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Dual-Therapy Regimens
An Aging Woman With Renal Disease and BMD Concerns: Is Dual Therapy an Option?

Released: April 11, 2017

Expiration: April 10, 2018

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In this HIV cases series, we highlight common patient case scenarios and the critical decision making that goes into selecting optimal patient management strategies. This case features an HIV-infected patient who is virologically suppressed on her current ART regimen but is experiencing increasing comorbidities that may necessitate ART modification. In this commentary, I discuss the candidacy of this patient for a dual-therapy ART regimen and review current data on dual-therapy strategies.

Case Details
A 62-year-old woman has been virologically suppressed for several years on darunavir (DRV)/ritonavir (RTV) plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Recent clinic visits have revealed diminishing renal function; over the past year, her creatinine has increased from 0.9 mg/dL to 1.2 mg/dL, and she has 1+ proteinuria. Her CD4+ cell count is 554 cells/mm3 and she has no baseline resistance and no history of treatment failure. She is growing concerned about the potential bone effects of her ART as she ages, and she is asking that she switch to a simplified regimen that would include the fewest drugs possible. Is this patient a candidate for a dual-therapy regimen?

Dual ART Rationale
Two main drivers underpin the rationale for dual therapy: reducing antiviral exposure to make treatment safer without sacrificing virologic control and reducing cost. There have been several successful studies of a boosted PI plus lamivudine (3TC) or FTC that support the viability of a boosted PI, dual-therapy strategy. In virologically suppressed patients receiving a boosted PI plus 2 NRTIs who experience toxicity concerns with either TDF or abacavir (ABC), I would feel comfortable dropping the TDF or ABC, provided they do not have resistance.

For this particular patient, I would start by dropping the TDF/FTC and switching to 3TC, continuing the DRV/RTV. Whereas the data on DRV and cardiovascular risk are of some concern, there are today insufficient data to recommend switching to dolutegravir (DTG) plus 3TC, although the ANRS 167 LAMIDOL study was promising.

Based on the results of the SWORD studies, DTG plus rilpivirine (RPV) is also feasible as maintenance therapy in patients with no resistance history who can comply with a regimen that requires food. DTG monotherapy is not recommended. Let’s have a closer look at the evidence for dual-therapy strategies.

An Important Failure
NEAT001/ANRS143 is the most relevant unsuccessful dual-therapy study. In this study, treatment-naive patients were randomized to DRV/RTV plus either raltegravir (RAL) or FTC/TDF (N = 805). Although similar rates of virologic suppression were observed in the overall population, in patients with HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3, there was an excess risk of virologic failure for dual vs triple therapy, and that excess virologic failure was associated with resistance. It is unclear why this strategy did not work. One potential explanation is that the resistance barrier with RAL is lower than with DTG, suggested by the fact that the risk of failure was highest in more advanced patients—the virologic “stress test.” Note that a similar finding was observed in ACTG A5262, a single-arm phase IIb study of DRV/RTV plus RAL for treatment-naive patients.

An Important Success
GARDEL was an early dual-therapy success story. This study showed that lopinavir (LPV)/RTV plus 3TC was as effective as LPV/RTV plus 2 NRTIs for treatment-naive patients (N = 426). The main issue with GARDEL is that LPV/RTV is not an optimal drug combination in today’s treatment landscape. This study did, however, suggest that dual-therapy strategies could be successful and lead to further studies assessing PI-based 2-drug regimens as maintenance therapy. Two studies assessed 3TC vs 2 NRTIs along with a boosted PI in virologically suppressed patients (ATLAS-M: atazanavir/RTV, N = 266; DUAL GESIDA: DRV/RTV, N = 257), and both studies demonstrated positive results. In DUAL-GESIDA, similar rates of adverse events and virologic suppression were observed with dual and triple therapy (HIV-1 RNA < 50 copies/mL: 89% vs 93%, respectively).

Dolutegravir-Based Dual Therapy
Studies have now begun to assess whether a dual-therapy strategy with the INSTI DTG, which has a high genetic barrier to resistance, can be successful.

SWORD-1 and -2 were parallel, randomized, open-label phase III noninferiority studies presented at CROI 2017 in which treatment-experienced, virologically suppressed patients receiving stable ART with no previous virologic failure (N = 1024) were randomized to continued baseline ART or DTG plus RPV dual therapy. At Week 48, 95% of patients maintained virologic suppression in each arm, and 2 treatment failures were noted in each treatment group. In 1 patient who experienced virologic failure on DTG plus RPV, the NNRTI resistance mutation K101K/E was detected at Week 36. This patient had high pretreatment HIV-1 RNA and evidence of on-study nonadherence between Weeks 24 and 36. She resuppressed virus while receiving continued dual therapy by Week 45.

Despite the noninferior virologic efficacy of DTG plus RPV, 21 patients in the switch arm discontinued treatment for adverse events vs only 3 in the continued baseline ART arm. This difference may be due, in part, to the open-label nature of the study. Patients switching from successful treatment may discontinue treatment at the appearance of any new adverse events.

Overall, the SWORD study results were as good as could be expected, but will clinicians choose a DTG plus RPV strategy? Introducing 2 new drugs is a dramatic regimen switch, and RPV, which has to be taken with food, is relatively less potent than other available antiviral drugs.

ANRS 167 LAMIDOL was an open-label, single-arm study assessing DTG plus 3TC as maintenance therapy for virologically suppressed patients. Patients were first switched to DTG and maintained their 2-NRTI backbone. If virologic suppression was maintained for 8 weeks on this regimen, they were switched to DTG plus 3TC. In 104 patients proceeding to dual therapy, only 1 virologic failure occurred through Week 48. A second patient with low-level viremia also switched back to triple therapy at the investigator’s discretion.

PADDLE was an open-label, single-arm exploratory trial of DTG plus 3TC conducted in treatment-naive patients. In total, 18 of 20 patients achieved virologic suppression at Week 48. One patient with baseline HIV-1 RNA > 100,000 copies/mL experienced protocol-defined virologic failure at Week 36 but resuppressed virus without treatment change by Week 60. Another patient died of suicide that was deemed unrelated to study drugs between Weeks 24 and 36. Larger studies of DTG plus 3TC in treatment-naive patients are needed before this regimen can be used in practice.

DTG Monotherapy: A Bad Idea
Of note, successes with DTG-based dual therapy should not be extrapolated to DTG monotherapy. Indeed, several DTG monotherapy studies have found an excess number of virologic failures with resistance on rebound. An example is the DOMONO/DOLUMONO study, in which virologically suppressed patients either switched to DTG monotherapy or continued receiving their baseline ART regimen. Although DTG monotherapy was noninferior to continued baseline ART for maintained HIV-1 RNA < 200 copies/mL at Week 24, the study was discontinued early due to an increase in virologic failure for patients in the monotherapy group that was associated with a high rate of INSTI resistance mutations. Thus, there is certainly no indication for DTG monotherapy.

Your Thoughts
Have you used a dual-therapy regimen to treat one of your patients? Do you feel dual-therapy strategies are a viable option for some patients? I encourage you to post your thoughts in the comments section below.

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