Antiretroviral%20therapy%20for%20hiv-infected%20adults Treatment

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:
  • All HIV-infected patients, including all HIV-infected women
  • 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
    • Early treatment during and after pregnancy
  • History of an AIDS-defining illness
  • HIV-associated nephropathy (HIVAN)
  • HIV/hepatitis B virus (HBV) and HIV/Hepatitis C (HCV) coinfections
  • HIV/active tuberculosis disease coinfection
    • TB treatment should be started not later than 8 weeks after its initiation
    • Alcohol dependence, active drug use and mental health disorders should not withhold TB treatment
  • 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-acquired immunodeficiency syndrome (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 ART

• Sustained suppression of viral load for maximum possible duration
• Restore and preserve immunologic function
• Reduce HIV-related morbidity and mortality
• Improve quality of life
• Increase lifespan
• Prevent HIV transmission
• Prevent emergence of HIV drug resistance

Predictors of Virologic Success

• Low baseline viremia
• High ARV regimen potency
• Tolerability of the regimen
• Convenience of the regimen
• Excellent adherence to the regimen

Initiating Antiretroviral Therapy in Treatment-Naive Patients

• ART is recommended for all HIV infected individuals regardless of CD4 count at the time of diagnosis if possible or within 2-4 weeks of diagnosis to decrease morbidity and mortality associated with HIV infection and prevent HIV transmission
  • In patients with much lower CD4 count, ART must be started immediately
  • Rapid ART initiation which is the initiation of ART within 7 days after HIV diagnosis, helps increase ART uptake and engagement in care, accelerate viral suppression time, reduce the time during which people with newly diagnosed HIV can transmit HIV
    • May benefit patients with advanced HIV disease, pregnant women, and those with acute HIV infection who are willing to start ART and without clinical signs/symptoms of active TB or other opportunistic infections
  • Advantages of early therapy include:
    • Reduction of viral load and size of viral reservoir causing reduction of viral genetic evolution
    • Reduction of immune activation and inflammation
    • Preservation of immune function and integrity of lymphoid tissue
    • Gut and neurological protection
    • Enhancement of post-treatment control and response to future treatment strategies
• 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
• Before starting ART, women in the reproductive age must undergo pregnancy test and the person's intentions regarding pregnancy should be discussed
  • Patient should attain maximum viral suppression before attempting conception to minimize the risk of perinatal HIV transmission to the infant
• Information regarding maintenance of plasma HIV RNA <200 copies/mL including any measurable value below this threshold should be given to people with HIV with ART to prevent sexual transmission of HIV to their partners

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
• Elite HIV controllers (patients with HIV with plasma HIV-1 RNA levels below level of quantification for years without ART) are recommended to start ART in the presence of HIV disease progression defined as decreasing CD4 counts or development of HIV-related complications
• 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: Start within 8 weeks of TB treatment
  • Patients with drug-resistant TB: Start ART within the 1st 8 weeks following TB treatment initiation regardless of CD4 cell count
• 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
• 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
• 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 to enhance adherence and support long-term treatment success
• Initial treatment for treatment-naive patients consists of 2 NRTIs plus either INSTI, NNRTI, or pharmacokinetic (PK)-enhanced PI
• 2-drug regimen (DTG + 3TC)] may also be used for initial therapy
• Viral suppression using another ART regimen is recommended for patients without previous ART and wish to start intramuscular CAB-LA and RPV before switching to oral then injectable CAB and RPV

Characteristics to Consider in All Patients with HIV

• Pretreatment HIV RNA level (viral load)
• Pretreatment CD4 count
• History of use of CAB-LA as pre-exposure prophylaxis
• HIV genotypic drug resistance test results
• HLA-B*5701 status
• Individual preferences
• Anticipated adherence to the regimen
• Initiation of ART before availability of baseline lab results

Recommended Antiretroviral Drug Regimens for Most Patients with HIV

• Regimens with durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use

Recommended Antiretroviral Drug Regimens in Certain Clinical Situations

• Effective and tolerable regimens but with some disadvantages compared to the preferred regimens and with fewer supporting data from randomized controlled trials

Integrase Strand Transfer Inhibitor (INSTI)-based Regimens

• BIC- and DTG-containing regimens have higher resistance barrier and lower pill burden compared to 1st-generation INSTI-based regimens containing EVG or RAL
• Initiation of INSTI-based regiments in ARV-naive patients is associated with greater weight gain compared to NNRTI- or boosted PI-based regimens

Bictegravir (BIC)

• BIC/TAF/FTC is recommended for most people with HIV without history of use of CAB-LA as pre-exposure prophylaxis
• Option for patients who will start ART before the availability of drug resistance test results
• Advantage: Coformulated with TAF/FTC as a single tablet regimen and and once daily dosing
• Disadvantages: Oral administration can be reduced by simultaneous administration with antacid that contains polyvalent cations (eg Al, Ca or Mg) or iron supplements
  • Use has been associated with increase in creatine kinase
  • BIC/TAF/FTC cannot be used for patients taking Rifamycins because Rifamycins will decrease BIC or TAF concentrations resulting to loss of therapeutic effect

Cabotegravir (CAB)

• Approved for use with RPV as part of a long-acting injectable complete ARV regimen to replace a stable oral regimen in patients with viral suppression
• CAB/RPV is not recommended for initial ART for patients with HIV due to insufficient data supporting its efficacy in ART-naïve patients
• Long-acting injectable CAB (CAB-LA) is approved for use as pre-exposure prophylaxis

• Inhibitor of HIV integrase
• Treatment of HIV-1 infection in adults and children
• Licensed for both treatment-naive and treatment-experienced patients
• Option for patients who will start ART before the availability of drug resistance test results
• DTG/ABC/3TC is recommended for most people with HIV and is only given in patients who are HLA-B*5701 negative and without HBV coinfection
• DTG/3TC is recommended for most people with HIV but is not recommended for:
  • Patients with viral loads >500,000 copies/mL
  • Patients with HBV coinfection or unknown HBV status
  • Patients starting ART before the availability of results for genotypic resistance testing for reverse transcriptase
• DTG plus TDF or TAF plus FTC or 3TC are now recommended for ART-naive patients
• DTG + RPV is only approved for people who have achieved viral suppression with another ART regimen and is not used for initial ART
• Advantages: Higher and more rapid rates of viral suppression, lower potential for drug-drug interaction, and higher genetic barrier for HIV drug resistance
• Disadvantages: Oral administration can be reduced by simultaneous administration with antacid that contains polyvalent cations (eg Al, Ca or Mg) or iron supplements
  • Use has been associated with increase in creatine kinase, myositis and hepatotoxicity
  • Use has been associated with depression and suicidal ideation especially in patients with pre-existing psychiatric illness

• EVG-containing regimens are recommended for initial ART in certain clinical conditions
• Has lower barrier to resistance compared to PI-, BIC- and DTG-containing regimens
• Non-inferior to a combination of ATV/c + TDF/TC
• EVG-containing regimens require PK boosting with Cobicistat

Elvitegravir/Cobicistat (EVG/c)

• Cobicistat is a potent CYP3A inhibitor that has no activity against HIV and acts as a PK booster for EVG
• EVG/c/TAF/FTC is only given in patients with pre-ART CrCl of ≥30 mL/min unless on chronic hemodialysis
• EVG/c/TDF/FTC is only given in patients with pre-ART CrCl of ≥70 mL/min
• Advantages: Coformulated with TDF/FTC as a single tablet regimen and once daily dosing; causes a smaller increase in the total and low-density lipoprotein cholesterol (LDL-C) 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)
  • Depression and suicidal ideation may be observed especially in patients with pre-existing psychiatric illness
• 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 and ARV-experienced patients and RAL-containing regimens are recommended as initial ART in certain clinical conditions
• Advantage: Has favorable lipid profile
• Disadvantage: Use has been associated with increase in creatine kinase, myopathy and rhabdomyolysis
  • Another potential disadvantage when comparing with other regimens is its twice-daily dosing; higher pill burden compared to other INSTI-based regimens
  • Has lower barrier to resistance compared to RTV-boosted PIs, BIC, and DTG
    • Like EFV, has a low genetic barrier to resistance
  • Oral administration can be reduced by simultaneous administration with antacid that contains polyvalent cations (eg Al, Ca or Mg)
  • Depression and suicidal ideation may be observed especially in patients with pre-existing psychiatric illness
• 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

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) and DOR 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

Doravirine (DOR)

• Available as single-drug tablet and also coformulated with TDF/3TC
• DOR/TDF/3TC and DOR +2 NRTIs (TDF/FTC or TAF/FTC) are recommended as initial ART in certain clinical conditions
• Noninferior to EFV/DRV/r
• Advantages: Better CNS tolerability compared to EFV, more favorable lipid profile compared to DRV/r and EFV, fewer potential drug interactions compared to EFV and RPV, and virologic efficacy not affected in patients with high RNA levels and low CD4 counts
• Disadvantages: Treatment-emergent resistance mutations with DOR may confer cross-resistance to certain other NNRTIs
  • Possibility of CYP450 drug interactions

• EFV with TDF/FTC, EFV with TDF/3TC and EFV with TAF/FTC are recommended as initial ART in certain clinical conditions
• It is coformulated with TDF/FTC or TDF/3TC
• 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
• Advantages: EFV-based regimens have excellent virologic efficacy except regimens containing AB/3TC; aside from potency, it is also preferred due to its tolerability
  • With minimal PK interaction with Rifamycins and may be an option for patients requiring treatment for TB
• 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
  • EFV-based regimens are associated with skin rash and neuropsychiatric adverse effects (eg depression and increase rate of suicidality)
  • Has low barrier to resistance and greater risk of resistance at the time of treatment failure than PIs
  • Possibility of CYP450 drug interactions
  • May increase LDL-C and triglycerides and cause QTc prolongation

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 (TDF/FTC or TAF/FTC) for ART-naive patients with pre-treatment viral load <100,000 copies/mL and CD4 counts >200 cells/mm³
• Also used as an extended-release injectable suspension as part of a long acting injectable complete ARV regimen when used with CAB
• Used for replacement of oral ART in patients with virologic suppression and without history of resistance to RPV or INSTIs
• Use of RPV with TDF/FTC should be limited to ART-naive patients with pre-treatment viral load copies of <100,000 copies/mL and  CD4 count >200 cells/mm³
• Advantages: 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
  • Favorable lipid profile
• Disadvantages: Lower virologic response compared with EFV in patients with high baseline viral loads (>100,000 copies/mL) and CD4 counts <200 cells/mm³ and requires acid to have an adequate absorption
  • Use of proton pump inhibitors (PPIs) is contraindicated and H2 antagonists must be used with caution
  • Has low barrier to resistance
  • Transmitted resistance is more common than PIs and INSTIs- More NNRTI-, TDF-, and 3TC-associated mutations at virologic failure compared to regimens which contain EFV and 2 NRTIs
  • Causes QTc interval prolongation
  • Possibility for CYP450 drug interactions
  • Frequency of depressive disorders and discontinuations secondary to depression are similar between RPV and EFV

NRTIs

• Eg ABC, Didanosine (ddI), FTC, 3TC, Stavudine (d4T), TAF, TDF, Zidovudine (ZDV)
• Older NRTIs (eg ddI, d4T and ZDV) are no longer recommended because of higher rates of serious toxicities including peripheral neuropathy and mitochondrial toxicity leading to myopathy, hepatic steatosis, lactic acidosis, lipoatrophy and bone marrow suppression
• NRTI combinations recommended for initial therapy include:
  • ABC/3TC
  • TAF/FTC
  • TDF/3TC
  • TDF/FTC
• 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

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
• ABC has the potential for serious hypersensitivity reactions
• ABC/3TC w/ EFV or ATV/r is recommended in patients with pre-treatment viral loads <100,000 copies/mL
• DTG/ABC/3TC is recommended as initial regimen for most people with HIV
• The fixed dose combination allows for once-daily dosing
• Should be used with caution in patients at higher risk for cardiovascular disease

Emtricitabine (FTC) and Lamivudine (3TC)

• Are used interchangeably in combination with other ARV
• Both have activity against HBV but are not sufficient for HBV treatment when used as monotherapy due to emergence of resistance
• Dose must be adjusted in patients with creatinine clearance (CrCl) <50 mL/min
• Well tolerated without significant treatment-limiting adverse effects
• Coadministration of sorbitol-containing drugs with 3TC should be avoided
• Suboptimal viral suppression will lead to selection of M184V mutation

Tenofovir alafenamide (TAF)/Emtricitabine (FTC) (Coformulated)

• TAF is a prodrug of Tenofovir (TFV) which is hydrolyzed to TFV in plasma and converted to TFV-diphosphate intracellularly where it acts as NRTI
• Recommended NRTI combination for initial ART in most people with HIV when given with BIC, DTG and RAL, and as part of recommended regimens in certain clinical conditions
• Coformulated with BIC, DRV/c, EVG/c or RPV and safe for patients with eGFR of ≥30 mL/min
  • May be used in patients with eGFR <30 mL/min and on chronic hemodialysis
• Have activity against HBV and may be used as NRTI pair in an ARV regimen in patients with HIV/HBV coinfection
• TAF has clinically significant greater virologic efficacy when used with PK boosters compared to TDF
• TAF is associated with lesser bone and renal toxicities compared to TDF
• TAF is recommended as 1st choice NRTI over TDF for the following:
  • Patients with known chronic kidney disease (CKD) or high risk for CKD
  • When nephrotoxic drugs are coadministered
  • Patients with previous TDF toxicity
  • Patients with osteoporosis or progressive osteopenia or high risk factors for osteoporosis
  • Patients with history of fragility fracture
• TAF should be avoided or used with caution with any Rifampicin-containing regimen

Tenofovir disoproxil fumarate (TDF)/Emtricitabine (FTC) (Coformulated) and TDF/Lamivudine (3TC) (Coformulated)

• Tenofovir is a nucleotide analog with potent activity against both HIV and 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
  • TDF is associated with lower lipid levels compared to TAF
  • Renal impairment with TDF use has been reported; greater risk of renal dysfunction when used in PI-based regimens
    • Causes renal toxicity, including proximal tubulopathy and acute or chronic renal insufficiency especially when in combination with PK boosters
    • Use of TDF is not recommended in patients with pre-existing renal insufficiency (CrCl <60 mL/min)
    • Dose adjustment is recommended when TDF is used and patient's CrCl falls <50 mL/min
  • TDF decreases bone mineral density (BMD) more than other NRTI combinations
    • TDF should be avoided or used with caution in patients with renal disease or osteoporosis
• TDF/FTC or TDF/3TC are recommended NRTI combinations for initial ART in most people with HIV when combined with DTG or RAL
• TDF plus either 3TC or FTC may be used as NRTI combination for patients coinfected with both HIV and HBV
  • TDF/FTC is the recommended dual-NRTI in patients co-infected with HIV/HBV
  • Use of a single HBV-active NRTI (either 3TC or FTC) is not recommended as it can lead to HBV resistance
• TDF/FTC is coformulated with EFV, EVG/c and RPV as a STRs and has more favorable lipid effects than ABC or TAF
  TDF/FTC 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
• TDF/3TC is coformulated with DOR and EFV
• Boosters should be avoided in patients taking TDF when possible

Protease Inhibitor (PI)-based Regimens

• Have demonstrated durability and virologic potency in ART-naive patients, and high barrier to resistance compared to NNRTIs, EVG and RAL
• Resistance mutations are seldom detected at virologic failure, unlike NNRTI- and integrase strand transfer inhibitor (INSTI)-based regimens
• Useful for patients at risk for intermittent treatment because of poor adherence

Boosted PI Regimens

• PK enhancement of PI-based regimens with either Cobicistat or RTV increases concentration and prolongs the half-lives of PI
• Boosted ATV or DRV-based regimens are recommended for rapid ART initiation or in the setting of acute HIV infection before the availability of resistance test results
• 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
  • PI resistance is not common at time of treatment failure with PH-boosted PIs
• 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 initial ART regimens for ART-naive patients in certain conditions regardless of pre-treatment HIV RNA
• ATV/c + TDF/FTC is not recommended for patients with CrCl <70 mL/minute
• ATV/c + TAF/FTC is not recommended for patients with CrCl <30 mL/min
• 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
• Advantages: A clinical trial has shown RTV-boosting of ATZ enhances ATV concentration, improving virologic activity as compared with ATV alone
  • Another advantage is the presence of fewer metabolic adverse events compared to older boosted-PI agents
• Disadvantages: 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
  • Higher rate of adverse effect-associated drug discontinuation

Darunavir + Cobicistat (DRV/c)

• Regimens consisting of DRV/c + either TAF or TDF / + either FTC or 3TC is recommended for most patients with HIV with history of CAB-LA use as pre-exposure prophylaxis before genotypic test results are available
• DRV/c + TDF/FTC is not recommended for patients with CrCl <70 mL/minutes
• DRV/c + TAF/FTC is not recommended for patients with CrCl <30 ml/min

Darunavir + Ritonavir (DRV/r)

• Regimen consisting of DRV/r + TAF or TDF/FTC or 3TC is recommended as initial ART in certain clinical conditions 
  • ARTEMIS study has shown DRV/r, compared with LPV/r (both in combination with TDF/FTC), to have a superior virologic response
• Must be used with caution in patients with sulfonamide allergies
• Advantages: Higher barrier to resistance and low rate of treatment-emergent resistance

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)

TPV/r

• Requires higher dose of RTV for boosting compared to other PIs
• Higher adverse events rates compared to other RTV-boosted PIs

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
• Fosamprenavir (FPV)
• Indinavir (IDV)
• Nelfinavir (NFV)
• Ritonavir (RTV)

2-Drug ARV Regimens When ABC, TAF and TDF Cannot be Used or Are Not Optimal

• Not recommended in patients with HBV coinfection (unless separate HBV therapy is also administered) or with known pre-existing resistance to any of the ARVs in the combination

DTG/3TC

• Preferred regimen for most people with HIV when ABC, TAF or TDF is not optimal
• Not recommended in the following:
  • Patients with viral load >500,000 copies/mL,
  • Patients with HIV/HBV coinfection, or
  • When ART is to be started before the availability of results of HIV genotypic resistance testing for reverse transcriptase

DRV/r + 3TC

• May be an option for people with HIV who cannot take ABC, TAF or TDF
• ANDES trial results showed that dual therapy with DRV/r + 3TC was noninferior to triple therapy with DRV/r + TDF/3TC and similar virologic suppression rates in patients with viral loads >100,000 copies/mL in both dual- and triple-therapy groups

DRV/r (once daily) + RAL (twice daily)

• Alternative regimen for patients who cannot take ABC, TAF or TDF• Recommended only for patients w/ baseline CD4 counts >200 cells/mm3 & viral loads <100,000 copies/mL

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 Regimen
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

• Treatment strategy wherein patient is switched from an effective ARV regimen to an alternative ARV regimen due to adverse events, drug-drug or drug-food interactions, pill burden, pregnancy, cost, or the wish to simplify a regimen
• Goal is to maintain viral suppression without compromising future treatment options
• Reasons to consider regimen optimization in the setting of viral suppression include:
  • Simplification of regimen by reducing pill burden and/or dosing frequency
  • Enhancement of tolerability and/or reduction of short- and long-term toxicity
  • Prevention or mitigation of drug-drug interactions
  • Elimination of fluid or food requirements
  • Switching to a long-acting injectable regimen for pill fatigue relief or reduction of potential stigma associated with daily oral medication intake
  • Coverage for HBV coinfection
  • For optimal use of ART during pregnancy or when pregnancy is desired
  • Cost reduction
• Patient's treatment history including virologic responses, previous ART-associated toxicities and intolerances, and cumulative resistance test results should be considered before selecting a new ARV regimen
  • Proviral DNA genotyping may be performed for individuals with multiple virological failures, unavailability of resistance history or low-level viremia at the time of switch
• Potential drug-drug interactions with ARV agents and concomitant medications should be considered in selecting a new regimen
• ART optimization for patients with existing NRTI resistance should include 2 NRTIs (TAF or TDF) + FTC or 3TC in the regimen together with a fully active, high resistance barrier agent such as DTG, boosted DRV, or BIC
• Administration of CAB-LA and RPV every 1 or 2 months is an optimization option for patients engaged with their health care, virologically suppressed on oral therapy for 3-6 months, and agree to make frequent follow-ups needed to receive injectable agents
• In patients with HIV/HBV coinfection, ARV agents active against HBV should be continued during the switch or initiation of specific anti-HBV agents should be done
• Referral to HIV specialist is recommended when planning ART optimization for patients with history of resistance to ≥1 drug classes
• Monitoring of tolerability, viral suppression, adherence and safety is recommended during the 1st 3 months after a regimen switch

Within-Class Switches in 3-Drug Regimens

• Prompted by adverse events or availability of ARVs in the same class which offer a better safety profile, decreased dosing frequency, high resistance barrier, lower pill burden, or not requiring PK enhancement
• Include switches:
  • From TDF or ABC to TAF
  • From RAL to DTG
  • From DTG, EVG/c or RAL to BIC
  • From EFV to RPV or DOR

Between-Class Switches in 3-Drug Regimens

• Examples include:
  • Switching from a boosted PI to an INSTI
  • Switching from a boosted PI to RPV or DOR
  • Switching from an NNRTI to an INSTI

2-Drug Regimen Switches

• Should be considered only for individuals with viral suppression if there is no historical resistance and without HBV coinfection
• DTG + RPV
• DTG + 3TC or FTC
• Boosted PI + 3TC is a reasonable optimization option for patients without resistance, and are suppressed with the current regimen and have no active HBV infection
• Boosted DRV + DTG is recommended only in the absence of alternative treatment options and may be an option for patients with resistance and/or intolerance to 3TC or FTC, ABC, and TAF or TDF
• Long-acting ART including Ibalizumab, an anti-CD4 monoclonal antibody given intravenously every 2 week in combination with optimized background therapy in heavily treatment-experienced patients, and long-acting injectable CAB in combination with RPV are approved for use
  • Improve quality of life in patients suffering from pill fatigue and has the advantage of reducing the frequency of dosing
  • Recommended for patients with consistent engagement in their health care
  • CAB-LA + RPV is recommended as replacement of an existing oral therapy in patients with sustained (3-6 months) virologic suppression (viral load <50 copies/mL) on a stable ARV regimen, without history of treatment failure, and without known or suspected resistance to either CAB or RPV
    • Administered IM once monthly or every 2 months
    • Viral load monitoring is recommended 4-8 weeks after a switch to long-acting CAB + RPV and drug resistance testing performed when viremia develops

Optimization Strategies for Patients with Viral Suppression and History of Limited Drug Resistance

• Within class switch from DTG to BIC
• Switching to BIC-based therapy

Optimization Strategies for Patients with Viral Suppression and History of Complex Underlying Drug Resistance

• Patient's ARV history and cumulative drug resistance profile should be considered
• Referral to a HIV specialist is recommended
• Switching to EVG/c/TAF/FTC + DRV has been shown to be a potential optimization strategy for patients on complicated salvage regimens

Optimization Strategies for Patients with Viral Suppression and History of Limited Drug Resistance

• Within class switch from DTG to BIC
• Switching to BIC-based therapy

Optimization Strategies for Patients with Viral Suppression and History of Complex Underlying Drug Resistance

• Patient's ARV history and cumulative drug resistance profile should be considered
• Referral to a HIV specialist is recommended
• Switching to EVG/c/TAF/FTC + DRV has been shown to be a potential optimization strategy for patients on complicated salvage regimens