antiretroviral%20therapy%20for%20hiv-infected%20adults
ANTIRETROVIRAL THERAPY FOR HIV-INFECTED ADULTS
Antiretroviral therapy is recommended for all HIV-infected individuals regardless of CD4 count to decrease morbidity and mortality associated with HIV infection.
Goals of antiretroviral treatment are suppression of viral load for maximum possible duration, restore & preserve immunologic function, reduce HIV-related morbidity & mortality and prevent HIV transmission.
Urgent initiation of antiretroviral treatment is recommended in the following individuals: pregnant women, patients w/ HIV with coinfections (HBV, HCV, active tuberculosis), AIDS-defining illness, HIV-associated nephropathy, low CD4 counts, acute opportunistic infections and HIV HBV with evidence of chronic liver disease.

Principles of Therapy

Indications and Recommendations for Starting Antiretroviral Therapy (ART)

  • Regardless of CD4 cell count or WHO clinical stage, initiation of ART is strongly recommended for individuals with the following conditions:
    • Pregnancy
      • All pregnant and breastfeeding women with acute or recent HIV infection should start a combination ART as soon as possible to prevent mother-to-child transmission of HIV
    • History of an AIDS-defining illness
    • HIV-associated nephropathy
    • HIV/hepatitis B virus (HBV) and IV/Hepatitis C (HCV) coinfections
    • HIV/Active tuberculosis disease coinfection
      • TB treatment should also be started immediately
    • Advanced HIV disease (clinical stage 3 or 4)
    • HIV-positive partners in serodiscordant couples
  • Treat all patients including asymptomatic individuals with CD4 T-cell count of 350-500 cells/mm3 regardless of the clinical stage but prioritize patients with CD4 cell count of  ≤350 cells/mm3 and those with advanced HIV disease
  • ART should be offered to patients who are at risk of transmitting HIV to sexual partners
    • Effective ART has been shown to prevent transmission of HIV from an infected individual to a sexual partner
  • ART is recommended in patients >50 years of age, regardless of CD4 cell count
    •  Immunologic response to ART may be reduced and risk of non-AIDS complications may increase in older HIV-infected patients
  • ART is recommended for all HIV-infected individuals to reduce the risk of disease progression and prevent its transmission
  • Patients starting ART should be willing, able to commit, understand the risks and benefits of therapy and the importance of adherence
  • All patients who are HIV-positive should be counseled on how the infection is being transmitted, how can it be prevented & the responsibility of notifying their partners about the infection

Goals of Antiretroviral Treatment

  • Suppression of viral load for maximum possible duration
  • Restore and preserve immunologic function
  • Reduce HIV-related morbidity and mortality
  • Improve quality of life
  • Prevent HIV transmission

Initiating Antiretroviral Therapy in Treatment-Naive Patients

  • ART is recommended for all HIV infected individuals regardless of CD4 count to decrease morbidity and mortality associated with HIV infection
    • In patients with much lower CD4 count, ART must be started immediately
  • Urgent initiation of ART is recommended in the following individuals:
    • Patients age ≥50 years 
    • Pregnant women
    • HIV with coinfections (HBV, HCV, active tuberculosis)
    • AIDS-defining illness, including HIV-associated dementia (HAD) and AIDS-associated malignancies
    • HIV-associated nephropathy (HIVAN)
    • Low CD4 counts (eg <200 cells/mm3)
    • Acute opportunistic infections (eg cryptosporidiosis, microsporidiosis and progressive multifocal leukoencephalopathy), as well as in patients with early/acute infections
    • HIV HBV with evidence of chronic liver disease
  • ART is also recommended for serodiscordant couples
  • When initiating ART, it is important to educate patients about its benefits and considerations in order to optimize compliance to therapy

ART in Special Populations

  • All pregnant and breastfeeding women with acute or recent HIV infection should start ART regimen as soon as possible to prevent mother-to-child transmission and protect their own health
  • Principles of active TB treatment in HIV-infected patients are the same as those for HIV-uninfected patients
    • All HIV patients coinfected with active TB should be immediately started on TB treatment
    • CD4 counts <50 cells/mm3: Start ART within 2 weeks of TB treatment
    • CD4 counts ≥50 cells/mm3 with severe clinical disease: Start within 2-4 weeks of TB treatment
    • CD4 counts ≥50 cells/mm3 without severe clinical disease: ART may be started within 8-12 weeks of TB treatment
  • In patients with HBV coinfection, ART drugs active against HBV should be continued even in the setting of HIV virologic failure
  • The drug active against HBV should be continued and combined with other suitable ART agents to achieve HIV suppression
  • Concurrent treatment of HIV and hepatitis C (HCV) infection may be complicated by overlapping drug toxicities and high pill burden
    • Decision to start HCV treatment should consider medical need for such treatment based on HCV stage
  • ART is recommended in patients >50 years of age regardless of CD4 count because immunologic response to ART may be reduced in older HIV-infected patients and the risk of non-AIDS complications may increase
  • ART is recommended for all individuals with  HIV-1 infection and to those with early HIV-1 infection (p I-1)
  • If treatment is initiated in a patient with early HIV-1 infection, the goal is to suppress plasma HIV-1 RNA to undetectable levels
  • In patients with early HIV-1 infection in whom therapy is initiated, testing for plasma HIV-1 RNA levels, CD4 T lymphocyte counts, and toxicity monitoring should be performed as described for patients with chronic HIV-1 infection
  • Genotypic drug resistance testing should be performed before initiation of ART to guide the selection of the regimen
  • In patients without transmitted drug resistant virus, therapy should be initiated with one of the combination regimens for patients with chronic HIV-1 infection
  • ART can be initiated before drug resistance test results are available
  • Patients starting ART should be willing and able to commit to treatment and should understand the possible benefits and risks of therapy and the importance of adherence

Regimen Selection

  • Selection of treatment regimen should be individualized based on virologic efficacy, toxicity, potential drug-drug interaction, dosing frequency, pill burden, resistance testing results, comorbidities, patient characteristics (eg pregnancy potential, adherence potential) and needs
  • Initial treatment for treatment-naive patients consists of 2 NRTIs (eg Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zalcitabine, Zidovudine) plus either INSTI, NNRTI, or PK-enhanced PI
    • First-line agents should include 2 NRTIs plus an NNRTI
    • Second-line agents should include 2 NRTIs plus a Ritonavir-boosted PI (eg ATV/r and LPV/r)
    • Third-line agents should include new drugs with minimal potential for cross-resistance with prior regimens (eg integrase inhibitors, 2nd-generation NNRTIs and PIs)

Pharmacotherapy

Recommended Antiretroviral Drug Regimens for Treatment-Naive Patients

Preferred boosted PI-based Regimens + 2 NRTIs

Ritonavir-boosted Darunavir + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine

Preferred INSTI-based Regimens + 2 NRTIs

Dolutegravir/Abacavir/Lamivudine1,3
Dolutegravir + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine
Cobicistat-boosted Elvitegravir/Tenofovir alafenamide/Emtricitabine or Cobicistat-boosted Elvitegravir/Tenofovir disoproxil fumarate/Emtricitabine
Raltegravir + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine

Alternative NNRTI-based Regimens + 2 NRTIs

Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine6
Efavirenz/Tenofovir alafenamide/Emtricitabine
Rilpivirine/Tenofovir disoproxil fumarate/Emtricitabine5 or Rilpivirine/Tenofovir alafenamide/Emtricitabine4,5

Alternative boosted PI-based Regimens + 2 NRTIs

(Cobicistat-boosted Atazanavir or Ritonavir-boosted Atazanavir) + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine
Cobicistat-boosted Darunavir or Ritonavir-boosted Darunavir + Abacavir/Lamivudine1,3
Cobicistat-boosted Darunavir + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine
Ritonavir-boosted Lopinavir + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine5

If HIV RNA <100,000 copies/mL & HLA-B*5701 Negative

Cobicistat-boosted Atazanavir or Ritonavir-boosted Atazanavir + Abacavir/Lamivudine
Efavirenz + Abacavir/Lamivudine1
Raltegravir + Abacavir/Lamivudine1

Other Regimens When TAF, TDF or ABC Cannot be Used

Ritonavir-boosted Darunavir + Raltegravir4 (twice daily)
Ritonavir-boosted Lopinavir + Lamivudine1 (twice daily)

Adapted from: Department of Health & Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents 2017, and the 2017 European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults.
¹3TC may be substituted for FTC & vice-versa
²Once daily LPV/r is not recommended in pregnant patients
³If HLA-B*5701 is negative
⁴If HIV RNA is <100,000 copies/mL and CD4 is >200 cells/mm³ 
5A recommended regimen by the EACS 2017 guidelines 
6To be used only if with HIV viral load of <100,000 copies/mL based on the EACS 2017 guidelines 

Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-based Regimens

  • Advantage: Have demonstrated virologic potency and durability
  • Disadvantage: Prevalence of NNRTI-resistant viral strains in ART-naive patients and the low genetic barrier of these agents for the development of resistance
    • All NNRTIs except for Etravirine (ETV) require only a single gene mutation to confer resistance; cross resistance among these NNRTIs are common
    • Partial resistance to Efavirenz (EFV), Nevirapine (NVP), or Rilpivirine (RPV) is conferred by a single mutation in the reverse transcriptase gene, hi and it may develop rapidly after virologic failure
  • A single tablet formulation consisting of EFV, Tenofovir (TDF) and Emtricitabine (FTC) allows one-tablet, once-daily dosing and is currently the preferred NNRTI-based regimen
    • Regimen consisting of RPV/TDF/FTC is only an alternative due to the limited data on durability to response lower virologic response to RPV

Delavirdine (DLV)

  • Requires 3-times daily dosing and has the least supporting data in clinical trials
  • Appears to have the least antiviral activity and as such is not recommended as part of an initial ART regimen

Efavirenz (EFV)

  • EFV with ABC/3TC is now recommended as other regimen
  • It is coformulated with TDF/FTC
  • Transmitted resistance is commonly reported than PIs and INSTIs
  • Only for patients with pre-ART viral load <100,00 copies/mL and negative HLA B*5701 status
  • Advantage: To date, no regimen has proven superior to EFV-based regimens with respect to virologic response; aside from potency, it is also preferred due to its tolerability
  • Disadvantages: Contraindicated in the 1st trimester of pregnancy or in women of childbearing potential who are trying to conceive, or in those not using effective and consistent contraception
    • Also, EFV-based regimens are associated with skin rash and neuropsychiatric adverse effects (eg depression and increase rate of suicidality)

Etravirine (ETV)

  • Advantage: Has in-vitro activity against some viruses with mutations that confer resistance to DLV, EFV, and Nevirapine (NVP)
  • Disadvantage: In RPV-treated patients, presence of RPV-resistant mutations at virologic failure is common and may confer cross-resistance to ETV

Nevirapine (NVP)

  • Advantage: May be used as an acceptable NNRTI option in women with aseline CD4 counts of ≤250 cells/mm3 or in men with pretreatment CD4 counts ≤400 cells/mm3
  • Disadvantage: Serious hepatic events have been observed when started in ART-naive patients
    • However, patients who experience increases in CD4 count to levels above the aforementioned thresholds can safely continue without an increased risk for hepatic events
    • Monitoring of serum transaminases at baseline, 2 weeks after dose increase and then monthly for the first 18 weeks are recommended by some experts

Rilpivirine (RPV)

  • May be used in combination with NRTIs for ART-naive patients with pre-treatment viral load <100,000 copies/mL
  • Use of RPV with TDF/FTC should be limited to ART-naive patients with pre-treatment viral load copies of <100,000 and  CD4 count >200 cells/mm3
  • Advantage: A once daily dosing and is coformulated with TDF/TFC; compared with FV, drug discontinuations with RPV due to adverse effects (eg dizziness, abnormal dreams, hyperlipidemia and rash) were less frequent
    • Frequency of depressive disorders and discontinuations secondary to depression are similar between RPV and EFV
  • Disadvantage: Lower virologic response compared with EFV in patients with high baseline viral loads and requires acid to have an adequate absorption

Protease inhibitor (PI)-based Regimens

  • Have demonstrated durability and virologic potency in ART-naive patients
  • Resistance mutations are seldom detected at virologic failure, unlike NNRTI- and Integrase Strand Transfer Inhibitor (INSTI)-based regimens

Boosted PI Regimens

  • Ritonavir (RTV)-boosted PI-based regimens have demonstrated good immunologic and virologic responses
  • Advantage: Drug resistance to most PIs require multiple mutations in the HIV protease gene and seldom develops after early virologic failure, especially when RTV boosting is used
  • Disadvantage: Are often associated with more gastrointestinal (GI) symptoms than EFV-based regimens; like EFV-based regimens, are also associated with hepatic transaminase elevations
    • Other disadvantages include higher pill burden and more clinically significant drug interactions are seen with RTV-boosted PI regimens than with NNRTI-based regimens

Atazanavir + Ritonavir (ATV/r) or Atazanavir + Cobicistat (ATV/c)

  • ATV/r and ATV/c combined with TDF/FTC are recommended as alternative regimens for ART-naive patients regardless of pre-treatment HIV RNA
  • ATV/c + TDF/FTC is not recommended for patients with CrCl <70 mL/minute
  • ATV/r or ATV/c + ABC/3TC is recommended as other regimen
    • Its use is limited to patients with pre-ART HIV RNA <100,000 copies/mL
  • Advantage: A clinical trial has shown RTV-boosting of ATZ enhances ATV concentration, improving virologic activity as compared with ATV alone
  • Disadvantage: Main adverse effect is indirect hyperbilirubinemia that is not associated with hepatic transaminase elevation; also requires acidic gastric pH for dissolution; thus, antacids, H2 agonists and proton pump inhibitors (PPI) may impair its absorption

Darunavir + Cobicistat (DRV/c)

  • Regimens consisting of DRC/c + TDF/FTC and DRV/c + ABC/3tc is recommended as alternative regimens for ART-naive patients
  • DRV/c + TDF/FTC is not recommended:
    • For patients with CrCl <70 mL/minutes

Darunavir + Ritonavir (DRV/r)

  • Regimen consisting of DRV/r + TDF/FTC is also a preferred PI-based regimen
    • ARTEMIS study has shown DRV/r, compared with LPV/r (both in combination with TDF/FTC), to have a superior virologic response

Fosamprenavir + Ritonavir (FPV/r)

  • Recommended as an alternative PI-based regimen, with once- or twice-daily dosing
  • Studies have shown similar CD4 and virologic benefits when compared with ATV/r, both in combination with TDF/FTC

Indinavir + Ritonavir (IDV/r)

  • Associated with high incidence of nephrolithiasis
  • Indinavir requires high fluid intake

Lopinavir + Ritonavir (LPV/r)

  • Is the only available coformulated boosted PI with RTV
  • LPV/r + TDF/FTC or LPV/r + ABC/3TC is recommended as other regimen
  • Compared with other PIs boosted with 100 mg/daily of RTV, LPV/r should be boosted with 200 mg/day of RTV
  • Associated with higher rates of GI side effects and hyperlipidemia
  • Once-daily LPV/r should not be given to patients who have HIV mutations associated with PI resistance
  • Twice-daily dosing is preferred for pregnant women, especially during 3rd trimester, when LPV levels are expected to decline

Saquinavir + Ritonavir (SQV/r)

  • Has a high pill burden and requires twice-daily dosing and 200 mg of RTV
  • At recommended dose, this regimen is associated with increases in both PR and QT prolongation
    • Degree of QT prolongation is greater than that seen with some other boosted PI
    • ECG is recommended prior to its initiation
  • May be an acceptable regimen but should be used with caution against certain ART-naive patients (contraindicated in patients with QT prolongation, complete AV block, refractory hypokalemia or hypomagnesemia)

Unboosted PI-based Component

Atazanavir

  • Given once daily and has fewer effects on lipid profiles compared with other PIs
  • May be an acceptable initial therapy when a once-daily regimen is desired and then there is concern for hyperlipidemia
  • Studies have shown it to have similar virologic efficacy to ATV-based combination regimens with either EFV- or NVP-based regimens
  • RTV boosting is needed when given with TDF or EFV since the latter can lower ATV concentration

Integrase Strand Transfer Inhibitor (INSTI)-based Regimens

Dolutegravir (DTG)

  • Inhibitor of HIV integrase
  • Treatment of HIV-1 infection in adults and children
  • Licensed for both treatment-naive and treatment-experienced patients
  • DTG/ABC/3TC is only given in patients who are HLA-B*5701 negative
  • DTG plus TDF/FTC or TAF/FTC are now recommended for ART-naive patients

Elvitegravir (EVG)

  • Potent, CYP3A inhibitor that has no activity against HIV
  • Non-inferior to a combination of ATC + TDF/TC
  • EVG/c/TAF/FTC is only given in patients with pre-ART CrCl of > 30 mL/minute
  • EVG/c/TDF/FTC is only given in patients with pre-ART CrCl of >70 mL/minute

Elvitegravir/Cobicistat (EVG/c)

  • Advantage: Coformulated with TDF/FTC as a single tablet regimen and once daily dosing; causes a smaller increase in the total and LDL cholesterol as comparted with ARTV/r
  • Disadvantage: Oral administration can be reduced by simultaneous administration with antacid that contains polyvalent cations (eg Al, Ca or Mg)
  • Cobicistat inhibits active tubular secretion of Cr and an increase serum Cr without affecting renal glomerular function
  • Since Cobicistat is a potent CYP3A4 inhibitor, it may have interactions with the substrates of CYP3A

Raltegravir (RAL)

  • Approved for use in ART-naive patients
  • Use has been associated with increase in creatine kinase, myopathy and rhabdomyolysis
  • A potential disadvantage when comparing with other regimens is its twice-daily dosing
  • Like EFV, has a low genetic barrier to resistance
  • The combination of TDF/FTC and RAL demonstrated similar virologic efficacy as that of EFV/TDF/FTC up to 156 weeks and is generally well tolerated
  • Co-administration of antacids containing Al or Mg is not recommended, as it significantly impairs the oral absorption of RAL
  • Combination with Ritonavir-based DRV should be avoided in patients with CD4 count of <200 cells/mm3

Raltegravir + 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

  • RAL + TDF/FTC is the preferred INSTI-based regimen for ART-naive patients, with immunologic and virologic responses similar to EFV + TDF/FTC and no safety concerns identified based on studies
  • RAL + Abacavir (ABC)/Lamivudine (3TC) is the preferred alternative INSTI-based regimen

Nucleoside Reverse Transcriptase Inhibitors (NRTI)Triple NRTI Regimens

  • Currently, three of the approved NRTIs have activity against hepatitis virus (HBV): 3TC, FTC and TDF
  • Single- and dual-NRTI therapy are not recommended as these have not demonstrated sustained and potent virologic activity
    • Stavudine (d4T) should not be used as 1st-line agent due to its metabolic toxicities
  • Dual NRTIs are commonly used in combination with an NNRTI, a PI, an INSTI or a CCR5 antagonist
    • In clinical practice, most dual NRTI combinations consist of a primary NRTI plus 3TC or FTC

Preferred Dual NRTI

Tenofovir (TDF)/Emtricitabine (FTC) [coformulated]

  • Tenofovir is a nucleotide analog with potent activity against both HIV and hepatitis B virus (HBV)
    • Has a long intracellular half-life which allows for once-daily dosing
    • Demonstrated potent virologic activity when used with either 3TC or FTC as part of an EFV-based regimen in ART-naive patients
    • Renal impairment with TDF use has been reported; greater risk of renal dysfunction when used in PI-based regimens
  • TDF plus either 3TC or FTC is the preferred NRTI combination, especially for patients coinfected with both HIV and HBV
    • Use of a single HBV-active NRTI (either 3TC or FTC) is not recommended as it can lead to HBV resistance
  • Superior to ZDV/3TC in virologic efficacy up to 144 weeks

Alternative Dual NRTI

Abacavir (ABC)/Lamivudine (3TC) [coformulated]

  • Remains a good alternative dual-NRTI option for some ART-naive patients
  • Should only be given to patients who tested negative for HLA-B*5701
  • Abacavir has the potential for serious hypersensitivity reactions
  • The fixed dose combination allows for once-daily dosing
  • Should be used with caution in patients at higher risk for cardiovascular disease and whose plasma HIV RNA levels are at ≥100,000 copies/mL

Dual NRTI

Tenofovir disoproxil fumarate (TDF)/Emtricitabine (FTC) [coformulated]

  • It is coformulated with  EFV, EVG/c and RPV as a STR
  • The recommended dual-NRTI in patients co-infected with HIV/HBV
  • Gives a better virologic response than ABC/3TC in patients with a baseline viral load of >100,000 copies/mL when combined with ATV/r or EFV
  • Causes renal toxicity, including proximal tubulopathy and acute or chronic renal insufficiency
  • It also decreases BMD more than other NRTI combinations

Zidovudine (ZDV)/Lamivudine (3TC) [coformulated]

  • Has extensive durability, tolerability and safety experience
  • Recommended only as an acceptable regimen due to its greater toxicity than other dual NRTIs and its requirement for twice-daily dosing

Triple NRTI

  • Triple NRTI regimens have been shown to have suboptimal virologic activity based on several controlled trials

ABC/3TC/ZDV (coformulated)

  • The only triple NRTI combination with available supporting randomized clinical trial data
  • With comparable virologic activity to IDV- and NFV-based regimens but was inferior to EFV-based regimen
  • Generally not recommended and should only be used when a preferred alternative or an acceptable NNRTI-, PI-, or INSTI-based regimen is less desirable due to toxicities, complexity of regimen or drug interactions

CCR5 Antagonist-based Regimens

CCR5-Antagonist (eg Maraviroc) + 2 NRTIs (Zidovudine/Lamivudine)

  • Maraviroc (MVC) is recommended only as an acceptable regimen for ART-naive patients due to its limited experience with regimens other than ZDV/3TC, its cost (requires tropism assay prior to use), and requirement for twice-daily dosing

Fusion Inhibitor-based Regimens

Enfuvirtide (T20)

  • An HIV-1 fusion inhibitor, is a treatment option for inclusion in a regimen when drug resistance to a previously given ART regimen is confirmed

Other Antiretroviral Regimens for Initial Therapy When Abacavir or Tenofovir Cannot Be Used

Darunavir/Ritonavir + Raltegravir (DRV/r + RAL)

  • Considered in patients with HIV RNA <100,000 copies/mL, CD4 cell counts >200 cells/mm3 and those who cannot take either TAF or ABC

Lopinavir/Ritonavir + Lamivudine (LPV/r + 3TC)

  • Recommended as initial therapy when both TDF and ABC are contraindicated
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