When selecting a regimen for an individual patient, a number of patient- and regimen-specific characteristics should be considered, with the goal of providing a potent, safe, tolerable and easy to adhere to regimen for the patient in order to achieve sustained virological control. Some of the factors can be grouped into the following categories:
Initial characteristics of the patient
- Pre-treatment HIV RNA level (viral load) – there are some regimens which are not recommended if RNA is > 100,000 copies/mL
- Pre-treatment CD4 cell count
- HIV genotypic drug resistance testing results will determine if any specific drugs should be avoided in the regimen
- HLA-B*5701 status – HLA B*5701 positive patients should not receive abacavir-containing regimens
- Patient preferences
- Patient’s anticipated adherence – patients with potential adherence difficulties should be commenced on a ritonavir-boosted protease inhibitor (PI/r)-based regimen.
Specific comorbidities or other conditions
- Cardiovascular disease, hyperlipidaemia, renal disease, osteoporosis, psychiatric illness, neurological disease, drug abuse or dependency requiring narcotic replacement therapy
- Pregnancy or pregnancy potential
- Co-infections: hepatitis C virus (HCV), hepatitis B virus (HBV), tuberculosis (TB).
Regimen-specific considerations
- Regimen’s genetic barrier to resistance
- Potential adverse drug effects
- Known or potential drug interactions with other medications
- Convenience (e.g., pill burden, dosing frequency, availability of fixed-dose combination products, food requirements)
- Choice of a regimen that is known to be potent i.e. one which includes at least three drugs from at least two classes, generally two drugs (backbone drugs) from the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI/NtRTI) class (backbone) and a third (anchor drug) from either the integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) or PI/r class
- Choice of a regimen that is currently recommended by the Australian Antiretroviral Guidelines Panel: alternatives to currently recommended therapy should generally only be used in the context of a specific clinical indication.
| Panel’s recommendations |
| An antiretroviral regimen for a treatment-naive patient generally consists of two nucleoside reverse transcriptase inhibitors in combination with a third active antiretroviral drug from one of three drug classes: an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer (cobicistat or ritonavir).
The Panel classifies the following regimens as recommended regimens for antiretroviral-naive patients: Integrase strand transfer inhibitor-based regimens · Dolutegravir/abacavir/lamivudine—only for patients who are HLA-B*5701 negative (AI) · Dolutegravir plus tenofovir disoproxil fumarate (tenofovir)/emtricitabine (AI) · Elvitegravir/cobicistat/tenofovir/emtricitabine—only for patients with pre-antiretroviral therapy creatinine clearance > 70 mL/min (AI) · Raltegravir plus tenofovir/emtricitabine (AI) Protease inhibitor-based regimen · Darunavir/ritonavir plus tenofovir/emtricitabine (AI) On the basis of individual patient characteristics and needs, an Alternative regimen or; less frequently, an other regimen; may in some instances be the optimal regimen for a patient.[35] Given the large number of excellent options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, comorbid conditions, and cost. Table 1 provides guidance on choosing an antiretroviral regimen based on selected clinical case scenarios.[36] |
| Rating of Recommendations: A: Strong; B: Moderate; C: Optional Rating of Evidence: I: Data from randomised controlled trials; II: Data from well-designed nonrandomised trials or observational cohort studies with long-term clinical outcomes; III: Expert opinion |
Note: Lamivudine may substitute for emtricitabine or vice versa in above regimens
The INSTI-based regimens were selected because of their high virologic efficacy, excellent safety and tolerability profiles, and (with RAL and dolutegravir [DTG]) low number of drug-drug interactions (see the INSTI section of the guidelines for discussion regarding the special characteristics and clinical trial results for each of the three recommended INSTIs). For patients who are at high risk for intermittent therapy because of poor adherence or have transmitted NRTI drug resistance, a PI/r-based treatment is preferred given the PIs high genetic barrier to resistance. In some situations, an NNRTI-based regimen may be a better choice for a particular patient.
Table 1 provides guidance on regimen selection based on various patient- and regimen-specific characteristics.
Table 1. Antiretroviral regimen considerations as initial therapy based on specific clinical scenarios[37]:
| Patient or regimen characteristics | Clinical scenario | Consideration(s) | Rationale/comments |
| Pre-ART characteristics | CD4 count < 200 cells/μL | Do not use the following regimens: • RPV-based regimens • DRV/r plus RAL |
Higher rate of virological failure observed in those with low pre-treatment CD4 cell count |
| HIV RNA >100,000 copies/mL | Do not use the following regimens: • RPV-based regimens • ABC/3TC with EFV or ATV/r • DRV/r plus RAL |
Higher rates of virological failure observed in those with high pre- treatment HIV RNA | |
| HLA-B*5701 positive Do not use ABC-containing regimen. | Do not use ABC-containing regimen | ABC hypersensitivity, a potentially fatal reaction, is highly associated with positivity for the HLA-B*5701 allele | |
| Must treat before HIV drug resistance results available | Avoid NNRTI-based regimen | Transmitted mutations conferring NNRTI resistance are more likely than mutations associated with PI or INSTI resistance
Some experts avoid using INSTI-containing regimens in this setting because of concern regarding their ability to fully suppress viral replication if transmitted NRTI mutations are present |
|
| ART-specific characteristics | One pill once daily regimen desired |
ART options include: • DTG/ABC/3TC • EFV/TDF/FTC • EVG/c/TDF/FTC • RPV/TDF/FTC (if HIV RNA <100,000 copies/mL and CD4 count >200/μL) |
Available as fixed-dose combination tablets |
| Food effects | Regimens that should be taken with food: • ATV/r or ATV/c-based regimens • DRV/r or DRV/c-based regimens • EVG/c/TDF/FTC • RPV/TDF/FTCRegimens that should be taken on an empty stomach: • EFV-based regimens |
Food improves absorption of the listed regimens
Taking EFV-based regimens with food increases EFV absorption and may increase CNS side effect |
|
| Presence of other conditions | Chronic kidney disease (defined as eGFR < 60 mL/min) | Consider avoiding TDF
If eGFR is < 70 mL/min, do not use: Options for CKD patients Other options (See text for discussion): |
TDF has been associated with renal tubulopathy
See Appendix B, Table 7 (in Guidelines)[38] for recommendations on ARV dose modification |
| Osteoporosis | Consider avoiding TDF. ABC/3TC if HLA-B*5701 negativeIf HIV RNA > 100,000 copies/mL, do not use ABC/3TC plus (EFV or ATV/r) |
TDF is associated with greater decrease in bone mineral density along with renal tubulopathy, urine phosphate wasting, and osteomalacia | |
| Psychiatric illness | Consider avoiding EFV-based regimens | EFV can exacerbate psychiatric symptoms and may be associated with suicidality | |
| HIV-associated dementia (HAD) | Avoid EFV-based regimens if possible
Favour DRV-based or DTG-based regimen |
EFV neuropsychiatric effects may confound assessment of the effect of ART on improvement of symptoms associated with HAD
Theoretical CNS penetration advantage |
|
| Narcotic replacement therapy required | If patient receiving methadone, consider avoiding EFV-based regimen.
If EFV is used, an increase in methadone dose may be necessary |
EFV reduces methadone concentrations and may lead to withdrawal symptoms | |
| High cardiac risk | Consider avoiding ABC- and LPV/r – based regimens | Increased cardiovascular risk in some studies (see ABC discussion in the guidelines | |
| Hyperlipidaemia | The following ARV drug classes or drugs have been associated with deleterious effects on lipids:
• PI/r |
TDF has been associated with beneficial lipid effects, thus it may be preferable to ABC | |
| Pregnancy | Refer to the Perinatal Antiretroviral Treatment Guidelines. | ||
| Presence of co- Infections | HBV infection | Use TDF/FTC (or TDF plus 3TC) whenever possible
If TDF is contraindicated: · For treatment of HBV, use FTC or 3TC with entecavir or another drug active against HBV |
TDF, FTC, and 3TC are active against both HIV and HBV. 3TC- or FTC-associated HBV mutations can emerge rapidly when these drugs are used without another HBV-active agent |
| HCV treatment required | Refer to recommendations in the HIV/HCV co-infection section of the guidelines | ||
| Tuberculosis infection | If rifampin is used:
· EFV-based regimens have the least drug- drug interactions · If RAL is used, increase RAL dose to 800 mg twice daily · Use DTG at 50 mg twice daily dose only in patients without selected INSTI mutations (refer to product label) If using a PI-based regimen, rifabutin should be used in place of rifampin in the tuberculosis regimen |
· Rifampin is a strong inducer of CYP3A4 and UGT1A1 enzymes, causing significant decrease in concentrations of PI, INSTI, and RPV
· Rifampin has a less significant effect on EFV concentration than on other NNRTIs, PIs, and INSTIs · Rifabutin is a less potent inducer and is a good option for patients receiving non- EFV-based regimens Refer to Tables 19a, b, d and e for dosing recommendations for rifamycins used with different ARV agents in the guidelines |
|
| 3TC: lamivudine; ABC: abacavir; ATV/r: ritonavir-boosted atazanavir; ART: antiretroviral therapy; ARV: antiretroviral; c: cobicistat; CKD: chronic kidney disease; CrCl: creatinine clearance; DRV/r: ritonavir- boosted darunavir; DTG: dolutegravir; eGFR: estimated glomerular filtration rate; EFV: efavirenz; EVG/c/TDF/FTC: elvitegravir/cobicistat/tenofovir/emtricitabine; FDA: Food and Drug Administration; FTC: emtricitabine; HBV: hepatitis B virus; HCV: hepatitis C virus; INSTI: integrase strand transfer inhibitor; LPV/r: ritonavir-boosted lopinavir; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; r/PI: ritonavir-boosted protease inhibitor; RAL: raltegravir; RPV: rilpivirine; RTV: ritonavir; TDF: tenofovir disoproxil fumarate | |||