Single-Tablet Regimens in the Treatment of HIV-1 Infection
Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine
The latest STR, Genvoya (Gilead Sciences), approved in 2015, combines the INSTI elvitegravir and cobicistat with the novel NRTI backbone alafenamide(TAF)/FTC. Like TDF, TAF is an oral prodrug of TFV, but it achieves lower plasma and higher intracellular TFV levels than does TDF, potentially leading to improved bone and renal tolerability. This combination pill is indicated for use in treatment-naïve adults and children aged ≥ 12 years as switch therapy for 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.44 Contraindications include use of concomitant medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance. Initiation of this STR is also not recommended in patients with an estimated CrCl < 30 mL/min or with severe hepatic impairment.
In 2 phase 3 RCTs in treatment naïve patients, EVG/c/TAF/FTC was virologically noninferior to EVG/c/TDF/FTC.45 Patients in the TAF arms had smaller declines in estimated glomerular filtration (eGFR) and reductions in bone mineral density (BMD) but higher fasting lipids compared with that of patients in the TDF arms. Switching virologically suppressed patients with mild-tomoderate renal insufficiency (eGFR 30-69 mL/min) from TDF-containing regimens to EVG/c/TDF/FTC also has demonstrated maintenance of virologic response while improving BMD and markers of renal function.46
In November 2015, EVG/c/TAF/FTC was added as a recommended regimen for initial ART treatment in patients with CrCl ≥ 30 mL/min.7 Advantages of this regimen include its favorable safety profile mentioned earlier and the indication for use in patients with mildto-moderate renal impairment, which is unique among the STRs. However, limitations still remain, including significant drug-drug interactions due to potent CYP3A inhibition and cobicistat-induced inhibition of renal tubular creatinine secretion. Also, more clinical data are needed to confirm the durability of this regimen and to assess whether its improved safety profile translates into fewer clinical outcomes such as renal failure or fractures.
Single-Tablet Regimen Pros and Cons
The proportion of patients on STRs has significantly increased over the past several years. A recently published report of the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women, has analyzed the use of STR. The study showed that the use of STR among ART users increased from 7% in 2006 to 27% in 2013.47
Advantages of STRs
Potential advantages of STRs include simplicity, convenience, and adherence, especially by eliminating the risk of selective nonadherence to components of the regimens. Observational cohorts and meta-analyses are beginning to confirm these theoretical advantages. A meta-analysis of 19 RCTs including 6,312 patients demonstrated that regimens with lower pill burdens and once-daily dosing were both associated with better adherence, and fewer pills also led to improved virologic suppression.48 In the analysis of the WIHS cohort, STR use was significantly associated with increasedadherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11).47 Another observational cohort analysis of commercially insured HIV-infected patients showed that patients on STRs were 1.3 times more likely to achieve at least 90% adherence.49
A recent RCT, which assigned 300 patients on stable ART to continue their current regimen or switch to EFV/TDF/FTC as an STR, demonstrated no difference in virologic suppression or patient-reported adherence between the 2 groups.21 However, 91% of patients in this study reported a preference for the STR regimen.50 Single-tablet regimen recipients also have been shown to be less likely to develop treatment-emergent, drug-resistance mutations (DRMs) at the time of virologic failure. In a recently published study, patients receiving the STR EFV/FTC/TDF had a significantly lower risk of DRMs on failure than did those receiving the same components individually in a non-STR regimen.51 Finally, recent data showed that prescription errors in inpatient ART are common and often go undetected, but coformulated regimens were associated with lower error rates.52
Disadvantages of STRs
Although outweighed by the advantages, there are potential disadvantages to the use of STRs. These include the inability to adjust dosages of components of the regimen for drug-drug or drug-food interactions. In particular, patients with preexisting renal impairment (estimated CrCl < 50 mL/min) have limited options and safety data for STRs. Also, STRs do not exist currently for all NRTI-anchor drug pairings. Notably, there is no available 2 NRTI plus boosted PI STR. This limitation may be important in treatment-experienced patients where PI-based regimens may be needed or in patients with comorbidities where a NRTI-sparing regimen would be considered.
