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Can high-dose dolutegravir be a rescue therapy?

Dolutegravir is a powerful anti-HIV drug sold under the following brand names:

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  • Tivicay – dolutegravir
  • Juluca – dolutegravir + rilpivirine
  • Triumeq – dolutegravir + abacavir + 3TC

Dolutegravir belongs to a class of anti-HIV drugs called integrase inhibitors. In adults who have not previously used an integrase inhibitor, the dose of dolutegravir recommended by the manufacturer, Viiv Healthcare, is 50 mg once daily as part of HIV combination therapy (ART).

Among people who have previously used integrase inhibitors and whose HIV is susceptible to dolutegravir, the recommended dose is 50 mg twice daily (for a total of 100 mg daily) as part of ART.

Dolutegravir may be taken with or without food.

Although dolutegravir is a powerful drug, in some cases, perhaps because of poor adherence, levels of dolutegravir in the blood can fall to less-than-effective levels. When this happens, HIV can develop the ability to overcome the effect of dolutegravir (and other HIV drugs). In such cases, HIV develops mutations or changes in its structure that allow it to resist dolutegravir and these changes are passed on to new copies of HIV.

An experiment in Milan

Doctors in Milan, Italy, reported the details of five patients (four men and one woman) who had an extensive treatment history. Analyses of their blood samples found that HIV had developed the ability to resist several classes of treatment.

All patients had detectable viral loads raining from 800 copies/mL to almost 100,000 copies/mL. Two of them had extremely low CD4+ cell counts—less than 10 cells/mm3—while the remaining three patients had between 350 and 640 cells/mm3. Patients ranged in age from 32 to 52 years.

Doctors had extensive tests done on blood samples from the patients. This allowed them to devise what they called an “optimized background regimen” (OBR). Such regimens are individualized: They are designed to make use of the anti-HIV drugs that resistance testing suggests have at least some antiviral activity against the strain of HIV in a person.

Other tests measured the levels of drug in patients’ blood samples to rule out malabsorption as a cause of treatment failure.

Taking all of this information into account, doctors decided to double the dose of dolutegravir normally prescribed for treatment-experienced people. This step was a gamble because doubling the dolutegravir dose to 100 mg twice daily has not been approved for use in any country. Furthermore, the researchers were unsure of what side effects might occur or if high-dose dolutegravir would be absorbed. Moreover, three of the five patients had previously used regimens containing dolutegravir 50 mg twice daily, but these regimens had failed.

The final regimens

Doctors prescribed optimal background therapy—usually consisting of the protease inhibitors atazanavir or darunavir, both drugs taken with a small dose of ritonavir—and Truvada (tenofovir DF + FTC). Additionally, everyone received dolutegravir 100 mg twice daily.

Results

Researchers conducted extensive blood tests once patients started taking their new regimens and found that high-dose dolutegravir was well absorbed. The concentration of dolutegravir in the blood of patients was generally about four-fold greater than what has been seen with a dose of 50 mg taken once daily.

Four out of five participants were able to achieve a suppressed viral load (less than 40 copies/mL) for nearly two years, the length of the period of observation reported by the Milan doctors.

However, the viral load of the fifth participant did not respond well to the new regimen—it remained detectable for 60 weeks, his duration in the study. The doctors noted that this person had entered the study with HIV that had a history of “extensive drug resistance.” This history of resistance to treatment would likely have largely “abolished” the antiviral effects of the study regimen, the doctors noted.

In four out of five participants, CD4+ cell counts increased.

Side effects

There have been reports from some observational studies that dolutegravir is associated with what researchers call “neuropsychiatric” side effects, including the following:

  • sleeping problems
  • anxiety
  • depression
  • impaired concentration

Some of these issues have also been reported with other integrase inhibitors. However, in the present study, no neuropsychiatric or serious side effects occurred.

Bear in mind

The present study is very interesting and explores a novel high-dose regimen of dolutegravir. However, the number of participants was very small and the results from the Italian study cannot be generalized to other HIV-positive patients with high-level resistance to ART. The Italian study results are promising and can be considered by other researchers, who can then plan a clinical trial to test high-dose dolutegravir-containing regimens.

—Sean R. Hosein

REFERENCE:

Ferrari D, Spagnuolo V, Manca M, et al. Increased dose of dolutegravir as a potential rescue therapy in multi-experienced patients. Antiviral Therapy. 2019; in press.