Patient adherence to medication is the cornerstone of successful long-term treatment. Simpler dosing regimens are associated with improved adherence and virological control. Other reasons to consider regimen simplification may arise in both treatment-naïve and treatment-experienced patients, most commonly due to the presence of comorbidities, and avoidance or management of long-term toxicity and adverse effects. Decisions to use alternative regimens should be evidence-based and made with expert advice.

Strategies to simplify regimens include use of:

• ART formulated as a single tablet, e.g., dolutegravir/lamivudine/abacavir (Triumeq) or bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy);
• once-daily regimens;
• drugs that do not require dosing with food;
• combination drug formulations replacing individual drugs, e.g., darunavir/cobicistat (Prescobix) replacing a separate dose of the pharmacokinetic enhancer ritonavir with co-formulated cobicistat into a single tablet.
• drugs with fewer adverse effects, e.g., replacing ritonavir with cobicistat as a pharmacological booster;
• 2-drug regimens where appropriate (see below);
• drugs with fewer potential DDIs for patients on concomitant potentially interacting drugs, e.g., tenofovir alafenamide/emtricitabine/bictegravir (Biktarvy) replacing tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat (Genvoya);
• nucleoside/nucleotide-sparing regimens to reduce risk of toxicity, particularly for patients with co-morbidities.

2-Drug Regimens (2DR)

To reduce risk of long-term toxicity, consider using an approved and recommended 2DR for initial antiretroviral treatment, or maintenance therapy in virologically suppressed individuals without:

• drug-resistance mutations that would compromise the two-drug option;
• chronic HBV infection;
• potential problematic adherence;
• Significant drug-drug interactions that might reduce either drug’s plasma concentration

In addition, use caution in the case of a very high HIV viral load (>500,000 copies/mL) and/or low CD4  count (<200/mL) as outcome data is limited in these sub-groups.

The antiretroviral drugs in a 2DR should target a minimum of two different sites of HIV replication and should include a potent N(t)RTI and an integrase inhibitor. Most 2DRs that include a single NRTI have used lamivudine, because of its potency and relatively low toxicity compared with other NRTIs. The improved tolerability and potency of newer integrase inhibitors has made simplification to 2DR more attractive. Bictegravir only comes in a FDC with 2N(t)RTIs so the only single tablet FDC is dolutegravir plus lamivudine.

Dolutegravir plus lamivudine: initial and maintenance therapy

Dolutegravir plus lamivudine has proven to be an effective 2DR in treatment-naïve individuals, with 48-week week data from randomised controlled trials demonstrating virological equivalence, and 96-week data showing fewer drug-related renal and bone adverse effects for the 2DR, although the comparator regimen which included tenofovir DF had lipid profile advantages.⁸

A phase 3 study of maintenance of virological suppression in treatment-experienced adults with fixed-dose dolutegravir plus lamivudine versus a TAF-containing three-drug regimen demonstrated non-inferiority at 48 weeks and 96 weeks.^[9,10]

Boosted protease inhibitors plus lamivudine for initial and maintenance therapy

Darunavir/ritonavir plus lamivudine was non-inferior to darunavir/ritonavir plus TDF/FTC after 48 weeks in a randomised open label study in treatment naïve individuals.^[11] Previous studies of boosted protease inhibitors plus lamivudine with or without another NRTI in treatment-naïve individuals showed virological equivalence but were either small studies or were impacted by the poor tolerability of lopinavir/ritonavir. In maintenance treatment, a number of studies using boosted protease inhibitors (atazanavir or darunavir) with lamivudine have met non-inferiority criteria without development of drug resistance.^[12]

Nucleoside/nucleotide-sparing regimens

Recent maintenance studies using rilpivirine with either ritonavir-boosted darunavir, dolutegravir, or cabotegravir have had excellent results to date.

• Randomised controlled open-label trial data support the use of dolutegravir plus rilpivirine as maintenance therapy in patients on their first or second regimen and without a history of virological failure.^[13]
• Several maintenance studies using cabotegravir, a structural analogue of dolutegravir, with rilpivirine or two NRTIs with either oral (LATTE study) or long-acting intramuscular dosing (LATTE-2), have shown virological equivalence.
• Fully powered phase 3 maintenance studies using long-acting cabotegravir plus rilpivirine every four weeks (ATLAS, FLAIR) and comparing 4 versus 8-weekly treatment intervals with long-acting cabotegravir plus rilpivirine (ATLAS-2M) have demonstrated efficacy and safety for the long-acting treatment with a virological failure rate of ~1% across studies.^{[14 – 17]}
• Virological suppression at week 48 was equivalent for ritonavir-boosted darunavir plus rilpivirine or 2 NRTIs in one small study.^[18]