DHHS Guidelines (11/2019): Recommended Initial Regimens for Most People with HIV

Recommended initial regimen for most people with HIV are those with demonstrated durable virologic efficacy with good tolerability:

Please see notes below if childbearing potential

INSTI + 2 NRTI

• DTG/ABC/3TC (AI, if HLA B*5701- negative);
• DTG + TDF/FTC (AI) or DTG +TAF/FTC(AI);
• BIC/TAF/FTC (AI)
• RAL+TDF/FTC (BI) or RAL+TAF/FTC(BII) (RAL may be given as RAL 400mg BID or RAL 1200mg once daily)

INSTI + 1 NRTI (new update to 2019 guidelines on the basis of two large randomized controlled trials that showed that a two-drug regimen of DTG/3TC was noninferior to DTG+TDF/FTC, except for individuals with HIV RNA>500,000, known active HBV, or initiating before genotype results)

• DTG/3TC (AI, except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available)

DHHS Guidelines (11/2019): Recommended initial regimen in certain clinical situations

• This section replaces the ’alternative regimens’ listed in prior DHHS guidelines.
• Recommended initial regimen in certain clinical situations:
  • Regimens that are effective and tolerable but that have potential disadvantages compared with the recommend regimens listed above, have limitations for use in certain patient populations, or have less supporting data from randomized clinical trials. May be the preferred for some patients.
  • INSTI-based regimens:
    • EVG/c/TAF/FTC or EVG/c/TDF/FTC (BI for both);
  • PI-based regimens: In general, boosted DRV is preferred over boosted ATV
    • ATV/c + TDF/FTC (BI); ATV/r + TDF/FTC (BI); ATV/r + TAF/FTC (BI); ATV/c + TAF/FTC (BI);
    • (DRV/c or DRV/r) + TDF/FTC (AI); (DRV/c or DRV/r) +TAF/FTC (AI);
    • (DRV/c or DRV/r) + ABC/3TC (BII, if HLA-B*5701 negative)
  • NNRTI-based regimens:
    • DOR/TDF/3TC (BI) or DOR plus TAF/FTC(BIII);
    • EFV plus (TAF or TDF) plus (FTC or 3TC)
      • EFV 600mg/TDF/FTC (BI);
      • EFV 400mg/TDF/3TC (BI);
      • EFV 600mg + TAF/FTC (BII);
    • RPV/TDF/FTC or RPV/TAF/FTC (for patients with VL < 100,000, CD4 >200, BI)
  • Regiments to consider when ABC, TAF, and TDF cannot be used or are not optimal
    • DTG plus 3TC (BI)
    • DRV/r plus RAL BID (CI)—if HIV RNA < 100,000 copies/ml and CD4 cell count >200
    • DRV/r once daily plus 3TC (CI)

DHHS Guidelines (11/2019): Other

• 3TC may be substituted for FTC and vice versa.
• ABC should not be used in patients who test positive for HLA-B*5701.
• ABC/3TC, TDF/3TC, TDF/FTC, and TAF/FTC are available coformulated and also as part of various single-tablet regimens.
• TAF and TDF are two forms of tenofovir approved by FDA. TAF has fewer bone and kidney toxicity than TDF, while TDF is associated with lower lipid levels and possibly less weight gain.
• ABC should not be used in patients who test positive for HLA-B*5701.
• CONSIDERATIONS before initiating DTG or other INSTI (DHHS guidelines 12/2019; DHHS recommendations for use of ARV in pregnant women January 17, 2020)
  • Pregnancy testing should be performed in those of childbearing potential prior to ART initiation.
  • DTG usage in pregnancy has been updated.
    • Initial studies highlighted a possible link between DTG and neural tube defects reported in May 2018 from a study in Botswana. Based on these preliminary findings, DHHS recommended providers discuss these risks with patietns (AIII). Data available as of Aug 2019 were used to update guidance.
    • Recommendations on use of DTG during first trimester and in whomen who are trying to conceive have been removed. DTG is now a preferred regimen throughout pregnancy, and an alternative regimen in women who are trying to conceive.
      • In 2019, new data from two large clinical trials comparing efficacy and safety of DTG and EFV was presented and suggested that the risk of neural tube defects are significantly lower than what initial studies suggested. Guidance was updated based on emerging data.
  • BIC is not recommended during pregnancy because of insufficient safety data.
  • EVG/c is not recommended because of low EVG concentration when drug is given during second and third trimesters.
  • See perinatal guidelines for full discussion of ARV selection in Pregnancy.
• ARV Regimen Considerations based on Clinical Scenarios:
  • Chronic kidney disease: Avoid TDF (eGFR < 60; use ABC or TAF; TAF may be used if eGFR >30. When ABC, TAF, or TDF cannot be used, consider DTG/3TC or DRV/boosted plus 3TC or DRV/boosted plus RAL (if CD4>200 and HIV RNA< 100,000)
  • Liver disease: Some ARVs contraindicated or require dose modification in patients with Child-Pugh class B or C disease; see guidelines
  • Bone disease: Avoid TDF with osteoporosis; use ABC or TAF
  • Psychiatric illness: Consider avoiding EFV- and RPV-based regimens
  • HIV-associated dementia: Avoid EFV-based regimens; favor DRV- or DTG-based regimens
  • Narcotic replacement therapy: Consider avoiding EFV-based regimens; increase methadone dose may be required
  • High cardiac risk: Consider avoiding ABC- and LPV/r-based regimens
  • HBV infection: Use either TDF or TAF plus either FTC or 3TC
  • HCV infection: See HCV guidelines
  • Pregnancy: See perinatal guidelines, and discussion above.
• Use of gastric acid-reducing agents (PPIs, H2 blockers): ATV/r should not be used in pts who require >20 mg omeprazole equivalent per day. Use with caution in pts on PPIs (any dose), H2-blockers, antacids. Avoid RPV with PPIs.
• Tuberculosis: TAF not yet recommended with rifamycin. However, recent data suggests that intracellular levels of tenofovir obtained when using TAF in the presence of rifampin are adequate (compared to intracellular tenofovir levels achieved with TDF without rifamycin). If rifampin used, can use EFV (standard dose), RAL (800 mg twice-daily), DTG (50 mg twice daily). DTG and RAL can be used at standard doses with rifabutin. BIC should not be used with a rifamcyin. If PI-based regimen used; use dose-adjusted rifabutin instead of rifampin.
• Resistance results not available: Avoid NNRTI based regimens and DTG/3TC. Avoid ABC. Use either DRV/boosted or (DTG or BIC) plus either TAF/FTC or TDF/FTC
• Single-tablet, once-daily regimens:BIC/TAF/FTC, DOR/TDF/3TC, DRV/c/TAF/FTC, DTG/3TC, DTG/ABC/3TC, EFV/TDF/3TC, EVG/COBI/TAF/FTC, EFV/COBI/TDF/FTC, RPV/TAF/FTC, RPV/TDF/FTC
  • Please note specific recommendations above. For example, ABC containing regimens should not be used in those that are HLA-B701 positive. DTG/3TC is not recommended with RNA >500,000, RPV regimens should not be used with RNA>100,000 or CD4< 200.
• Food effects
  
  • Without regard to food: BIC-, DOR-, RAL- or DTG-based regimens
  • With food: ATV/r-, ATV/c-, DRV/r-, DRV/c-, EVG/c-, and RPV-based regimen
  • Empty stomach: EFV based regimens

IAS-USA Guidelines (2018)

• "Generally Recommended initial ART regimens":
  • BIC/TAF/FTC (AIa)
  • DTG + ABC/3TC (AIa)
  • DTG+TAF/FTC (AIa)
• Initial therapy options for patients in whom regimens above are not an option
  • (DRV/r or DRV/c) + (TAF/FTC, TDF/FTC, or ABC/3TC) (AIa)
  • EFV/TDF/FTC (AIa)
  • RPV/TAF (or TDF)/FTC (AIa, if HIV RNA < 100,000 and CD4>200)
  • EVG/COBI/(TAF or TDF)/FTC (AIa)
  • RAL + (TAF or TDF)/FTC (AIII)
  • IAS-USA suggests initial 2 drug regimens are only recommended in situations that patients cannot take ABC, TAF, or TDF (BIa). We note that emerging data may see a shift in recommendations in the future.

• Notes:
  • TDF: not recommended in patients with or at risk for kidney or bone disease (BIII). Avoid or dose adjust before eGFR < 60 (AIa)
  • TAF: Not recommended if eGFR < 30 (AIa)
  • ABC: Use only in HLA B*5701-negative pts

Guidelines have recently been updated to favor INSTI based regimens (with 2 NRTI) as the recommended initial regimen for most people with HIV. For most patients INSTI-anchored regimens are effective with infrequent adverse effects and few drug-drug interactions.

• Recommended regimens:
  • INSTI-based regimen (alphabetical order): DTG/ABC/3TC (AI, if HLA B*5701-negative); DTG + TDF/FTC (AI);DTG +TAF/FTC(AII); EVG/COBI/TAF/FTC (AI); EVG/COBI/TDF/FTC (AI); RAL + TDF/FTC (AI); RAL +TAF/FTC(AII)
  • PI-based regimens: DRV/r + TDF/FTC (AI); DRV/r +TAF/FTC (AII)

General

Guidelines have recently been updated to favor INSTI-based regimens (with 1 or 2 NRTI) as the recommended initial regimen for most people with HIV. For most patients INSTI-anchored regimens are effective with infrequent adverse effects and few drug-drug interactions.

Integrase Inhibitor-Based Regimens

All IAS-USA recommended regimens and DHHS recommended regimens are now InSTI-based, and many are single tablet regimens. EVG/c based regimens have moved to regimens to consider in some situations, but is not considered preferred for most individuals due to the potential for drug interactions.

• Advantages: Toxicity and efficacy advantages demonstrated for some InSTIs over some PI- and NNRTI-based regimens. In ART-naïve patients started on BIC- or DTG- regimens, resistance has not been commonly seen in patients experiencing failure and transmitted resistance is rare.
• Disadvantages: Potential for resistance with failure with some INSTIs (RAL and EVG/c); drug interactions (EVG/c); twice-daily dosing (RAL, though once daily dosing now available)
• BIC: Advantage: Available as part of a single tablet once-daily regimen with TAF and FTC, few side effects or drug interactions and likely high barrier to resistance. Evaluated in two large RCT comparing BIC to DTG with 2 NRTI with good results demonstrating high levels of viral suppression at 48 weeks, with few side effects. Disadvantages: inhibits tubular excretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (like COBI).
• RAL: Advantages: First INSTI approved.RAL + TDF/FTC superior to DRV/r + TDF/FTC and ATV/r + TDFFTC based on tolerability (ACTG A5257); non-inferior to EFV/TDF/FTC (superior at 4-5 years) and better tolerated in STARTMRK trial, with more rapid virologic suppression. Disadvantages: Barrier to resistance loower than DTG; twice-daily dosing (but two 600 mg tabs once-daily non-inferior and expected to be approved).
• EVG: Advantages: Available in two once-daily, single-tablet coformulations (EVG/COBI/TDF/FTC and EFV/COBI/TAF/FTC); non-inferior and better tolerated than TDF/FTC/EFV. Disadvantages: No longer a preferred regimen ’for most patients’. Requires boosting with COBI, resulting in more drug interactions than with other INSTIs. COBI inhibits tubular secretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (but not actual GFR). TDF-containing version should be used only if eGFR < 70 mL/min and should be stopped if eGFR falls to < 50 mL/min; TAF-containing version can be used with eGFR >30 mL/min. Barrier to resistance lower than DTG.
• DTG: Advantages: Once-daily administration, few drug interactions; higher barrier to resistance than RAL or EVG; superior to EFV and DRV/r (primarily based on tolerability advantages), coformulated with ABC/3TC in first non-TDF-based single-tablet regimen. Emerging data support use of two drug therapy with DTG plus 3TC, which is available coformulated. Disadvantages: inhibits tubular excretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (like COBI). Some cases of neuropsychiatric adverse events have been reported.

NNRTI-Based Regimens

• Advantages: simplicity, tolerability, relative lack of long-term toxicity, 3 single-tablet regimens available including generic formulations of some. Demonstrated virologic potency and durability.
• Disadvantages: lower genetic barrier to resistance: greater resistance consequences with failure than with PI/r; specific drug toxicities. High-level resistance to all NNRTI may occur (ecept ETR or DOR) with a single mutation. In RPV-treated patients, presence of RPV mutations may confer cross resistance to other NNRTI including ETR.
• EFV: Advantages: has been gold standard for many years; coformulated with TDF/FTC; long-term tolerability; better virologic suppression with EFV than LPV/r in ACTG 5142; efficacy at all VL and CD4 strata. Disadvantages: CNS side effects including possible increased risk of suicidality, rash, likelihood of NNRTI resistance with failure, teratogenicity, greater lipid effects than other preferred regimens; lower CD4 response with EFV than with most comparators. No TAF coformulation available.
• RPV: Advantages: coformulated with TDF/FTC and TAF/FTC; better tolerated than EFV with fewer CNS effects, less rash and lipid effects; more effective at VL < 100,000. Disadvantages: less effective at VL >100,000 and/or CD4 < 200 with greater resistance at failure, including cross-resistance to ETR; contraindicated with proton pump inhibitors; requires meal for absorption
• NVP: Advantages: acceptable in women with CD4 < 250 and men with CD4 < 400 well tolerated; safe in pregnancy; less lipid effects than with EFV.Disadvantages: risk of serious skin reactions and hepatotoxicity, especially in women and at higher pre-treatment CD4 counts; not as well studied as EFV with TDF/FTC or ABC/3TC
• ETR: Advantages: well tolerated; active against most NNRTI-resistant virus, including K103N mutations. Disadvantages: minimal data in ART-naive pts and not recommended for initial therapy, though could have a role for pts infected with EFV/NVP-resistant virus
• DOR: Advantages: Found to be non-inferior to EFV in DRIV-AHEAD, and had less neuropsychiatric side-effects than EFV. No change in LDL and non-HDL cholesterol while both increased in EFV. In DRIVE-FORWARD, DOR was non-inferior to DRV/r at 48 weeks(superior at 96 weeks with higher discontinuation in DRV/r group). Available in single-tablet coformulations. Disadvantages: Emergent resistant mutations confer cross-resistance to other NNRTI, though usually susceptible to ETR. Have not been compared to INSTI-based regimens in clinical trials.

PI-Based Regimens

• Advantages: typically no PI resistance with failure of PI/r-based regimen. Given infrequent transmitted resistance, PI regimens are often recommended if early ART initiation is necessary prior to resistance test results.
• Disadvantages: greater pill burden than with single-tablet regimens; more GI side effects; more lipid effects than INSTIs
• ATV/r, ATV/c, or ATV: Advantages: well tolerated; similar efficacy to EFV in ACTG 5202; less hyperlipidemia than LPV/r; does not require boosting. Best choice if RTV boosting not possible (with ABC/3TC, not TDF/FTC). Disadvantages: ATV/r inferior to RAL and DRV/r in ACTG 5257 with more GI toxicity; potential for jaundice; associated with nephrolithiasis, cholelithiasis, and kidney toxicity; requirement for gastric acidity (decreased absorption with proton pump inhibitors, H2 blockers, antacids); food requirement. RTV or COBI boosting preferred, and essential with TDF or EFV; greater loss of bone density than DRV/r or EFV
• DRV/r or DRV/c Advantages: DRV/r 800/100 mg once-daily superior to ATV/r in ACTG 5257; noninferior to LPV/r, and superior in pts with VL >100,000; well tolerated, with less hyperlipidemia than LPV/r; no jaundice or gastric acid concerns (vs. ATV/r or ATV/c). Now available coformulated single tablet regimen DRV/c/TAF/FTC. Disadvantages: potential for rash.
• LPV/r: Advantages: convenience (coformulated with RTV); no food restriction with tablet formulation; best studied PI/r in pregnancy. Disadvantages: GI side effects; hyperlipidemia, requires 200 mg/d of RTV
• FPV +/- RTV: Advantages: once- or twice-daily dosing (once-daily with FPVr 1400/100-200 mg only for PI-naive pts); FPV/r twice-daily equivalent to LPV/r twice-daily in KLEAN study; no food restrictions. Disadvantages: No clear advantage of 700/100 mg twice-daily over coformulated LPV/r; less clinical data with better tolerated FPV/r 1400/100 mg once-daily dose compared to ATV/r and DRV/r; potential for rash.
• SQV/r : Advantages: well tolerated with less diarrhea and more favorable lipid effects than LPV/r. Disadvantages: higher pill burden than other PIs (6/d); no clear advantages over PI/r regimens that include only 100 mg/d of RTV; black box warning for PR and QTc prolongation.
• IDV +/- RTV: Advantages: None. Disadvantages: not recommended; minimal data; nephrotoxicity; fluid requirement; elevated indirect bilirubin; dermatologic changes
• NFV: Advantages: None. Disadvantages: not recommended; higher failure rate than other PIs; diarrhea; food requirement; inability to effectively boost with RTV; potential for PI resistance with failure (including L90M)
• TPV/r: Not recommended for initial therapy

Choice of NRTI Backbone (as component of HAART regimen)

• TDF/FTC: Advantages: well tolerated; 1 tab once-daily; no food restrictions; no mitochondrial toxicity; superior to AZT/3TC in GS934 with less toxicity, failure, and resistance (M184V); less K65R with TDF/FTC than TDF/3TC, increased AZT susceptibility w/ M184V and/or K65R; coformulated with EFV, RPV, EVG/COBI. Disadvantages: nephrotoxicity, esp. in pts with preexisting renal dysfunction and in pts on PI- or COBI-based regimen; cross-resistance to ABC and ddI with K65R/M184V; greater loss of bone mineral density during initial therapy than with other NRTIs
• TAF/FTC: Advantages: Advantages of TDF/FTC listed above but with less kidney and bone toxicity; coformulated with RPV, EVG/COBI, BIC, DRV/COBI and as dual-NRTI combination. Disadvantages: higher lipids than with TDF/COBI because of lower plasma tenofovir levels (tenofovir has lipid-lowering effects).
• ABC/3TC: Advantages: well tolerated; 1 tab once-daily; no food restrictions; no mitochondrial toxicity. Disadvantages: need for HLA B*5701 testing to decrease risk of ABC hypersensitivity; decreased activity (vs. TDF/FTC) in pts with baseline VL >100,000 in ACTG 5202 (combined with EFV or ATV/r) but not when combined with DTG; possible association with risk of MI; cross-resistance to ddI (L74V, K65R), TDF (K65R); coformulated with DTG.
• AZT/3TC: Advantages: well studied; resistance to AZT (TAMs) occurs gradually; M184V increases AZT activity. Disadvantages: not recommended; anemia; GI intolerance; mitochondrial toxicity; including lipoatrophy, twice-daily dosing, extensive NRTI cross-resistance when multiple TAMs present; inferior to TDF/FTC in GS934 with more toxicity, failure, and resistance (M184V)

Use of Other Agents

• MVC: Advantages: R5 virus more common among ART-naive pts; well tolerated; efficacy similar to EFV in MERIT study when enhanced sensitivity tropism assay used. Disadvantages: baseline tropism testing required; twice-daily dosing (once-daily dosing under study), lack of long-term safety data; studied only with AZT/3TC
• ENF: No role for initial therapy due to high cost, need for twice-daily injection, and lack of data

Chronic Liver Disease/Viral Hepatitis

• No regimen contraindicated. Use caution with PIs (esp. TPV), NNRTIs (esp. NVP), d4T. Severe liver disease: decrease dose of some PIs (APV, FPV, ATV, IDV) (DHHS reference).
• Chronic HBV: Use regimen that includes TDF/FTC, TAF/FTC (or TDF+3TC) for dual anti-HBV therapy

Renal Insufficiency

• Avoid IDV, TDF, and possibly ATV, or use with caution. Dose adjust some NRTIs (ddI, 3TC, FTC, AZT, d4T, TDF)
• ART recommended for all patients with HIVAN, regardless of CD4 and VL

Pregnancy or Child-bearing Potential

• Before initiating ART in a person of childbearing potential, a pregnancy test should be performed (AIII). Before prescribing ART in a person of child bearing potential, consider the safety of different INSTI-based regimens around the time of conception.
• ART recommended for all pregnant women with HIV, regardless of VL and CD4. Transmission is less likely, but still possible, with VL < 1000.
• Start ART as soon as possible. NRTI backbone plus INSTI or PI anchor is preferred
• Preferred NRTI backbones: ABC/3TC, TDF/FTC (or TDF + 3TC), AZT/3TC,
  • (TAF has insufficient PK data)
• Preferred PI anchor: ATV/r, DRV/r
• Preferred INSTI anchor:
  • RAL: PK data are available for RAL use in pregnancy, and there is increasing experience with use in pregnancy. Associated with rapid viral load reduction (which may be useful for women who present for initial therapy late in pregnancy). Useful when drug interactions with PI regimens are a concern. Twice-daily dosing required. Thus far, based on data from the ARV pregnancy registry and the drug manufacturer, and a cohort study in the U.S., no cases of NTD have been reported and the rate of fetal malformations is within the expected range in the US. RAL anchor is designated as preferred among individuals who are trying to concerive (DTG would be an alternative).
  • DTG: Note, in the prior guidelines (2018) DTG was not recommended < 14 weeks from last menstrual period but was considered preferred after first trimester. No safety problems have been identified when DTG is initiated during pregnancy.
    • Preliminary data from a study in Botswana suggested a higher risk of NTDs among infants born to women who conceived while taking DTG. More recent data were presented in 2019 that suggests that the magnitude of risk is less than that identified in initial reports (rate of neural tube defects was reduced from 0.9% to 0.3%); however this rate is still higher than the rate reported for infants born to individuals receiving ART that did not contain DTG (0.1%). It should be noted that as a result of these new data, assessing benefits and risks, the WHO recommends the use of dolutegravir (DTG) as the preferred first- and second-line treatments for all populations, including pregnant women and those of childbearing potential. It is not yet known whether use of other INSTIs around conception poses a risk of NTD’s. DHHS guidance in 2019 provided updated recommendations:
    • Providers should discuss benefits fo using DTG and the risk of neural tube defects in persons of childbearing potential to allow person to make informed decisions.
    • DTG may be used as an alternative ARV for individuals of childbearing potential and trying to conceive or not using contraception; for individuals using effective contraception, DTG may be used as a recommended option. Additional information is in the Perinatal Guidelines.
  • BIC and EVG/c are not currently recommended. EVG/c should not be used because of inadequate drug concentrations in second and third trimesters. There remains limited safety and PK data on BIC.
• Alternative NNRTI anchor: ·EFV ; RPV. Now an alternative due to neuropsychiatric side effects. Note that RPV is not recommended if HIV Vl>100,000 or CD4< 200. Previously concern for use of EFV in first trimester, but now considered acceptable based on large amount of treatment experience. Lack of data for DOR.
• Alternative PI anchor : LPV/r
• Avoid starting NVP in women with CD4 >250 (hepatotoxicity).
• Several drugs are NOT RECOMMENDED: DRV/COBI, ATV/COBI, EVG/COBI. Concerns regarding low levels of COBI in second and third trimesters when used with DRV or EVG, leading to low levels of DRV or EVG and poor virologic suppression. PK data on ATV/COBI are not yet available, but low levels of these drugs are also expected to occur during the second and third trimesters.
• See Perinatal Guidelines (ref) for information on prevention of perinatal transmission.