Single-Tablet Regimens in the Treatment of HIV-1 Infection
Efavirenz/tenofovir DF/emtricitabine
The first widely used STR, Atripla (Bristol-Myers Squibb and Gilead Sciences) combines the NRTIs tenofovir DF and FTC with the NNRTI EFV and was released in 2006. It is indicated for use alone or in combination with other ARTs for treatment of HIV-1 infection in adults or children aged > 12 years.18 Contraindications include hypersensitivity to efavirenz or coadministration with voriconazole. Major precautions are required for patients with severe psychiatric disease or suicidality; new or worsening renal impairment; women in the first trimester of pregnancy or of childbearing age not on effective contraception; or osteoporosis or history of fragility fractures. Patients with chronic liver disease also should be monitored for hepatotoxicity.
Large RCTs confirmed the potency and durability of viral suppression of EFV/TDF/FTC in treatment-naïve patients19,20 or in the context of antiretroviral switching for treatment simplification in patients previously suppressed with NNRTI- or PI-based regimens.21 This combination
has been shown to be noninferior or superior to multiple PI-based,22 NNRTI-based,23 and INSTI-based regimens.18 However, it recently was found to be associated with lower virologic response than was the INSTI-based regimen of ABC/3TC plus dolutegravir (DTG) and higher discontinuation rates than that of a TDF/FTC plus RAL regimen.24,25 Due to lingering concerns about an EFV association with suicidality26 and neural tube defects with first trimester exposure,27 EFV/TDF/FTC was downgraded to an alternative regimen for treatmentnaïve patients, because other available regimens are better tolerated with equal or superior efficacy.7
Rilpivirine/tenofovir DF/emtricitabine
Approved in 2011, Complera was the second STR (Gilead Sciences), combining the NNRTI rilpivirine (RPV) with the NRTI backbone TDF/FTC. It is indicated for use in (1) treatment-naïve adults with a baseline HIV-1 RNA ≤ 100,000 copies/mL and baseline CD4+ > 200 cells/mm3; or (2) switch therapy (changing from a previous antiretroviral regimen) in patients virologically suppressed (HIV-1 RNA ≤ 50 copies/mL) for at least 6 months without history of virologic failure or resistance to any of the component drugs.28 Contraindications include administration with other drugs that significantly lower RPV concentrations, such as certain acid-lowering drugs. Although not associated with as many neuropsychiatric or teratogenic effects as EFV/TDF/FTC, this combination still requires caution in circumstances of preexisting renal impairment, severe hepatic disease, or bone disease.
Two phase 3 studies and 1 open-label phase 3b study confirmed that RPV-based STRs were noninferior to EFVbased STRs overall.23,29 Importantly, patients with higher baseline viral loads experienced higher rates of virologic failure and higher rates of NRTI backbone resistance. Patients with baseline CD4+ < 200 cells/mm3 also had higher virologic failure rates. Because of these virologic and immunologic prerequisites for use, RPV/TDF/FTC is considered an alternative regimen for treatment-naïve patients.7 On the other hand, in the aforementioned studies,
fewer patients in the RPV arms discontinued therapy due to adverse events (AEs), and a switch from EFV/TDF/FTC to RPV/TDF/FTC was shown to be safe and effective.30 Its greater tolerability and safety profile make RPV/TDF/FTC an option for patients who do not tolerate EFV/TDF/3TC, who are pregnant, and who have a psychiatric illness.
Elvitegravir/cobicistat/tenofovir DF/emtricitabine
Released in 2012, Stribild (Gilead Sciences) was the first treatment to combine an INSTI and elvitegravir (EVG) with the pharmacologic booster cobicistat and the TDF/FTC backbone. It is indicated for use in treatmentnaïve adults or as switch therapy in patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.31
Two double-blind, active-controlled trials established that EVG/c/TDF/FTC was virologically noninferior and had greater safety and tolerability than that of EFV/TDF/FTC32 and ATV/RTV plus DF/FTC33 in treatment-naïve patients. It also maintained virologic suppression in patients switching from a boosted PI34 or an NNRTI-based regimen.35 On the basis of this efficacy and safety data, EVG/c/TDF/FTC is considered a recommended regimen for initial ART treatment.7 However, limitations to this regimen include significant drug-drug interactions due to potent CYP3A inhibition by cobicistat, potential renal and bone toxicity due to TDF, and cobicistat-induced inhibition of renal tubular creatinine secretion, which can lead to a mild creatinine increase (≤ 0.4 mg/dL) and may complicate renal function monitoring. Therefore, it is contraindicated
in patients concomitantly taking medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance, patients with reduced renal function (estimated creatinine clearance [CrCl] < 70 mL/min), and those receiving polyvalent cationic antacids or supplements.
Dolutegravir/abacavir/lamivudine
Approved in 2014, Triumeq (ViiV Healthcare) is the first and only currently available STR with an NRTI backbone of ABC/3TC rather than a tenofovir (TFV) derivative, combined with the INSTI DTG. It is indicated for the treatment of HIV-1 infection in patients without prior resistance to the INSTI class of ART or the other component drugs in this combination pill.36 The major contraindication is presence of the HLA-B*5701 allele, a polymorphism that predicts abacavir-related hypersensitivity, or moderate-tosevere hepatic impairment.37 Caution is required in patients with hepatitis B virus (HBV) co-infection due to the risk of 3TC drug resistance and subsequent acute exacerbation of HBV. Coadministration with dofetilide is contraindicated, and coadministration of some medications, most notably rifampin, requires an additional dose of DTG alone be given.36 Dolutegravir absorption is also decreased when coadministered with polyvalent cationic antacids or laxatives.
Dolutegravir-based regimens have been shown to be noninferior to RAL-based regimens38 and superior to EFV/TDF/FTC24 and boosted DRV-based regimens.39 Treatment-emergent resistance to DTG has been rare, suggesting a high genetic barrier to resistance compared with that of other INSTIs. On this basis, DTG/ABC/3TC is considered a recommended regimen for initial ART treatment.7 Another advantage of DTG/ABC/3TC is fewer drug-drug interactions than those of PI- or NNRTI-based regimens or the EVG/c/TDF/FTC STR.24,38,39 Limitations include the requirement to confirm a negative HLAB* 5701 allele, the potential association of abacavir with cardiovascular (CV) events seen in some but not all studies, and a small increase in creatinine due to DTG effects on renal tubular secretion.40-43
