Antiretroviral%20therapy%20for%20hiv-infected%20adults Treatment
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
- Pregnancy
- 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 |
Alternative NNRTI-based Regimens + 2 NRTIs |
Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine6 |
Alternative boosted PI-based Regimens + 2 NRTIs |
(Cobicistat-boosted Atazanavir or Ritonavir-boosted Atazanavir) + either Tenofovir disoproxil fumarate/Emtricitabine or Tenofovir alafenamide/Emtricitabine |
If HIV RNA <100,000 copies/mL & HLA-B*5701 Negative |
Cobicistat-boosted Atazanavir or Ritonavir-boosted Atazanavir + Abacavir/Lamivudine |
Other Regimens When TAF, TDF or ABC Cannot be Used |
Ritonavir-boosted Darunavir + Raltegravir4 (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