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New Switch Data
Switch Strategies in Virologically Suppressed Patients: My Take on New Data From Recent Scientific Meetings

Released: January 22, 2016

Expiration: January 20, 2017

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When contemplating switching ART in patients who are virologically undetectable on a stable regimen, some basic principles should be followed. We must be mindful that switching can lead to significant new problems for patients, in particular resistance and new toxicities. In addition, I believe that patients should have a viable reason to switch, including to improve adherence and/or tolerability, to mitigate or prevent comorbidities, to avoid significant drug–drug interactions, to minimize food requirements, or to optimize treatment during pregnancy. Patient preference for a new regimen is also a significant reason to contemplate switching. In all cases, the pros and cons of a regimen switch should be fully discussed. It is crucial to thoroughly review a patient’s full antiretroviral history, viral load and resistance test results, and past AEs before employing a switch.

Recent data from EACS, ICAAC, and IDWeek 2015 have highlighted new switch strategies. Some may expand our options for optimizing long-term virologic suppression in our patients; each should be scrutinized carefully before incorporating into practice.

Switching to DTG/ABC/3TC
At ICAAC 2015, Trottier and colleagues presented results from the phase III STRIIVING study, in which 551 stably suppressed patients were randomized to switch from a variety of ART regimens to the fixed-dose combination DTG/ABC/3TC or remain on their pre-enrollment regimen. Patients had to have undetectable HIV-1 RNA on their current regimen for more than 6 months with no previous virological failure and be HLA-B*5701 negative. Patients were either switched immediately or had a deferred switch at 24 weeks. The intent-to-treat analysis revealed that 85% of patients in the switch arm maintained HIV-1 RNA < 50 copies/mL at 24 weeks after switching vs 88% in the control arm. These rates were lower than what we might expect in such studies, likely because the study recruited rapidly and had numerous protocol deviations (ie, patients who did not meet eligibility criteria). Indeed, analysis of the per-protocol population found a 93% virologic success rate in both arms. Notably, the reason for switching was not presented, and there were multiple discontinuations with switching. Ten patients (4%) in the switch arm discontinued due to AEs vs none in the continuation arm. It is hard to know whether the AEs were directly related to DTG/ABC/3TC, as the frequency of serious AEs was similar between the 2 arms. Switching was associated with a significant increase in a treatment satisfaction score vs continuing baseline regimen. Based on these data, I would consider switching certain patients to DTG/ABC/3TC, including those who want to simplify to a single pill and have no resistance associated mutations (except for NNRTI resistance mutations). I would also consider this switch strategy for those patients who are experiencing intolerable AEs with a boosted PI. As a reminder, patients’ HLA-B*5701 and hepatitis B status should be checked before switching to this regimen.

Switching to EVG/COBI/TAF/FTC
In the open-label phase III GS-109 study, presented at IDWeek 2015, patients with virologic suppression receiving EVG/COBI/FTC/TDF whose eGFR was > 50 mL/min were randomized to continue their current regimen or switch to the recently approved single-tablet regimen EVG/COBI/FTC/TAF. At the 48-week primary endpoint, virologic efficacy was 98% in the switch arm and 97% in the continuation arm. In addition, patients in the EVG/COBI/FTC/TAF arm showed improvements in serum creatinine, tubular proteinuria, and bone mineral density. Concerns have been raised about the effects of a lifetime of TDF on bone mineral density and renal function, and these data support switching from TDF to TAF, especially for patients who have or who are at risk of renal and/or bone problems. Moreover, my colleague Samir Gupta presented data at ICAAC 2015 demonstrating that switching from a suppressive TDF or non-TDF regimen to EVG/COBI/FTC/TAF led to continuing virologic control and improvements in eGFR and proteinuria among patients with eGFR as low as 30 mL/min. We now have a new drug option to use in patients with renal impairment. Cost permitting, I will be switching my patients who are receiving EVG/COBI/FTC/TDF to EVG/COBI/FTC/TAF. In addition, although I generally avoid TDF in patients with renal impairment, I will recommend a switch to EVG/COBI/FTC/TAF for any who are receiving TDF.

Simplifying to EVG/COBI/FTC/TAF Plus DRV
What about switching ART regimens to simplify pill burden? An interesting study presented at IDWeek 2015 switched virologically suppressed patients receiving DRV-containing ART with resistance to ≥ 2 antiretroviral classes, but no INSTI resistance, to EVG/COBI/FTC/TAF plus DRV. In this open-label study, patents were randomized to switch immediately or at Week 48. Very interestingly, at Week 48, 94% of patients on the new regimen maintained HIV-1 RNA < 50 copies/mL vs 76% of those who continued their baseline regimen. Although there are biases with open-label studies, the data suggest that simplification in terms of pill numbers might be possible for patients with susceptibility to this new ART combination and who are able to take only 2 pills/day. The important caveat for success was in the inclusion criteria that stated: resistance to ≥ 2 ART classes, including ≤ 3 thymidine analogue mutations and K65R, but not integrase inhibitors, unless currently receiving raltegravir, and no DRV resistance. It is important that, in clinical practice, we are very careful who we select for such simplification strategies, as developing new mutations—especially to integrase inhibitors—can be catastrophic for such patients.

Simplifying to ATV/RTV Plus 3TC
What about simplifying to dual therapy with a boosted PI and another agent? The phase IV ATLAS-M study, presented at EACS 2015, randomized virologically suppressed patients receiving ATV/RTV plus 2 NRTIs to switch to ATV/RTV plus 3TC or continue their current regimen. Patients had to have undetectable HIV-1 RNA for more than 6 months with no virologic failure and no previous or current resistance to 3TC. Among those who switched, 89.5% maintained virologic suppression vs 80% of those who remained on ATV/RTV plus 2 NRTIs. These results are not surprising, considering that even monotherapy with a boosted PI has been shown to maintain virologic suppression in many patients. However, retaining a single NRTI (3TC) does appear to reduce “blipping” and rates of virologic failure. For patients whose baseline regimen contained TDF, simplification to ATV/RTV plus 3TC was associated with a small improvement in eGFR. However, the “cholesterol lowering effect” of TDF was lost, as greater increases in HDL were observed among those who switched. This simplification strategy is interesting, and I would be comfortable employing it for patients experiencing problems with toxicity or tolerability to one of 2 NRTIs (after thoroughly reviewing resistance and hepatitis B status).

Switching to a Boosted PI + Maraviroc
For those in search of an NRTI-free regimen, switching patients to a boosted PI plus maraviroc does not seem to be an optimal strategy, as evidenced by results from the MARCH study presented at EACS 2015. When virologically suppressed patients with R5 tropic virus who were receiving a boosted PI plus 2 NRTIs were randomized to replace the 2 NRTIs with maraviroc, 84% maintained virologic suppression. By comparison, 98% of those who continued their baseline regimen and 94% of those who replaced the boosted PI with maraviroc maintained virologic suppression. Most patients with virologic failure did not develop X4 tropic viral variants or mutations conferring resistance to PIs. These data support what we have seen from many studies in treatment-naive and treatment-experienced patients: NRTIs appear to be important components of combination ART.

Simplifying to DTG Monotherapy
Switching to boosted PI monotherapy has been used with some success as a niche strategy, with patients carefully screened for lack of DRV resistance mutations and a CD4+ cell count > 200 cells/mm3 at nadir. Along these lines, 2 European groups presented results at EACS 2015 of an experimental switch strategy to DTG monotherapy. This approach is based on observations in previous studies of treatment-naive patients where no incidents of DTG resistance have occurred in patients receiving DTG-based triple-drug regimens and a subsequent conclusion by many that the resistance threshold barrier of DTG is similar to boosted PIs (although this has not been proven).

The first study was an open-label pilot study of a Spanish cohort of 33 patients with virologic suppression on ART for ≥ 12 months. Of importance, patients had at least 2 reasons for switching off of their current therapy, including comorbidities, drug–drug interactions, AEs, and resistance. Before switching to DTG, 67% of patients were receiving boosted PI–based therapy, 27% were receiving NNRTI-based therapy, and the remaining 6% were receiving an integrase inhibitor–based regimen. At the Week 24 primary endpoint, 32 of 33 patients remained undetectable, with HIV-1 RNA < 37 copies/mL. The one patient who failed had a history of virologic failure on a raltegravir-based combination but no integrase inhibitor resistance (using standard RNA testing) at baseline. However, at Week 24, a 118R mutation was detected in PBMC DNA that had been absent at Week 4.

The second study was one of clinical practice from Paris in which 28 patients who were highly treatment experienced (median ART duration: 17 years) and virologically suppressed for almost 7 years were switched to DTG monotherapy. Patients had to be integrase inhibitor naive or have no history of treatment failure with an integrase inhibitor. After 24 weeks of DTG monotherapy, 3 of 28 patients experienced virologic failure; all 3 had previous exposure to integrase inhibitors. Of interest, all had optimal DTG drug levels at the time of failure.

Until we have long-term results from well-designed trials, I believe DTG monotherapy is a high-risk strategy. There may be individual cases where this might be the only option, but wherever possible, at least 2, and preferably 3, highly active drugs should be given to patients.

If integrase inhibitor resistance develops or is selected out, then an entire class of drugs, which could have been used in combination with other potent therapy, may well be lost. Until we have more data it would be advisable, even in extreme situations, not to follow this strategy. This is especially prudent in patients with previous exposure to integrase inhibitors, even if no integrase inhibitor–resistant variants have been detected by standard resistance testing.

Switching ART regimens is an important tactic that most patients will undergo at least once, considering that therapy may continue for decades. As clinicians, when approaching switch strategies, we must remain cautious, careful, and wise and remember the words “primum non nocere.”

Your Thoughts?
Do recent data from EACS, ICAAC, and IDWeek influence your approach to switching ART in virologically suppressed patients? I encourage readers to post your thoughts in the comments section below.

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