By Dr. Geoffrey Modest
The vast majority of recommended HIV drug regimens include tenofovir (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC) as the nucleoside/tide reverse transcriptase inhibitor (NRTI) backbone. From the 2015 HIV guidelines (see https://blogs.bmj.com/bmjebmspotlight/2015/04/17/primary-care-corner-with-geoffrey-modest-md-updated-hiv-guidelines-2015/ for review) of the 5 initial recommended regimens, all have NRTI backbones: 4 include TDF/FTC and one has ABC/3TC. Similarly, of the 2 NNRTI-based (non-nucleoside reverse transcriptase inhibitor) and 4 PI-based (protease inhibitor) alternative regimen options, 5 have TDF/FTC and 1 has ABC/3TC as the backbone; and of the “other regimen options”, 5 have either ABC/3TC or TDF/FTC. For those “who cannot have TDF or ABC”, there is only one which is NRTI-free: darunavir/ritonavir (DRV/r) plus raltegravir (RAL), with the caveat not to use if the HIV viral load is >100K copies/ml. For treatment-experienced patients, they recommend at least 2 and preferably 3 fully active agents. They comment that a boosted PI plus an INSTI (integrase strand transfer inhibitor) may be a viable option in patients with no INSTI resistance, as the only mention of an NRTI-free regimen. So, almost all of the studies and recommendations include an NRTI backbone. In this light, there was a recent article looking specifically at the efficacy of NRTI-free regimens in treatment-experienced patients failing therapy (See Ann Intern Med. 2015;163:908-917).
- 360 people (26% women, median age 46, 32% white/41%black/23% hispanic, 80% with HIV viral load <50K, median CD4 of 207, 47% with AIDS) who were treatment-experienced with HIV infections and had viral resistance (though 66% were sensitive to TDF, 30% to 3TC, 29% to FTC, 40% to AZT, 49% to ABC) from 2008-2011. All had been on PI-based therapy and had either used or were found to be resistant to some NRTIs and NNRTIs.
- Put on open-label optimized regimens not including NRTIs, based on treatment history and resistance testing, then were randomized to adding or omitting NRTIs.
- For the optimized regimens, they assessed the cPSS (continuous phenotypic susceptibility) score, a research tool to measure antiretroviral activity, making sure it was greater than 2 (this score is the sum of the scores of the individual agents used, where a score of “1” signified that the HIV was susceptible to the drug, “0” if resistant, and the continuum from 0-1 if there were partial resistance, reflecting the degree of resistance from the upper limit of “non-resistant” to the lower-limit of “resistant” — see their Appendix Table 1 for details).
- 93% completed a 48-week visit
- The optimized regimens turned out to be: RAL (raltegravir)+DRV/r(darunavir/ritonavir)+ETR (etravirine) in 56%; RAL+DRV/r+MVC (maraviroc) in 14%, and about 8% each to RAL+DRV/r+ETR+MVC, RAL+ETR+MVC, RAL+DRV/r+ETR+ENF (enfuvirtide), or other
- The added NRTI mix was 81% TDF+(3TC or FTC); 14% TDF+(3TC or FTC)+AZT; 6% other
- Cumulative probability of treatment failure was:
- 8% in the omit-NRTI group vs 25.9% in the add-NRTI group (nonsignificant)
- No difference in primary safety endpoints or % of people achieving HIV viral load <50 copies/ml
- No deaths in the omit-NRTI group vs 7 in the add-NRTI one
- Conclusion was that it’s okay to omit NRTIs in these patients starting a new optimized regimen, thereby reducing pill burden, cost, and toxicities.
So, this is a useful article for patients either with broad HIV resistance to NRTIs, or to patients who are intolerant of them (and I have had one treatment-naive patient who pretty clearly developed a neuropathy to 3TC, thereby eliminating virtually all of the current and past recommended initial therapies). The basic approach in the past was to include NRTIs, even if there were resistance (e.g., continuing the pressure of 3TC on the virus in patients resistant to 3TC selected a less-fit and less-aggressive virus). This article shows that with our newer and better and easier-to-take and tolerate regimens, there is no compelling reason to add an NRTI-based backbone, even though a pretty good % of the patients in this study were in fact not resistant to them.