Abacavir/dolutegravir/lamivudine

Abacavir/dolutegravir/lamivudine should only be used in pregnancy if the potential benefits outweigh the risks.[1][6]

The US Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV.[7][8] This recommendation is coupled with the potential for serious adverse reactions in nursing infants. Dolutegravir and abacavir were shown to be excreted in the milk of lactating rats. Lamivudine was shown to be excreted in human breast milk.[9]

The patent was filed on April 28, 2006,[10] and expires on October 5, 2027.[11] It was approved for use in the United States and in the European Union in 2014.[3][2]

In August 2015, the Food and Drug Administration (FDA) sent a bulletin regarding label updates for dolutegravir and Triumeq regarding drug-drug information.[9]

Drug interactions was updated to include a statement that in vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.[9] Furthermore, information regarding drug interactions with carbamazepine and metformin.[9]

Additionally, less common adverse reactions observed in clinical trials was updated to include suicidal ideation, attempt, behavior, or completion in order to be consistent with dolutegravir label.[12]

In September 2015, the FDA added a boxed warning of hypersensitivity reactions, lactic acidosis, and severe hepatomegaly in abacavir-containing products regarding HLA-B*507 allele.[13]

Boxed warning (9/2015)

• Hypersensitivity reactions
• Lactic acidosis and severe hepatomegaly with steatosis
• Exacerbations of hepatitis B

Dosage and administration

• Dosage recommendation with certain concomitant medications (8/2015)
• Not recommended due to lack of dosage adjustment (9/2015)

Contraindications (9/2015)

Warnings and precautions, hypersensitivity reactions (9/2015)

A year supply of abacavir/dolutegravir/lamivudine costs around US$33,000 as it is under patent and not available as a generic.[5]

In July 2015, ViiV Healthcare struck a deal with Shanghai-based Desano Pharmaceuticals for a cheaper supply of dolutegravir (Tivicay) with the goal of cutting the cost in China and other developing countries. After approval of dolutegravir (Tivicay) in 2014, it came with a retail cost of $14,000 per year in the United States.[14]

Efficacy of abacavir/dolutegravir/lamivudine was demonstrated in antiretroviral treatment-naive participants by SINGLE (ING114467), the randomized, controlled trial and other trials in treatment-naive subjects (see dolutegravir).

In the SINGLE trial, 414 participants received dolutegravir + abacavir/lamivudine once daily and 419 participants received efavirenz/emtricitabine/tenofovir once daily. dolutegravir + abacavir/lamivudine compared to efavirenz/emtricitabine/tenofovir showed a reduction in viral load of HIV-1 RNA <50 copies/mL in 80% of participants compared to 72% of participants, respectively. Furthermore, in participants with baseline plasma viral load of <100,000 and >100,000 copies/mL, dolutegravir + abacavir/lamivudine compared to efavirenz/emtricitabine/tenofovir showed a reduction to <50 copies/mL in 85% and 71% compared to 73% and 72%, respectively.[15]

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported voluntarily from a population of unknown size. As such, it is not always possible to estimate frequency or establish a causal relationship to drug exposure.[9]

Abacavir and/or Lamivudine

• Digestive System: stomatitis
• Gastrointentional: pancreatitis
• General: weakness
• Blood and Lymphatic Systems: aplastic anemia, anemia, enlarged lymph nodes, enlarged spleen
• Hypersensitivity: sensitization reactions (including anaphylaxis), urticaria
• Metabolism and Nutrition Disorders: hyperprolactinemia
• Musculoskeletal System: muscle weakness, CPK elevation, rhabdomyolysis
• Nervous System: paresthesia, peripheral neuropathy, seizures
• Respiratory System: abnormal breath sounds/wheezing
• Skin: hair loss, erythema multiforme. Suspected Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in participants receiving abacavir primarily in combination with medications that are known to be associated with SJS and TEN, respectively.

The safety and tolerability of Triumeq was evaluated for amyotrophic lateral sclerosis (ALS) patients as part of the Lighthouse trial, an open-label, phase 2a study, conducted in Australia beginning in late 2016 over 24 weeks.[16][17] The study premise was human endogenous retroviruses, specifically human endogenous retrovirus K (HERV-K) may be a trigger or cause of ALS. Research has linked HERV-K to ALS based on increased nonspecific reverse transcriptase activity in the cerebrospinal fluid and blood of ALS patients, as well as HERV-K being found in the motor neurons of ALS patients. Triumeq was chosen as all three component drugs have good penetration of the central nervous system, particularly dolutegravir, which has high clearance rates for CNS HIV. The study found a significant decrease in HERV-K DNA in serum among study participants and showed a decrease in the slope of clinical progression based on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) of roughly 30%.[17] The trial has since progressed to Phase 3.