(Last updated:17/10/2017; last reviewed:17/10/2017)
Some antiretroviral (ARV) regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below.
The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: delavirdine (DLV), didanosine (ddI), indinavir (IDV), nelfinavir (NFV), and stavudine (d4T).
Nucleoside reverse transcriptase inhibitor (NRTI) monotherapy is inferior to dual-NRTI therapy.1 Protease inhibitor (PI) monotherapy is inferior to combination antiretroviral therapy (ART).2-6 Integrase strand transfer inhibitor (INSTI) monotherapy has resulted in virologic rebound and INSTI resistance (AI). 7,8
Antiretroviral Components Not Recommended
Atazanavir (ATV) + indinavir (IDV).
Didanosine plus Stavudine
The combination of ddI and d4T can result in peripheral neuropathy, pancreatitis, and lactic acidosis, and it has been implicated in the deaths of several pregnant women (AII). 13
Didanosine plus Tenofovir Disoproxil Fumarate
Tenofovir disoproxil fumarate (TDF) increases ddI concentrations,14 serious ddI-associated toxicities,15,16 immunologic nonresponse,17 early virologic failure,18,19 and resistance18,20 (AII).
Two Non-Nucleoside Reverse Transcriptase Inhibitor Combinations
Excess clinical adverse events and treatment discontinuation were reported in patients randomized to receive treatment with two non-nucleoside reverse transcriptase inhibitors (NNRTIs).21 Efavirenz (EFV) and nevirapine (NVP) are enzyme inducers, and both of these drugs can reduce concentrations of etravirine (ETR) and rilpivirine (RPV) (AI). 22
Emtricitabine plus Lamivudine
Both drugs have similar resistance profiles and have minimal additive antiviral activity. Inhibition of intracellular phosphorylation may occur in vivo (AIII). 23
Etravirine plus Unboosted Protease Inhibitor
ETR may induce the metabolism and significantly reduce the drug exposure of unboosted PIs. Appropriate doses of the PIs have not been established (AII). 22
Etravirine plus Fosamprenavir/Ritonavir
ETR may alter the concentrations of these PIs. Appropriate doses of the PIs have not been established (AII). 22
Etravirine plus Tipranavir/Ritonavir
Tipranavir/ritonavir (TPV/r) significantly reduces ETR concentrations (AII). 22
Nevirapine Initiated in ARV-Naive Women with CD4 Counts >250 cells/mm3 or in ARV-Naive Men with CD4 Counts >400 cells/mm3
Initiating NVP below these CD4 count thresholds increases the risk of symptomatic, and sometimes lifethreatening, hepatic events.24-26 Patients with CD4 counts above these thresholds due to ART can safely switch to NVP (BI). 27
Unboosted Darunavir, Saquinavir, or Tipranavir
The virologic benefit of these PIs has been demonstrated only when they were used with concomitant RTV, or in the case of DRV, also with COBI (AII).
Stavudine plus Zidovudine
These NRTIs are antagonistic in vitro28 and in vivo29 (AII).
Tenofovir Alafenamide plus Tenofovir Disoproxil Fumarate
This combination may be prescribed inadvertently, especially during transition from one formulation to another. There is no data supporting any potential additive efficacy or toxicity if TAF and TDF are used in combination.
|Table 10. Antiretroviral Regimens or Components That Should Not Be Offered At Any Time
|Antiretroviral Regimens Not Recommended|
|Monotherapy with NRTI (AII)||• Rapid development of resistance
• Inferior ARV activity when compared with combination of three or more ARV agents
|• No exception|
|Dual-NRTI regimens (AI)||• Rapid development of resistance
• Inferior ARV activity when compared with combination of three or more ARV agents
|• No exception|
|Triple-NRTI regimens (AI) except for ABC/ZDV/3TC (BI)
or possibly TDF + ZDV/3TC (BII)
|• High rate of early virologic nonresponse seen when triple-NRTI combinations, including ABC/TDF/3TC and TDF/ddI/3TC, were used as initial regimen in ART-naive patients.
• Other triple-NRTI regimens have not been evaluated.
|• ABC/ZDV/3TC (BI) and possibly TDF + ZDV/3TC (BII) in patients in whom other combinations are not desirable|
|Antiretroviral Components Not Recommended as Part of an Antiretroviral Regimen|
|ATV + IDV (AIII)||• Potential additive hyperbilirubinemia||• No exception|
|ddI + d4T (AII)||• High incidence of toxicities: peripheral neuropathy, pancreatitis, and hyperlactatemia
• Reports of serious, even fatal, cases of lactic acidosis with hepatic steatosis with or without pancreatitis in pregnant women
|• No Exception|
|ddI + TDF (AII)||• Increased ddI concentrations and serious ddI-associated toxicities
• Potential for immunologic nonresponse and/or CD4 cell count decline
• High rate of early virologic failure
• Rapid selection of resistance mutations at failure
|• Clinicians caring for patients who are clinically stable on regimens containing TDF + ddI should consider altering the NRTIs to avoid this combination.|
|2-NNRTI combination (AI)||• When EFV combined with NVP, higher incidence of clinical adverse events seen when compared with either EFV- or NVP-based regimen.
• Both EFV and NVP may induce metabolism and may lead to reductions in ETR exposure; thus, they should not be used in combination with ETR.
|• No exception|
|EFV in first trimester of pregnancy or in women with significant childbearing potential (AIII)||• Teratogenic in nonhuman primates||• When no other ARV options are available and potential benefits outweigh the risks (BIII)|
|FTC + 3TC (AIII)||• Similar resistance profiles
• No potential benefit
|• No exception|
|ETR + unboosted PI (AII)||• ETR may induce metabolism of these PIs; appropriate doses not yet established||• No exception|
|ETR + RTV-boosted ATV or FPV (AII)||• ETR may alter the concentrations of these PIs; appropriate doses not yet established||• No exception|
|ETR + RTV-boosted TPV (AII)||• ETR concentration may be significantly reduced by RTV-boosted TPV||• No exception|
|NVP in ARV-naive women with
CD4 count >250 cells/mm3 or men with
CD4 count >400 cells/mm3 (BI)
|• High incidence of symptomatic hepatotoxicity||• If no other ARV option available; if used, patient should be closely monitored|
|d4T + ZDV (AII)||• Antagonistic effect on HIV-1||• No exception|
|Unboosted DRV, SQV, or TPV (AII)||• Inadequate bioavailability||• No exception|
Acronyms: 3TC = lamivudine, ABC = abacavir, ATV = atazanavir, d4T = stavudine, ddI = didanosine, DRV = darunavir, EFV = efavirenz, ETR = etravirine, FPV = fosamprenavir, FTC = emitricitabine, IDV = indinavir, NVP = nevirapine, RTV = ritonavir, SQV = saquinavir, TDF = tenofovir, TPV = tipranavir, ZDV = zidovudine
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- Delfraissy JF, Flandre P, Delaugerre C, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS. Jan 30 2008;22(3):385-393. Available at https://www.ncbi.nlm.nih.gov/ pubmed/18195565.
- Swindells S, DiRienzo AG, Wilkin T, et al. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA. Aug 16 2006;296(7):806-814. Available at https:// www.ncbi.nlm.nih.gov/pubmed/16905786.
- Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. Jan 16 2010;24(2):223-230. Available at https://www.ncbi.nlm.nih. gov/pubmed/20010070.
- Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. Sep 242010;24(15):2365-2374. Available at https://www.ncbi.nlm.nih.gov/pubmed/20802297.
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