ViiV/Janssen's Double-Edged SWORD: Four Drugs Good, Two Drugs Better?

Data from ViiV Healthcare and Janssen's SWORD study point the way to a two-drug future in HIV for Tivicay/Edurant, but will doctors want to rock the boat, especially with Gilead's bictegravir impressing in Phase II?

The possibility of a two-drug regimen for HIV maintenance therapy has come further into view with the full data for the SWORD studies showing that patients can be switched from a three- or four-drug regimen to ViiV Healthcare's Tivicay (dolutegravir) plus Janssen Inc.'s Edurant (rilpivirine) without sacrificing any anti-HIV efficacy. The companies are planning regulatory filings for the two-drug regimen as a single tablet this year.

The dolutegravir and rilpivirine regimen achieved non-inferior viral suppression (HIV-1 RNA <50 copies/mL) at 48 weeks compared with a three- or four-drug regimen in both pooled and individual analyses of the SWORD 1 and SWORD 2 studies, according to data presented Feb. 14 at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle (see box). The 148-week studies are ongoing.

ViiV’s Chief Scientific and Medical Officer John Pottage said the studies could change the understanding of how HIV can be managed. "For more than 20 years, we thought that three or more drugs were required to maintain virologic suppression, but the SWORD studies provide compelling data that suppression may be maintained with a two-drug regimen of dolutegravir and rilpivirine. These data mark an exciting first step towards making two drug regimens a reality in HIV treatment," he said.

SWORD Study Results

The SWORD-1 and-2 trials are identical 148-week, randomized, open-label, non-inferiority studies to assess the antiviral activity and safety of switching to dolutegravir plus rilpivirine from current integrase inhibitor-, non-nucleoside reverse transcriptase inhibitor-, or boosted protease inhibitor-based antiretroviral regimen in HIV-1-infected adults who are virologically suppressed with a three- or four-drug regimen.

The dolutegravir and rilpivirine regimen achieved non-inferior viral suppression (HIV-1 RNA <50 copies/mL, the primary endpoint) at 48 weeks compared with a three- or four-drug regimen in both pooled and individual analyses: current antiretroviral therapy (CAR) 485/511 (95%), dolutegravir + rilpivirine 486/513 (95%) [adjusted difference -0.2% (95% CI: 3.0%, 2.5%%], pooled analysis]).

Virologic failure rates were <1% in the dolutegravir/rilpivirine arm and 1% in the three- or four- antiretroviral-drug arm. No integrase strand inhibitor (INSTI) resistance-associated mutations were reported. Protocol-defined virologic failure with a non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance-associated mutation (RAMs, K101K/E) was reported in only one patient in the dolutegravir/rilpivirine arm in the context of documented non-adherence, but with no impact on regimen efficacy as the subject re-suppressed on dolutegravir and rilpivirine before withdrawal from the study.

The overall number of serious adverse events was comparable between treatment groups at 27 patients for dolutegravir/rilpivirine and 21 for CAR. As expected when switching from a stable regimen to a new regimen, more adverse events were reported and led to withdrawal from the study in the DTG+RPV arm, 21 vs. 3 for CAR. The safety profiles for dolutegravir and rilpivirine in these studies were consistent with their product labels.

The main benefit to patients would be a simplified treatment regimen, particularly compared with commonly used used second-line and beyond integrase strand transfer inhibitors (INSTIs)/protease inhibitor (PI)-based regimens which require boosting agents (e.g. Truvada + Prezista + Norvir; Truvada + Reyataz + Norvir; Truvada + Isentress + Norvir).

The advantages could transfer to payers too. "The combined cost of dolutegravir/rilpivirine would be much cheaper than the cost of commonly used regimens, and given that the drugs are intended to be taken for life, the accrued savings could make a big impact on payers’ budgets," commented Datamonitor Healthcare senior analyst Michael Haydock.

Doctors May Be Cautious

Overall, Haydock was encouraged by the SWORD data but said some doctors might be cautious. "These are really promising data for the two-drug regimen given that the standard of care for HIV treatment is currently to use three or four drugs to maintain virologic suppression. It is quite an ambitious approach because reducing the number of antiretroviral agents runs the theoretical risk of resistance generation and therefore virologic failure – so physicians are generally reluctant to rock the boat,” Haydock noted.

“But encouragingly, the rates of virologic failure were comparable between both arms (<1% for dolutegravir/rilpivirine and 1% for other arm). This is no doubt because of dolutegravir’s very high barrier to resistance (rilpivirine belongs to the NNRTI class which have quite poor barriers to resistance), as demonstrated by the fact that no INSTI resistance-associated mutations were reported in the dolutegravir/rilpivirine arm."

Jefferies analyst Brian Abrahams also wondered whether doctors and patients would be tempted to change the status quo. "Overall, we see little incentives for patients to switch to a dolu/rilpivirine dual-regimen," he said in a research note, adding that the SWORD data were of little threat to ViiV's major HIV rival Gilead Sciences Inc.'s long-term prospects in the disease.

Now that Gilead has its better-tolerated Viread (TDF) successor tenofovir alafenamide (TAF), he thinks the benefits for the dolutegravir/rilpivirine combo are limited. "A dual regimen would also have a theoretically lesser cushion for noncompliance vs. a triple regimen, something that would be difficult for GSK to disprove in a clinical trial setting-- though dolu does have a very high barrier to resistance, which could mitigate this concern a bit.” Abrahams said. “In fact, in SWORDs, resistance development was low, but one patient who did not adhere perfectly to the dual regimen did develop a resistance-associated mutation (through they were re-suppressed)."

Gilead's Bictegravir In The Wings

Moreover, Abrahams pointed to new Phase II data also presented at CROI for Gilead's new once-daily INSTI bictegravir.

The study compared a combination of bictegravir (75 mg) and emtricitabine/tenofovir alafenamide (200/25 mg) versus dolutegravir (50 mg) and emtricitabine/tenofovir alafenamide (200/25 mg) in treatment-naïve, HIV-1 infected adults and both regimens both demonstrated high virologic response rates at weeks 24 and 48.

“The high virologic response rates seen in this study show that the pairing of bictegravir with emtricitabine/tenofovir alafenamide could potentially offer patients and physicians a new HIV treatment option with preclinical data supporting few drug interactions and a high barrier to resistance,” said lead investigator Paul Sax, clinical director of infectious diseases at Brigham and Women’s Hospital.

Based on the data, bictegravir was rapidly advanced into four Phase III trials as part of a single tablet regimen in combination with emtricitabine/tenofovir alafenamide for the treatment of HIV (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg). The studies are fully enrolled and Gilead expects to see data later this year.

Abrahams commented: "With hints today that Gilead's own integrase, bictegravir, may actually have some modest advantage vs. dolutegravir, we see little incentive to switch to this dolu/rilpivirine dual or to start with/switch to GSK's other dual dolu/lamivudine, unless GSK prices more aggressively and payers become more proactive managing HIV formularies."

This story was updated on Feb. 15 to correct the adverse event data to reflect that it was 27 patients on dolutegravir/rilpivirine and 21 on CAR that experienced a serious adverse event, rather than 27% and 21% of patients respectively as previously reported. Also, 21 and 3 patients, respectively, withdrew from the studies due to adverse events rather than 21% and 3%. (See box.)