Dolutegravir in people who experienced virological failure with older integrase inhibitors

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Antiretroviral regimens containing dolutegravir, a next-generation integrase inhibitor, are durable and achieve high rates of viral suppression in people who experienced virological failure with older integrase inhibitors, Italian investigators led by S Rusconi at the Università degli Studi di Milano, Italy, report.

The “real-world” study involved 89 highly treatment-experienced people enrolled in a drug-resistance database. After 19 months of follow-up, 89% were still taking dolutegravir and all had an undetectable viral load.

“Since a consistent proportion of patients who receive DTG [dolutegravir] outside clinical trials are failing an INI [integrase inhibitor]-containing regimen, a highly relevant clinical question is the cross-resistance to INI,” comment the authors. “The main result of our study is that in our real life retrospective scenario of triple-class-experienced subjects followed for a median of 18.8 months, only 10 subjects discontinued DTG.”

Clinical trials have shown that dolutegravir is effective against both wild-type and integrase inhibitor-resistant virus. In these studies, the drug performed well in people with previous experience of antiretroviral therapy and also in treatment-naïve individuals. Dolutegravir has a high genetic barrier to resistance.

However, little is known about the durability of dolutegravir-containing combinations in people with experience of older integrase inhibitors.

Investigators in Italy therefore retrospectively analysed the durability of dolutegravir-based therapy among a cohort of highly treatment-experienced people. The patients’ data were obtained from the Antiviral Response Cohort Analysis database.

All the people had experienced virological failure while taking raltegravir or elvitegravir and had resistance testing at the time of treatment failure. The investigators analysed the virological and patient characteristics associated with the durability of dolutegravir therapy.

After approximately 19 months of follow-up, 79 people (89%) were still taking dolutegravir. The ten people who discontinued the drug did so after a median of three months of therapy.

All of the people remaining on dolutegravir had an undetectable viral load. This compared to a 50% rate of suppression among individuals who stopped taking the drug. A high proportion of people – including over 40% of individuals with suppression at the end of follow-up – had one or more viral load blips, but these were not associated with treatment outcomes.

Factors associated with a detectable viral load at the end of follow-up were non-B HIV-1 subtype (HR = 5.77; 95% CI, 1.73-19.27, p < 0.0001) and a detectable viral load at the start of dolutegravir therapy (HR = 4.5; 95% CI, 0.90-22.66, p = 0.068), though this second factor fell just short of significance.

Factors associated with increased chances of viral suppression were a nadir CD4 cell count above 200 cells/mm3 (p = 0.038), experience of at least ten previous antiretroviral regimens (p = 0.04) and integrase inhibitor-associated resistance mutations at baseline (p = 0.023).

“In our group of patients who have been exposed to first-generation INIs, treatment with DTG showed long durability in the majority of cases and did not show virological rebound after virological suppression,” conclude the authors. “The bottom line is that subjects infected with non-B HIV-1 subtype and detectable HIV-1 RNA at DTG start had a greater risk of having detectable HIV-1 RNA at the last observation, thus INI-experienced patients could have a potential high risk of not responding to DTG, notwithstanding its favourable genetic barrier.”

Abstract
Background: Dolutegravir (DTG) is a next-generation HIV integrase inhibitor (INI) with an increased genetic barrier to resistance with respect to raltegravir (RAL) or elvitegravir (EVG). Few data are available on the durability of DTG-containing regimens.
Objectives: We aimed at investigating the duration of the DTG-containing regimen, the occurrence of an HIV-1 RNA blip, and factors associated with DTG virological response.
Study design: From the Antiviral Response Cohort Analysis database, we selected 89 HIV-1-positive four-class-experienced subjects who started DTG after receiving RAL or EVG. Factors associated with durability and virological response were analysed by logistic regression.
Results: After a median duration of 18.8 [0.4–76.2] months, 79/89 (88.8%) subjects were still on DTG. All subjects remaining on DTG at the end of follow-up had undetectable HIV-1 RNA, compared to 5/10 subjects who discontinued DTG. DTG discontinuation was less frequent in patients who had experienced ≥10 regimens (HR 0.11, p = 0.040). The probability of having an HIV-1 RNA positive value at the last follow-up significantly increased in patients with non-B HIV-1 subtype (HR 5.77, p < .001) and significantly decreased in patients with CD4 nadir >200/μL (HR 0.29, p = 0.038), with more than 10 previous regimens (HR 0.27, p = 0.040), and who harbored virus with IN mutations (HR 0.12, p = 0.023) at DTG start.
Conclusions: After previous exposure to first-generation INIs, treatment with DTG showed long durability and did not show virological rebound after virological suppression. Subjects infected with a non-B HIV-1 subtype had a greater risk of having detectable HIV-1 RNA at the last observation.

Authors
S Rusconi, F Adorni, P Tau, V Borghi, M Pecorari, R Maserati, D Francisci, L Monno, G Punzi, P Meraviglia, S Paolucci, A Di Biagio, B Bruzzone, A Mancom, Viheli, M Zazzi

Aidsmap material
Journal of Clinical Virology abstract


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