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All-Nucleoside Reverse Transcriptase Inhibitor Regimens

Triple-NRTI regimens studied in several clinical trials have shown suboptimal virologic activity.22-23, 109-112

Abacavir/Lamivudine/Zidovudine (coformulated). ABC/3TC/ZDV is the only triple-NRTI combination for which randomized, controlled trials are available. ABC/3TC/ZDV demonstrated comparable ARV activity to IDV-based104-105 and NFV-based regimens112 but was inferior virologically to an EFV-based regimen.22 This combination is generally not recommended (BI) and should be used only when a preferred, an alternative, or an acceptable NNRTI-, PI-, or INSTI- based regimen is less desirable because of concerns about toxicities, drug interactions, or regimen complexity.

Zidovudine/Lamivudine + Tenofovir. The DART study demonstrated that the combination of ZDV/3TC + TDF has antiviral activity.113 However, because comparative data with standard regimens are not available, this combination cannot be recommended in routine clinical practice (BIII).

Zidovudine/Lamivudine + Abacavir + Tenofovir. A quadruple-NRTI regimen of ZDV/3TC + ABC + TDF first showed comparable virologic responses to an EFV-based regimen in a small pilot study.114 A larger study randomized 322 subjects to receive TDF/FTC combined with EFV, ATV/RTV, or a quadruple-NRTI regimen with ZDV and ABC. Although the threshold of noninferiority for the protocol-defined virologic response was satisfied by the quadruple-NRTI regimen, the proportion of patients reaching HIV RNA <50 copies/mL was lower with the quadruple-NRTI regimen and the rate of serious toxicity was twice as high as that observed with the EFV-based regimen.115 Thus, this regimen cannot be recommended (BI).

Table 6. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy

ARV Class ARV Agent(s) Advantages Disadvantages
Key to Abbreviations: 3TC = lamivudine, ABC = abacavir, APV = amprenavir, ART = antiretroviral therapy, ARV = antiretroviral, ATV = atazanavir, ATV/r = atazanavir/ritonavir, AV = atrioventricular, BMD = bone mineral density, CNS = central nervous system, CYP = cytochrome P, d4T = stavudine, ddI = didanosine, DRV/r = darunavir/ritonavir, ECG = electrocardiogram, EFV = efavirenz, FPV = fosamprenavir, FPV/r = fosamprenavir/ ritonavir, FTC = emtricitabine, GI = gastrointestinal, HBV = hepatitis B virus, HSR = hypersensitivity reaction, INSTI = integrase strand transfer inhibitor, LPV/r = lopinavir/ritonavir, MI = myocardial infarction, msec = milliseconds, MVC = maraviroc, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, NVP = nevirapine, PI = protease inhibitor, PPI = proton pump inhibitor, RAL = raltegravir, RPV = rilpivirine, RTV = ritonavir, SJS = Stevens-Johnson syndrome, SQV/r = saquinavir/ritonavir, TAM = thymidine analogue mutation, TDF = tenofovir, TEN = toxic epidermal necrosis, ZDV = zidovudine
NNRTIs (in alphabetical order)   NNRTI Class Advantages:
  • Long half-lives
NNRTI Class Disadvantages:
  • Greater risk of resistance at the time of treatment failure with NNRTIs than with PIs
  • Potential for cross resistance
  • Skin rash
  • Potential for CYP450 drug interactions (See Tables 14, 15b, and 16b.)
  • Transmitted resistance more common with NNRTIs than with PIs
EFV
  • Virologic responses equivalent or superior to all comparators to date
  • Once-daily dosing
  • Coformulated with TDF/FTC
  • Neuropsychiatric side effects
  • Teratogenic in nonhuman primates. Several cases of neural tube defect in infants born to women who were exposed to EFV in the first trimester of pregnancy reported. EFV use should be avoided in women with potential for pregnancy and is contraindicated in the first trimester.
  • Dyslipidemia
NVP
  • No food effect
  • Fewer lipid effects than EFV
  • Once-daily dosing with extended-release tablet formulation
  • Higher incidence of rash, including rare but serious HSRs (SJS or TEN), than with other NNRTIs
  • Higher incidence of hepatotoxicity, including serious and even fatal cases of hepatic necrosis, than with other NNRTIs
  • Contraindicated in patients with moderate or severe (Child-Pugh B or C) hepatic impairment
  • Some data suggest that ART-naive patients with high pre-NVP CD4 counts (>250 cells/mm3 for females, >400 cells/mm3 for males) are at higher risk of symptomatic hepatic events. NVP is not recommended in these patients unless benefit clearly outweighs risk.
  • Early virologic failure of NVP + TDF + (FTC or 3TC) in small clinical trials
RPV
  • Once-daily dosing
  • Coformulated with TDF/FTC
  • Compared with EFV:
    • Fewer discontinuations for CNS adverse effects
    • Fewer lipid effects
    • Fewer rashes
  • More virologic failures in patients with pretreatment HIV RNA >100,000 copies/mL than with EFV-based regimen
  • More NNRTI- and 3TC-associated mutations at virological failure than with regimen containing EFV + two NRTIs
  • Food requirement
  • Absorption depends on lower gastric pH. (See Table 15a for detailed information regarding interactions with H2 antagonists and antacids.)
  • Contraindicated with PPIs
  • RPV-associated depression reported
  • Use RPV with caution when coadministered with a drug having a known risk of torsades de pointes.
PIs (in alphabetical order)   PI Class Advantages:
  • Higher genetic barrier to resistance than NNRTIs and RAL
  • PI resistance uncommon with failure while on first PI regimen
PI Class Disadvantages:
  • Metabolic complications such as dyslipidemia, insulin resistance, hepatotoxicity
  • GI adverse effects
  • CYP3A4 inhibitors and substrates: potential for drug interactions (more pronounced with RTV-based regimens) (See Tables 14 and 15a.)
ATV
  • Fewer adverse effects on lipids than other PIs
  • Once-daily dosing
  • Low pill burden
  • Good GI tolerability
  • Signature mutation (I50L) not associated with broad PI cross resistance
  • Indirect hyperbilirubinemia sometimes leading to jaundice or scleral icterus
  • PR interval prolongation: generally inconsequential unless ATV combined with another drug with similar effect
  • Cannot be coadministered with TDF, EFV, or NVP (See ATV/r.)
  • Nephrolithiasis
  • Skin rash
  • Food requirement
  • Absorption depends on food and low gastric pH. (See Table 15a for detailed information regarding interactions with H2 antagonists, antacids, and PPIs.)
ATV/r
  • RTV boosting: higher trough ATV concentration and greater antiviral
    effect
  • Once-daily dosing
  • Low pill burden
  • More adverse effects on lipids than unboosted ATV
  • More hyperbilirubinemia and jaundice than unboosted ATV
  • Food requirement
  • Absorption depends on food and low gastric pH. (See Table 15a for interactions with H2 antagonists, antacids, and PPIs.)
  • RTV boosting required with TDF and EFV. With EFV, use ATV 400 mg and RTV 100 mg once daily (PI-naive patients only).
  • Should not be coadministered with NVP
DRV/r
  • Once-daily dosing
  • Potent virologic efficacy
  • Skin rash
  • Food requirement
FPV/r
  • Twice-daily dosing resulted in efficacy comparable to LPV/r
  • RTV boosting results in higher trough APV concentration and greater antiviral effect
  • Once-daily dosing possible with RTV 100 mg or 200 mg daily
  • No food effect
  • Skin rash
  • Hyperlipidemia
  • Once-daily dosing results in lower APV concentrations than twice-daily dosing
  • For FPV 1400 mg + RTV 200 mg: requires 200 mg of RTV and no coformulation
  • Fewer data on FPV 1400 mg + RTV 100 mg dose than on DRV/r and ATV/r
PIs (in alphabetical order) LPV/r
  • Coformulated
  • No food requirement
  • Recommended PI in pregnant women (twice daily only)
  • Greater CD4 count increase than with EFV-based regimens
  • Requires 200 mg per day of RTV
  • Lower drug exposure in pregnant women—may need dose increase in third trimester
  • Once-daily dosing not recommended in pregnant women
  • Once-daily dosing results in lower trough concentration than twice-daily dosing
  • Possible higher risk of MI associated with cumulative use of LPV/r
  • PR and QT interval prolongation have been reported. Use with caution in patients at risk of cardiac conduction abnormalities or receiving other drugs with similar effect.
SQV/r
  • Similar efficacy but less hyperlipidemia than with LPV/r
  • Highest pill burden (6 pills per day) among available PI regimens
  • Requires 200 mg of RTV
  • Food requirement
  • PR and/or QT interval prolongations in a healthy volunteer study
  • Pretreatment ECG recommended
  • SQV/r is not recommended for patients with any of the following conditions: (1) congenital or acquired QT prolongation; (2) pretreatment ECG >450 msec; (3) on concomitant therapy with other drugs that prolong QT interval; (4) complete AV block without implanted pacemakers; (5) risk of complete AV block.
INSTI RAL
  1. Virologic response noninferior to EFV
  2. Fewer drug-related adverse events and lipid changes than EFV
  3. No food effect
  4. Fewer drug-drug interactions than PI- or NNRTI-based regimens
  • Twice-daily dosing
  • Lower genetic barrier to resistance than with boosted PI based regimens
  • No data with NRTIs other than TDF/FTC in ART-naive patients
  • Increase in creatine kinase, myopathy, and rhabdomyolysis have been reported
  • Rare cases of severe skin reactions (including SJS and TEN) have been reported and systemic HSRs with rash and constitutional symptoms, with or without hepatitis, have been reported.
CCR5 Antagonist MVC
  • Virologic response noninferior to EFV in post hoc analysis of MERIT study (See text.)
  • Fewer adverse effects than EFV
  • Requires viral tropism testing prior to initiation of therapy, which results in additional cost and possible delay in initiation of therapy
  • More MVC-treated than EFV-treated patients discontinued therapy due to lack of efficacy in MERIT study
  • Less long-term experience in ART-naive patients than with boosted PI- or NNRTI-based regimens
  • Limited experience with dual-NRTIs other than ZDV/3TC
  • Twice-daily dosing
  • CYP 3A4 substrate; dosing depends on presence or absence of concomitant CYP3A4 inducer(s) or inhibitor(s)
Dual-NRTI pairs (in alphabetical order) ABC/3TC
  • Virologic response noninferior to ZDV/3TC
  • Better CD4 count responses than with ZDV/3TC
  • Once-daily dosing
  • Coformulation
  • No food effect
  • No cumulative TAM-mediated resistance
  • Potential for ABC HSR in patients with HLA-B*5701
  • Increased potential for cardiovascular events, especially in patients with cardiovascular risk factors
  • Inferior virologic responses in patients with baseline HIV RNA >100,000 copies/mL when compared with TDF/FTC in ACTG 5202 study; however, this was not seen in the HEAT study.
TDF/FTC
  • Better virologic responses than with ZDV/3TC
  • Better virologic responses than with ABC/3TC in patients with baseline HIV RNA >100,000 copies/mL in ACTG 5202 study; however, this was not seen in the HEAT study.
  • Active against HBV; recommended dual-NRTI for HIV/HBV coinfection
  • Once-daily dosing
  • No food effect
  • Coformulated (TDF/FTC, EFV/TDF/FTC, and RPV/TDF/FTC)
  • No cumulative TAM-mediated resistance
  • Potential for renal impairment, including Fanconi syndrome and acute renal insufficiency
  • Early virologic failure of NVP + TDF + (FTC or 3TC) in small clinical trials
  • Potential for decrease in BMD
ZDV/3TC
  • Coformulated (ZDV/3TC and ZDV/3TC/ABC)
  • No food effect (although better tolerated with food)
  • Preferred dual NRTI in pregnant women
  • Bone marrow suppression, especially anemia and neutropenia
  • GI intolerance, headache
  • Mitochondrial toxicity, including lipoatrophy, lactic acidosis, hepatic steatosis
  • Compared with TDF/FTC, inferior in combination with EFV
  • Less CD4 increase compared with ABC/3TC
  • Twice-daily dosing

Table 7. Antiretroviral Components or Regimens Not Recommended as Initial Therapy

ARV drugs or components (in alphabetical order) Reasons for NOT recommending as initial therapy
Key to Abbreviations: 3TC = lamivudine, ABC = abacavir, ART = antiretroviral therapy, ARV = antiretroviral, d4T = stavudine, ddI = didanosine, DLV = delavirdine, DRV = darunavir, ETR = etravirine, FPV = fosamprenavir, FTC = emtricitabine, GI = gastrointestinal, IDV = indinavir, NFV = nelfinavir, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor, RTV = ritonavir, SQV = saquinavir, T20 = enfuvirtide, TDF = tenofovir, TPV = tipranavir, ZDV = zidovudine
ABC/3TC/ZDV (coformulated) as triple-NRTI combination regimen (BI)
  • Inferior virologic efficacy
ABC + 3TC + ZDV + TDF as quadruple-NRTI combination regimen (BI)
  • Inferior virologic efficacy
DRV (unboosted)
  • Use without RTV has not been studied
DLV (BIII)
  • Inferior virologic efficacy
  • Inconvenient (three times daily) dosing
ddI + 3TC (or FTC) (BIII)
  • Inferior virologic efficacy
  • Least clinical trial experience in ART-naive patients
ddI + TDF (BII)
  • High rate of early virologic failure
  • Rapid selection of resistance mutations
  • Potential for immunologic nonresponse/CD4 T-cell decline
  • Increased ddI drug exposure and toxicities
T20 (BIII)
  • No clinical trial experience in ART-naive patients
  • Requires twice-daily subcutaneous injections
ETR (BIII)
  • Insufficient data in ART-naive patients
FPV (unboosted) (BIII)
  • Less potent than RTV-boosted FPV
  • Virologic failure with unboosted FPV-based regimen may select mutations that confer resistance to DRV
IDV (unboosted) (BIII)
  • Inconvenient dosing (three times daily with meal restrictions)
  • Fluid requirement
IDV (RTV-boosted) (BIII)
  • High incidence of nephrolithiasis
NFV (BI)
  • Inferior virologic efficacy
  • High incidence of diarrhea
RTV as sole PI (BIII)
  • High pill burden
  • GI intolerance
SQV (unboosted) (BI)
  • Inferior virologic efficacy
d4T + 3TC (BI)
  • Significant toxicities including lipoatrophy; peripheral neuropathy; and hyperlactatemia, including symptomatic and life-threatening lactic acidosis, hepatic steatosis, and pancreatitis
TPV (RTV-boosted) (BI)
  • Inferior virologic efficacy

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