Foundations of ART Management in Heavily Treatment–Experienced Patients

The NADIA trial investigated the use of DTG and DRV/RTV as second-line regimens after clinical failure with 2 NRTIs (TDF plus [FTC or 3TC]) plus 1 NNRTI in a setting where no active NRTIs were available.¹⁰ As with EARNEST, no resistance testing was available for the trial population. Participants were randomly assigned to DTG or DRV/RTV. DRV/RTV is a more contemporary, better-tolerated boosted PI than LPV/RTV used in previous studies of this kind.

There was also a second randomization after assignment to the “anchor” or third drug: the NRTI assignment of 3TC/TDF or 3TC/zidovudine (ZDV).

Since HIV-1 RNA testing was not available, failure was detected late and many had developed extensive resistance to the first-line regimen, that is, NNRTI and NRTIs. In fact, one half of patients at baseline had the K65R mutation, which should confer resistance to tenofovir, and 86% had M184V/I. Therefore, of the NRTIs in the second-line regimen, ZDV might be predicted to be the most active.

At 48 weeks, approximately 90% of each comparison group (DRV/RTV and DTG; TDF and ZDV) had HIV-1 RNA <400 copies/mL.¹⁰ When they looked at the proportion who had HIV-1 RNA <50 copies/mL, again all of the subgroup comparisons were similar, in the 80% range. These were very high rates of virologic suppression among those with first-line failure.

When they analyze virologic suppression based on the number of active NRTIs in each regimen, even those with no NRTIs predicted to be active had virologic response rates in the 90% range and were similar between DRV/RTV and DTG. So, this study demonstrated that even in a group with a large number of patients with the K65R mutation, high response rates could be achieved with DTG even without any fully active NRTIs in the regimen. 

This slide details the 96-week follow-up data from NADIA that continued to show similar response rates between the study arms.¹¹ Also of interest—and perhaps a surprise—was that by 96 weeks, those who were randomly assigned to 3TC/TDF had a higher rate of HIV-1 RNA <400 copies/mL than those randomized to 3TC/ZDV, despite high proportions of the patients having the K65R mutation.

Similar to DAWNING, this study suggests that if the regimen contains a second-generation INSTI—in this case, DTG—response rate will be high, although in this case, even without any fully active NRTIs. 

However, as was seen in DAWNING, resistance did emerge in a small subset of 9 individuals who received DTG. Approximately two thirds of these patients were on the 3TC/ZDV arm. No one receiving DRV/RTV developed resistance, again suggesting that the resistance barrier for a boosted PI seems to be a bit higher than that for DTG.

In conclusion, drug resistance testing is an important first step in addressing virologic failure. In the current era, the majority of patients with first-line or second-line treatment failure will have fully active drugs with a high barrier to resistance, such as boosted DRV, DTG, or BIC available for inclusion in the next regimen.

Finally, when the new regimen includes a fully active drug with a high barrier to resistance, viral suppression is possible, with ≤1 additional fully active drug or possibly even with only partially active NRTIs, if no other options are readily available.