Since 2016, WHO has recommended tenofovir disoproxil fumarate (TDF) + lamivudine (3TC) (or emtricitabine, FTC) + efavirenz (EFV) 600 mg as the preferred firstline antiretroviral therapy (ART) regimen for adults and adolescents. WHO recommended dolutegravir (DTG) as an alternative option to EFV for first-line ART because of the uncertainty regarding the safety and efficacy of DTG during pregnancy and among people living with HIV receiving rifampicin-based tuberculosis (TB) treatment.
Since WHO published the 2016 ARV guidelines (1), several studies have evaluated the safety and efficacy of DTG during pregnancy and the periconception period, among children and among people with HIV-associated TB infection. In addition, increasing levels of pretreatment antiretroviral (ARV) drug resistance documented in low- and middle-income countries prompted WHO to issue guidelines recommending that countries with pretreatment resistance to EFV or nevirapine (NVP) at or above 10% should urgently consider using an alternative regimen that does not contain non-nucleoside reversetranscriptase inhibitors (NNRTIs) such as EFV (2). DTG has been approved for children older than six years, and raltegravir (RAL) has now been approved for use from birth, providing additional options for neonates and children living with HIV.
DTG in first-line ART
An updated systematic review conducted in 2018 showed that a regimen with two nucleoside reverse-transcriptase inhibitors (NRTIs) paired with DTG was more effective, with higher viral suppression and CD4 cell count recovery rates and lower risk of treatment discontinuation compared with EFV-based regimens among treatment-naive adults. DTG also had better efficacy at suppressing viral loads than other integrase inhibitors. DTG has other advantages compared with EFV, including lower potential for drug–drug interactions, more rapid viral suppression and a higher genetic barrier to developing ARV drug resistance. DTG is also active against HIV-2 infection, which is naturally resistant to EFV. The availability of this drug as a generic fixed-dose formulation at a price comparable to current regimens in most low- and middle-income countries also supports the use of DTG as a better option for initiating ART. However, there are concerns regarding the safety of women and adolescent girls using DTG at conception (Box 1).
Adolescent girls and women of childbearing potential who do not currently want to become pregnant can receive DTG together with consistent and reliable contraception; based on limited data, hormonal contraception and DTG have no reported or expected drug–drug interactions. The 2016 WHO ARV guidelines (1) recommended an EFV-based regimen as an alternative safe and effective first-line regimen that adolescent girls and women of childbearing potential can use during the period of potential risk for developing neural tube defects (at conception and up to eight weeks after conception).
The United States Food and Drug Administration and the European Medicines Agency approved paediatric dosing that supports the use of DTG for children older than six years and weighing more than 30 kg and 15 kg, respectively. The approved dosing for children younger than six years or weighing less than 15 kg is expected in late 2019. Among children for whom approved dosing of DTG is not available, RAL is considered an effective integrase inhibitor and is approved for use among infants starting at birth. RAL successfully reduces viral load among highly viraemic infants and is safe and well tolerated among neonates and infants at high risk of infection.
In summary, ample evidence supports using DTG as a preferred first-line ARV drug for everyone living with HIV older than six years and weighing more than 15 kg, including women and adolescent girls of childbearing potential who are using consistent and reliable contraception. Health-care providers should give women information and options to enable them to make informed choices about using lifelong ART regimens (Box 2).
Current concerns about using DTG during the periconception period are based on limited data. WHO is working actively with national health ministries, academic institutions and implementing partners to undertake ongoing assessment of this potential risk and will update the guidance on using DTG for women of childbearing potential as soon as there are sufficient data to justify a change.
In countries with national pretreatment resistance at or above 10%, the choice of alternative options to EFV needs to be made by weighing ARV drug availability and the toxicity profile. In these settings, DTG (provided with consistent and reliable contraception for adolescent girls and women of childbearing potential) and atazanavir/ritonavir (ATV/r) are suitable ARV drug options to be considered (Fig. 1).
Recent data on the efficacy and safety of DTG co-administered with rifampicin among people coinfected with HIV and TB showed that the dose of DTG needs to be increased to 50 mg twice daily because of drug–drug interactions with rifampicin. This extra dose of DTG was well tolerated, with equivalent efficacy in viral suppression and recovery of CD4 cell count compared with EFV.