG and COBI, see Antiretroviral Therapy: Appendix A: Elvitegravir table; for drug-drug interactions using tenofovir, see Antiretroviral Therapy: Appendix A: Tenofovir table; for drug-drug interactions using emtricitabine, see Antiretroviral Therapy: Appendix A: Emtricitabine table)
- Main side effects: Nausea, diarrhea, vomiting, flatulence, abnormal dreams, headache, dizziness, insomnia, somnolence
- Adverse effects: New-onset or worsening renal impairment, which can include acute renal failure and Fanconi syndrome. Calculate glomerular filtration rate before initiation of therapy, 1 month after initiation, and every 4 months thereafter.
- FDA Pregnancy Category: B – No adequate and well-controlled studies in pregnant women. Not teratogenic in animal studies.
COBI is a pharmacokinetic enhancer that has been approved by the FDA as part of the combination formulation Stribild to prolong the effectiveness of EVG by inhibiting CYP3A. The use of COBI allows for once-daily dosing of Stribild as a fully potent regimen for ART-naïve HIV-infected patients.
Although COBI is currently approved by the FDA only as a component of the Stribild combination formulation, evidence from a phase II trial suggests that twice-daily dosing of COBI is non-inferior to ritonavir in boosting the PI atazanavir.3 However, unlike the pharmacokinetic enhancer ritonavir, COBI does not have anti-HIV activity.
For more information, see Antiretroviral Therapy: Appendix A: Dolutegravir table.
Updated November 2011
Clinicians should perform resistance testing before changing from a PI-boosted regimen to raltegravir (see Antiretroviral Therapy: Section VI. B. HIV Resistance Assays). (AII)
Clinicians should discontinue raltegravir in patients who develop signs or symptoms of severe skin reactions or hypersensitivity reactions.
Raltegravir has been approved by the FDA for use in both ART-naïve and ART-experienced adults for construction of a potent, fully suppressible regimen for patients with intolerance or resistance to first- or later-line agents. In one study, raltegravir was as effective as efavirenz when used in ART-naïve patients receiving combination treatment.4
Raltegravir has been demonstrated to be effective in ART-experienced adults with triple-class-resistant HIV-1 infection.5 Phase III studies have shown that an optimized regimen plus raltegravir is superior to an optimized regimen alone in suppressing HIV RNA below detection and in increasing CD4 counts. Raltegravir has been successfully used as a substitution for enfuvirtide in virally suppressed patients,6 but was not as effective when substituted for lopinavir/ritonavir in extensively ART-experienced patients.7 If change from a boosted-PI regimen to raltegravir is under consideration because of treatment failure, evaluation for potential resistance to the background regimen is critical. The use of raltegravir in patients who require a change in ART because of side effects continues to be studied.
Raltegravir has been approved by the FDA for use in initial regimens for treatment-naïve patients. Raltegravir may also be used as part of a salvage regimen in treatment-experienced patients when resistance or side effects have limited the use of other available agents.
- Dosing: 400 mg PO twice daily. Dose adjustment is not required for mild to moderate hepatic insufficiency or severe renal insufficiency.8 Raltegravir should be used with caution in patients with severe hepatic impairment.
- When used with etravirine: Monitor for virologic efficacy with co-administration
- When used with tipranavir/ritonavir: Monitor closely
- When used with rifampin: Recommended dosing of raltegravir is 800 mg PO twice daily, but there are no clinical data. Use of rifabutin should be considered with raltegravir co-administration.
- Main side effects: Rash and diarrhea
- Adverse effects: Severe, potentially life-threatening, and fatal skin reactions have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Discontinue immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema.
- FDA Pregnancy Category: C – No human data. Animal developmental studies found a higher incidence of supernumerary ribs compared to control.
III. CCR5 Co-Receptor Antagonist: Maraviroc
Reviewed September 2013
Maraviroc should be prescribed only for patients with CCR5-tropic HIV, as determined by a highly sensitive tropism assay that is performed at the time that therapy is considered. (AII) Maraviroc should not be used outside of clinical trials in patients with dual/mixed- or CXCR4-tropic virus. (AII)
The CCR5 co-receptor antagonist maraviroc is a potent agent that has been approved by the FDA for therapy in patients with CCR5-tropic HIV. CXCR4-tropic and dual/mixed tropic HIV entry is not inhibited by maraviroc. Maraviroc is approved for use in both ART-naïve and ART-experienced patients for construction of a potent, fully suppressible regimen for patients with intolerance or resistance to first- or later-line agents. A phase III study showed that maraviroc achieved comparable viral suppression when compared to efavirenz in ART-naïve patients receiving combination treatment. However, more ART-naïve patients treated with maraviroc experienced virologic failure and developed lamivudine resistance compared to efavirenz.9 Maraviroc has been demonstrated to be effective in ART-experienced adults.10,11
Screening with a highly sensitive co-receptor tropism assay should be performed at the time that therapy is considered because previous results may not be valid due to tropism changes. The sensitivity of some co-receptor tropism assays has been enhanced, but treatment with agents in the CCR5 co-receptor antagonist class remains a challenge (see Diagnostic, Monitoring, and Resistance Laboratory Tests for HIV). In the past, many patients who failed therapy with maraviroc and other investigational CCR5 receptor antagonists were found to have dual- or mixed-tropic HIV that was not detected by the screening assay used.12
- Maraviroc may be used as part of a second- or later-line regimen in treatment-experienced patients with CCR5-tropic HIV when resistance or side effects have limited the use of other available agents. Maraviroc is also approved by the FDA for use in initial alternative regimens for treatment-naïve patients with CCR5-tropic HIV.
- For patients with dual/mixed-tropic virus, maraviroc should not be used outside of clinical trials. Evidence suggests that maraviroc is no more effective than placebo when used with an optimized background regimen in individuals with dual/mixed tropic virus.13
- Dosing: 300 mg PO twice daily, with the following caveats:
- The metabolism of maraviroc is affected by strong CYP3A inducers and inhibitors; therefore, co-administration of potent CYP3A inducers and potent CYP3A inhibitors may require dosing adjustments (see Table 1 and HIV Drug-Drug Interactions: Table 2).
- Maraviroc should not be prescribed for patients with severe renal impairment or ESRD who are receiving potent CYP3A inducers or potent CYP3A inhibitors. Patients with severe renal impairment or ESRD who are not receiving potent CYP3A inducers or inhibitors may require dose adjustments for maraviroc to avoid cardiovascular risks associated with postural hypotension (see Antiretroviral Therapy: Appendix A: Maraviroc table).
- Should not be co-administered with the following:
- The CYP3A inducer St. John’s wort (Hypericum perforatum) or products containing St. John’s wort.
- Main side effects: cough, fever, colds, rash, muscle and joint pain, stomach pain, and dizziness; however, it is generally well tolerated.
- FDA Pregnancy Category: B
For additional prescribing information, see Antiretroviral Therapy: Appendix A: Maraviroc table, as well as the manufacturer’s maraviroc label.
1. Zolopa A, Sax PE, Dejesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/
2. Rockstroh JK, Dejesus E, Henry K, et al. A randomized, double-blind comparison of co-formulated elvitegravir/
3. Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/
4. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: A multicentre, double-blind randomised controlled trial. Lancet 2009;374:796-806. [PubMed]
5. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008;359:339-354. [PubMed]
6. Towner W, Klein D, Kerrigan HL, et al. Virologic outcomes of changing enfuvirtide to raltegravir in HIV-1 patients well controlled on an enfuvirtide based regimen: 24-week results of the CHEER study. J Acquir Immune Defic Syndr 2009;51:367-373. [PubMed]
7. Eron J, Andrade J, Zajdenverg R, et al. Switching from stable lopinavir/ritonavir-based to raltegravir-based combination ART resulted in a superior lipid profile at week 12 but did not demonstrate non-inferior virologic efficacy at week 24. The 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 3-6, 2008. Abstract 70aLB.
8. Iwamoto M, Hanley WD, Petry AS, et al. Lack of a clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother 2009;53:1747-1752. [PubMed]
9. Heera J, Ive P, Botes M, et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. The 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, July 19-22, 2009, Cape Town, South Africa. Abstract TUAB103.
10. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008;359:1429-1441. [PubMed]
11. Fatkenheuer G, Nelson M, Lazzarin A, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008;359:1442-1455. [PubMed]
12. Heera J, Saag M, Ive P, et al. Virological correlates associated with treatment failure at week 48 in the phase 3 study of maraviroc in treatment-naive patients. The 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 3-6, 2008. Abstract 40LB.
13. Mayer E, van der Ryst E, Saag M, et al. Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. The 16th International AIDS Conference, Toronto, Ontario, Canada, August 13-18, 2006. Abstract THLB0215.