Dolutegravir is potent but twice-daily works better for integrase-resistant

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The novel integrase inhibitor dolutegravir is among the most potent antiretroviral agents studied to date, but treatment-experienced individuals with resistance to raltegravir need to take it twice-daily in order to achieve optimal concentrations, according to findings presented yesterday at the 13th European AIDS Conference (EACS) in Belgrade.

Dolutegravir (formerly S/GSK1349572 or GSK572) is a next generation integrase inhibitor that remains active against HIV that has developed resistance to the sole approved drug in its class, raltegravir (Isentress).

In the original VIKING study (Cohort I), previously treated patients with extensive drug resistance were treated with 50mg once-daily oral dolutegravir as "functional monotherapy" for ten days, then added an optimised background regimen and continued through week 24.

Glossary

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

mathematical models

A range of complex mathematical techniques which aim to simulate a sequence of likely future events, in order to estimate the impact of a health intervention or the spread of an infection.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

oral

Refers to the mouth, for example a medicine taken by mouth.

Although viral suppression was good overall, pharmacokinetic modelling suggested better response might be achieved with higher drug exposure, especially for people with a specific unfavourable pattern of raltegravir resistance mutations.

But drug concentrations reached a plateau when researchers tried to administer larger once-daily doses, leading them to instead test 50mg twice-daily administration in a second group of patients (Cohort II). Again, participants received dolutegravir for ten days then added an optimised regimen through week 24.

As presented by Vincent Soriano from Hospital Carlos III in Madrid, this open-label, single-arm trial enrolled 24 participants on failing antiretroviral therapy with pre-existing resistance to raltegravir and any two other antiretroviral classes. They were required to have at least one available fully active drug to add for regimen optimisation.

Most participants (75%) were men and the median age was 47 years. They were generally similar to people in the original Cohort I, except they had less advanced HIV disease and were more likely to be coinfected with hepatitis B or C (about 20%). The median CD4 cell count was about 200 cells/mm3. They had been taking antiretrovirals for a median of 15 years and had used a median of 15 different drugs; half were already resistant to the newest available agents.

Participants were divided into two groups based on integrase resistance pattern at baseline; 46% had the Q148 mutation plus at least 1 secondary mutation¾which significantly reduces susceptibility to dolutegravir¾whilst 54% had all other mutation patterns combined.

At 24 weeks 75% of participants receiving twice-daily dolutegravir achieved undetectable viral load below 50 copies/mL, compared with just 41% of those who took the drug once-daily in Cohort I. As expected, people who had more available active drugs for optimisation did better (67% undetectable with one active drug, 79% with two).

Six participants were classified as nonresponders: four who never suppressed viral load through week 24, one who did so but then experienced viral rebound, and one protocol violation; there were no discontinuations due to adverse events and no deaths in Cohort II. Dolutegravir was well-tolerated overall, with the most common side-effect being mild diarrhoea.

In a multivariate analysis of Cohort I and Cohort II combined, factors that independently predicted response to dolutegravir at 24 weeks were baseline integrase resistance mutation pattern, availability of other active drugs for optimisation, higher baseline CD4 cell count and dolutegravir concentration in the blood at day 10.

Based on these findings, 50mg twice-daily dolutegravir was chosen for further evaluation in a Phase 3 trial. Soriano said an expanded access program is expected to begin in early 2012.

As raltegravir must also be give twice-daily, this dosing frequency does not put dolutegravir as a disadvantage in an era when people with HIV and their clinicians favour once-daily therapy.

Data from the SPRING-1 study showed that once-daily dolutegravir is adequate for treatment-naive individuals, however, suggesting that this is another drug that will be dosed differently depending on prior treatment history.

References

Soriano V et al. Dolutegravir (DTG, S/GSK1349572) treatment of subjects with raltegravir (RAL) resistance: viral suppression at week 24 in the VIKING study. 13th European AIDS Conference, PS1/2, Belgrade, 2011.