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Rigshospital, University of Copenhagen
Centre of Excellence for Health, Immunity and Infection (CHIP)
Rigshospital, University of Copenhagen
Jens D. Lundgren, MD, DMSc, has no relevant conflicts of interest to report.
Recently released updated guidelines from the European AIDS Clinical Society (EACS) recommend 6 combinations of antiretroviral agents for initial HIV therapy (Table). Five of the 6 options include an integrase strand transfer inhibitor (INSTI) (dolutegravir [DTG], bictegravir [BIC], or raltegravir [RAL]), and 1 includes a nonnucleoside reverse transcriptase inhibitor (NNRTI) (doravirine [DOR]). Five of the 6 options include 2 nucleoside reverse transcriptase inhibitors (NRTIs) (either abacavir [ABC], tenofovir alafenamide [TAF], or tenofovir disoproxil fumarate [TDF] in combination with either lamivudine [3TC] or emtricitabine [FTC]). The other includes only a single NRTI (either 3TC or FTC in combination with DTG).
Table. EACS Recommended Regimens for Initial Antiretroviral Therapy (ART)
Selecting Among Initial ART Recommendations
All 6 combinations fulfil features of an optimal HIV treatment regimen, including documented long-term efficacy, high barrier to resistance, safety, tolerability, and few drug‒drug interactions. They all are able to provide durable control of viral replication pending good to excellent compliance with the regimen. Of note, existing evidence suggests similar viral suppression efficacy irrespective of being dosed as a single tablet or provided as 2 separate pills. The 2-drug regimen of 3TC and DTG should not be used in persons who experienced failure of HIV PrEP due to an increased risk of underlying resistance to 3TC. This 2-drug regimen also is not recommended in persons with very high pretherapy HIV-1 RNA levels, for example, patients with advanced HIV-related disease progression.
Hence, the key differentiating features of the 6 recommended regimens relate to the presence of coinfections and risk of adverse events. All of the INSTIs, as well as TAF, are associated with increased risk of weight gain, which may result in increased risk of metabolic and cardiovascular disease compared with combinations that do not contain these drugs. Conversely, ABC is associated with increased risk of cardiovascular disease and, in persons with the HLA-B*5701 allele, hypersensitivity reaction, whereas TDF is associated with bone demineralization and kidney dysfunction. In general, TDF and TAF can be used interchangeably. The exceptions in which TAF is the preferred agent are patients with established or high risk of chronic kidney disease, use of other nephrotoxic agents, osteoporosis (or progressive osteopenia), and/or a history of fragility fractures. In patients with hepatitis B virus coinfection (ie, HBsAg positive), it is necessary to include 2 drugs with activity against this virus (eg, either TDF or TAF in combination with 3TC or FTC). Finally, DOR is not active against HIV-2.
The choice among the 6 options, provided they are all available, should reflect a decision process based on the patient’s individual characteristics and clinical circumstances. If none of the relative or absolute contraindications is present, some clinics continue to use a combination of 3 drugs including an INSTI, 3TC or FTC, and TDF or TAF as standard practice.
Considerations for Switching ART in Patients With Viral Suppression
In routine care, most patients are receiving a fully suppressive ART regimen. In total, there are 9 indications for switching 1 or more of the agents in a fully suppressive ART regimen.
1) Documented toxicity
2) Prevention of long-term toxicity
3) Avoidance of drug‒drug interaction
4) Females planning pregnancy
5) Aging and comorbidities
7) Protection from hepatitis B virus infection
8) Regimen fortification
9) Cost reduction
All of these indications should be considered at each clinic visit, including by a pointed interview with the patient and appropriate laboratory evaluations. One cannot assume that a given patient is optimally treated merely because his or her HIV-1 RNA level is <50 copies/mL. It is beyond the scope of this commentary to address all aspects of these indications. The EACS guidelines provide detailed considerations and should be consulted before making decisions on regimen switches. However, a few recent advances warrant highlighting, including the role of the genetic barrier to resistance and considerations for 2-drug therapies.
Switches within the same drug class (eg, for indications 1 and/or 2 listed above) are usually safe and are unlikely to lead to reduced virologic control. The most frequent within-class substitutions include the switch from TDF to TAF and switching from efavirenz (EFV) to either DOR or rilpivirine (RPV). Likewise, switching from a drug class with a low genetic barrier to resistance to a drug from another class with a similar or higher genetic barrier to resistance is considered virologically safe (eg, switch from EFV to an INSTI). Conversely, switching from a drug with a high genetic barrier to resistance (eg, boosted protease inhibitor, DTG, BIC) to a drug with a lower genetic barrier to resistance (eg, RAL, DOR, RPV) poses a higher risk for loss of virologic control. This is because the patient’s virus may not be fully susceptible to all drugs in the current regimen. Hence, in such situations, it is important to optimize the chance that the virus is fully susceptible to all drugs in the new regimen.
Several 2-drug regimens have recently undergone clinical evaluation and are now available among switch options. These include DTG plus RPV, DTG plus 3TC or FTC, boosted (with cobicistat or ritonavir) darunavir plus 3TC or FTC, and long-acting cabotegravir (CAB) and RPV (injected bimonthly in Europe). Of note, careful attention to whether the patient’s virus has developed resistance to either of the drugs within the regimen is essential. If that is the case, 2-drug therapy is not recommended. Oral 2-drug options are particularly relevant in situations where it is desirable to switch patients off ABC or TDF due to observed or projected increased risk of specific drug-related adverse events. The long-acting injectable regimen is clearly an attractive option for persons unable to comply with daily drug intake, possibly because of unstable/inconsistent personal lifestyle or frequent travel. However, the long-acting regimen currently requires an oral lead-in period and IM injections every 60 days; hence, it requires substantive patient and health system resources to be administered on schedule. Consequently, only very select patients are likely to benefit from using this regimen. Also of note, in pregnant women, RPV plasma concentrations may decrease during the second and third trimesters, warranting additional viral load monitoring; therefore, RPV is considered an alternative rather than a recommended option during pregnancy.
In conclusion, strategies for optimizing initial and switch ART continue to evolve, and this evolution is reflected in the latest 2021 iteration of the EACS guidelines.
How will the updated EACS guidelines for initial and switch ART regimens influence your clinical practice? Answer the polling question and join the discussion by posting a comment. For more discussion of HIV treatment, comorbidities, prevention, and COVID-19–related issues, download the slides and watch the videos from our recent HIV Annual Update symposium.