NRTI-sparing regimens

As it became increasingly clear that nucleoside reverse transcriptase inhibitors (NRTIs) were associated with long-term symptoms thought to be due to mitochondrial toxicity – in particular, fat loss in the face and limbs – researchers began studying regimens that omitted NRTIs but included non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and – more recently – integrase inhibitors.

The PROGRESS study, an open-label Phase III trial, randomly assigned 206 previously untreated participants to receive twice-daily lopinavir/ritonavir (Kaletra) in combination with either 400 mg twice-daily raltegravir or once-daily tenofovir/emtricitabine (Truvada). An intent-to-treat analysis at 48 weeks found the NRTI-sparing combination to be non-inferior to the three-drug HAART regimen: 83% in the raltegravir group and 85% in the tenofovir/emtricitabine group achieved viral load below 40 copies/ml. Both study regimens were generally well-tolerated and there was no statistically significant difference in CD4 cell gains.¹

In the open-label Bitherapy Kaletra-Sustiva study, 65 treatment-naive and 21 treatment-experienced people received an NRTI-sparing regimen consisting of lopinavir/ritonavir (Kaletra) plus efavirenz (Sustiva). After 48 weeks, 69% had a viral load below 50 copies/ml, and the mean CD4 cell gain was 238 cells/mm³.²

ACTG 5142, in addition to showing that efavirenz suppressed HIV better than lopinavir/ritonavir when combined with two NRTIs, also found that an NRTI-sparing regimen of lopinavir/ritonavir plus efavirenz was non-inferior to the two NRTI-containing regimens with regard to viral suppression, but that there was more resistance in the NRTI-sparing arm.³ This regimen was associated with less lipoatrophy, but also produced the largest blood lipid increases.⁴

The randomised CTN 177 study compared lopinavir/ritonavir/nevirapine against AZT/3TC/nevirapine and AZT/3TC/lopinavir/ritonavir. Viral load suppression and CD4 cell gains were similar across all arms, but people taking the two regimens containing lopinavir/ritonavir experienced greater lipid elevations.⁵

A study looking at the protease inhibitor-only regimen of lopinavir/ritonavir plus saquinavir found that 14 out of 20 treatment-naive patients achieved viral suppression after 48 weeks; two others suppressed HIV after adding tenofovir.⁶

The SPARTAN study looked at the combination of unboosted atazanavir plus raltegravir in previously untreated people. The study randomised 94 participants on a two-to-one basis to take either a twice-daily regimen of 300mg unboosted atazanavir plus 400mg raltegravir, or else a once-daily regimen of 300mg atazanavir plus 100mg ritonavir booster plus tenofovir/emtricitabine (Truvada). Although virological outcomes were similar, a significantly higher rate of grade 4 hyperbilirubinaemia was seen in the two-drug arm, leading to the termination of the study.⁷

A second new class study, combining atazanavir/ritonavir with maraviroc 150mg once daily, found similar virological outcomes but a higher rate of grade 3 and 4 bilirubin elevations when compared to atazanavir/ritonavir plus tenofovir/FTC in 121 participants, but no difference in the rate of treatment discontinuation due to adverse events. A phase III study of this combination is now planned.⁸

On the whole, studies indicate that while NRTI-sparing regimens may prevent some types of side-effects, they can cause others. The balance between benefits and drawbacks, therefore, will differ from person to person depending on individual risk factors.

Current UK and US treatment guidelines do not recommend NRTI-sparing regimens for people starting antiretroviral therapy due to concerns about toxicity, premature treatment discontinuation, and drug resistance.