Clinical Pearls & Morning Reports
Published August 28, 2019
In the ADVANCE trial, Venter et al. compared treatment with dolutegravir combined with either of two tenofovir prodrugs to the first-line standard-of-care regimen used in the majority of patients with human immunodeficiency virus (HIV) infection in low- and middle-income countries. Read the Original Article here.
Q: What limitations are associated with the regimen of tenofovir disoproxil fumarate, lamivudine (or emtricitabine), plus efavirenz as first-line treatment for HIV infection?
A: A first-line regimen of tenofovir disoproxil fumarate (TDF) with either lamivudine (3TC) or emtricitabine (FTC) plus efavirenz (EFV) for the treatment of HIV infection is recommended by the World Health Organization because it can be safely used in pregnancy and during tuberculosis treatment. However, the regimen has a low resistance barrier, and there are relatively high incidences of toxic effects among some patients. Other antiretroviral agents are recommended in high-income countries.
Q: What new drugs are under consideration for inclusion in first-line HIV regimens?
A: Two drugs under consideration for inclusion in new regimens are dolutegravir (DTG), to replace EFV, and tenofovir alafenamide fumarate (TAF), to replace TDF, both prodrugs of tenofovir. DTG has potency, resistance, and side-effect benefits over EFV, and there are widespread plans to rapidly expand its use in low- and middle-income countries. However, associations of DTG with teratogenic effects (specifically, neural-tube defects), neuropsychiatric symptoms, and weight gain have aroused concern, as has the complexity of twice-daily administration with rifampin-containing tuberculosis treatment. TAF has similar efficacy to that of TDF, with fewer effects on markers of renal or bone toxicity, but lacks data in low- and middle-income countries and in patients who are receiving rifamycins for tuberculosis therapy and in those who are pregnant.
A: The primary end point was the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. In the primary efficacy analysis, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group. Both DTG-containing regimens showed noninferior efficacy to the standard-care regimen. There was no significant difference in efficacy between groups in the three pairwise comparisons, at the prespecified significance level of 0.017. After virologic failure, no resistance to integrase inhibitors was observed in patients receiving the DTG-containing regimens.
A: At week 48, absolute weight gain and the percentage of patients in whom obesity emerged during treatment were highest in the TAF-based group (6 kg, 14% new obesity), but the values in the TDF-based group (3 kg, 7% new obesity) were also higher than those in the standard-care group (1 kg, 6% new obesity). Weight gain was significantly higher in female patients than in male patients across all three groups, with no clear plateau in the increase. Regression analysis showed that obesity that emerged during treatment at week 48 was associated with a lower CD4 count, a higher viral load, and older age.