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:
  • 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)

Recommended Antiretroviral Drug Regimens for Treatment-Naive Patients

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