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HIV11: Dolutegravir Remains Effective for Treatment-experienced People with Multidrug-resistant HIV

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The investigational HIV integrase inhibitor dolutegravir, which has shown comparable or superior efficacy to widely used drugs in clinical trials to date, works well for people with highly resistant HIV, including virus with mutations conferring resistance to other drugs in its class, researchers reported at the 11th International Congress on Drug Therapy in HIV Infection (HIV11) this week in Glasgow.

Integrase inhibitors work by preventing HIV from inserting its genetic material into a host cell's chromosomes, a necessary step in viral replication. The first approved integrase inhibitor, raltegravir (Isentress), and others in the pipeline are well-tolerated, as they do not target processes that are also important for human cells.

Dolutegravir  (formerly S/GSK1349572), being jointly developed by Shionogi and ViiV Healthcare, has so far shown promising outcomes for both treatment-experienced people in the VIKING trials and previously untreated individuals in the SPRING and SINGLE studies. The SAILING study is currently looking at once-daily dolutegravir for treatment-experienced people without integrase inhibitor resistance.

Garrett Nichols from GlaxoSmithKline (which formed ViiV with Pfizer in 2009) presented the latest data from the VIKING-3 trial (aka ING112574), which evaluated the safety of efficacy of dolutegravir in people with resistance to multiple antiretroviral drugs including raltegravir and elvitegravir (Gilead Science's integrase candidate, which was recently approved as a component of the Stribild single-tablet regimen).

Participants in this open-label study first added 50 mg twice-daily dolutegravir to their failing antiretroviral therapy (ART) regimen, without raltegravir or elvitegravir. At day 8, their background regimen was optimized to include the most active drugs according to resistance testing, and they started this new regimen while continuing on dolutegravir.

Three-quarters of the 183 VIKING-3 participants were men, about 70% were white, and about 20% were coinfected with hepatitis B or C. They had been on ART for an average of 13 years, their median baseline CD4 T-cell cout was a low 140 cells/mm3, and more than half had AIDS-defining conditions (CDC class C).

All participants had evidence of genotypic and phenotypic resistance to raltegravir or elvitegravir. In addition, about 80% showed resistance to at least 2 nucleoside/nucleotide reverse transcriptase inihibitors (NRTIs), 75% had resistance to at least 1 NNRTI, 70% had 2 or more protease resistance mutations, and about 60% had virus that did not use the CCR5 coreceptor. However, they had to have at least 2 other active agents available so they could construct an optimized background regimen.

Results

  • During the first 7 days, when dolutegravir was used as "functional monotherapy," mean HIV RNA levels declined by 1.4 log copies/mL.
  • After optimizing their background regimen, 63% of participants were able to  achieve undetectable viral load (HIV RNA < 50 copies/mL).
  • 6 participants (3%) discontinued study drugs prematurely due to adverse events.
  • The most frequently reported side effects were diarrhea, nausea, and headache, each occurring in no more than 5% of patients.

"A majority of the highly treatment-experienced subjects in VIKING-3 achieved suppression with dolutegravir-based therapy," the resarchers concluded. "Dolutegravir had a low rate of discontinuation due to adverse events at 50 mg [twice-daily] in this advanced patient population."

ViiV indicated in a press release that data from these Phase 3 trials would be submitted to global regulatory authorities to support dolutegravir's approval, starting by the end of 2012. ViiV previously revealed that it is working on a single-tablet regimen containing dolutegravir plus the NRTIs abacavir and lamivudine (the drugs in Epzicom).

Abstracts from the HIV11 Congress have been published in a supplement of the Journal of the International AIDS Society, which can be viewed online or downloaded at www.jiasociety.org/index.php/jias/issue/view/1461.

11/16/12

Reference

G Nichols, A Mills, R Grossberg, et al. Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3. 11th International Congress on Drug Therapy in HIV Infection (HIV11). Glasgow, November 11-15, 2012. Abstract O232.

Other Source

ViiV Healthcare. ViiV Healthcare Presents Phase III Data From VIKING-3 Study of Dolutegravir in HIV-1 Infected Integrase Inhibitor-Resistant Adults. Press release. November 13, 2012.