Dolutegravir Switch Maintains Second-Line HIV Suppression

Switching people living with HIV from a ritonavir-boosted protease inhibitor (PI) to a dolutegravir (Tivicay)-based regimen maintained viral suppression just as well, according to a randomized trial out of Kenya.

Among a cohort of nearly 800 participants, 5.0% who switched to dolutegravir and 5.1% who continued taking a ritonavir-boosted PI had a plasma HIV type 1 RNA level of at least 50 copies/mL, which met the noninferiority margin for between-group difference in this primary endpoint at 48 weeks.

Serious adverse event risk was similar between groups and no mutations conferring resistance to dolutegravir or the ritonavir-boosted PI were detected at the time of treatment failure, Loice Ombajo, MBChB, MMed, of the University of Nairobi in Kenya, and colleagues reported in the New England Journal of Medicine.

Almost 75% of the more than 83,000 patients currently take ritonavir-boosted PI-based second-line therapy in Kenya and others in similar settings might be considered for the switch, Ombajo's group suggested.

"High pill burdens, long-term toxic effects, challenges regarding side effects, and high costs of regimens containing a ritonavir-boosted PI are well-established and are considerable disadvantages of the current second-line regimens in much of sub-Saharan Africa," the group explained. "In settings with a high prevalence of tuberculosis, the effect of potential drug–drug interactions between a ritonavir-boosted PI and rifampin is considerable."

In secondary efficacy analysis, 90.4% of the dolutegravir group and 91.9% of the ritonavir-boosted PI group had a viral load of less than 50 copies/mL at 48 weeks, with a difference of -1.5 percentage points (95% CI -5.4 to 2.5), which also met the prespecified noninferiority criterion.

The researchers noted that virologic response was similar across the prespecified subgroups.

Moreover, the researchers noted they enrolled participants without genotypic resistance history. Since genotypic tests are not recommended after treatment failure with a first-line regimen in Kenya, the researchers wanted to be sure patients who were at risk for longer-term treatment failure and possible development of resistance mutations could be identified early and regain viral suppression. They noted that continued surveillance to identify resistance would be needed as people switched to the new regimen.

In three out of 20 patients with protocol-defined virologic failure at 48 weeks who remained on ritonavir-boosted PI, genotypic resistance amplification was seen. Of these, one had no mutations and two had integrase strand-transfer inhibitor and non-nucleoside reverse-transcriptase inhibitor resistance mutations without PI-resistance mutations.

In the dolutegravir group, 19 of the 20 participants with virologic failure had a viral load of less than 200 copies/mL. None had genotypic resistance amplification.

The trial was conducted in 795 patients at four HIV-treatment sites in Kenya during February to September 2020 who didn't have genotype information but had viral suppression while receiving treatment containing a ritonavir-boosted PI. Researchers randomized 398 patients to switch to dolutegravir and 397 to remain on a ritonavir-boosted PI. The cohort included 66.2% female participants, and the median age was 46 (range 19-74). All participants were Black persons.

With intensive adherence counseling in the trial, 95.2% taking dolutegravir and 94.9% taking ritonavir-boosted PI had "adequate" adherence, based on pill counts.

Patients with exposure to an integrase strand-transfer inhibitor or baseline conditions such as advanced kidney or liver disease and grade 3 or 4 lipid abnormalities were excluded.

Pregnant or breastfeeding patients were also excluded, but five patients became pregnant on dolutegravir and three conceived while taking ritonavir-boosted PI, all of whom withdrew from the trial. In follow-up, researchers found one in each group lost a pregnancy in the first trimester.

Treatment-related grade 3 or 4 adverse event rates were similar in both the dolutegravir and ritonavir-boosted PI groups (5.7% and 6.9%, respectively).

Researchers noted there was a 2.1% increase in body mass index in the dolutegravir group versus 1.3% in the ritonavir-boosted PI group. "Weight gain is well recognized with dolutegravir use, particularly in women and Black persons," the researchers noted.

The main limitation of the trial was its open-label design. "However, the high percentages of participants who continued in the trial and strict viral-load cutoffs should minimize bias," the group suggested. Exclusion of children and adolescents also limits the generalizability.

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