Third-line HIV regimens effective in resource-limited settings

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Third-line regimens with darunavir/ritonavir and raltegravir are highly effective in certain patients with HIV in resource-limited settings, Healio reports according to researchers. Targeted real-time genotyping also helps direct more costly drugs to patients with greater resistance to treatment, they said the 2018 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

“With an increasing number of individuals using antiretroviral therapy worldwide – first-line and second-line – not everyone does well with therapy, so we have an increasing number of people who are failing second-line therapy, and we still don’t have a public health approach for patients failing second line,” researcher Dr Beatriz Grinsztejn, of the Instituto Nacional de Infectologia Evandro Chagas in Rio de Janeiro, Brazil, said at a CROI press conference. “Our objective was to see if newer antiretrovirals plus real-time genotyping, plus viral load monitoring could be a way for these individuals to have a better virological response.”

In their study, Grinsztejn and colleagues assessed patients with a viral load of at least 1,000 copies/mL after more than 24 weeks of treatment with protease inhibitor-based, second-line ART. They included patients enrolled between 2013 and 2015 in Africa, Asia, the Caribbean and South America.

The researchers separated the patients into cohorts based on prior ART use and treatment resistance based on real-time genotyping. Each cohort then received a range of ART options. The researchers assessed which patients achieved viral suppression to 200 copies/mL or less at 48 weeks of follow-up.

One cohort comprised 287 patients without resistance to lopinavir/ritonavir (LPV/r). Because of the lack of resistance, those patients continued to receive second-line ART. Of those patients, 44% achieved viral suppression. Meanwhile, 51% had confirmed virologic failure.

Another cohort consisted of 154 patients who were resistant to LPV/r but susceptible to darunavir/ritonavir (DRV/r) and to etravirine. They received third-line regimens containing DRV/r and raltegravir (RAL). Of those, 88% achieved viral suppression.

A third cohort consisted of 70 patients with resistance to LPV/r and etravirine but who were susceptible to DRV/r and had no prior treatment with RAL. According to the researchers, 90% of those patients achieved viral suppression.

Grinsztejn said the data show that more novel treatment options are needed for people failing second-line therapy. “Now we have some data to show the profile of people failing second-line therapy,” she concluded. “It’s really important for us to better understand what is the best (treatment) we can offer so that individuals can truly have better outcomes.”

Individuals presenting for 3rd line ART are a challenge in resource limited settings (RLS) because of uncertain ARV susceptibility and limited data on virologic responses to remaining available ARV regimens.
A5288 is an open-label strategy study in RLS in HIV-1 infected individuals presenting with confirmed plasma HIV RNA (VL) ≥ 1000 copies after > 24 weeks of protease-based (PI) 2nd line ART. Primary objective was to use novel antiretrovirals and contemporary management tools, including standard genotyping to select an appropriate 3rd-line regimen, interventions to improve adherence, and VL monitoring, to achieve virologic suppression in ≥65% at 48 weeks of follow-up. Review of prior ART, combined with real-time standard genotype, determined Cohort A-D assignment (Table). An exploratory randomized comparison in Cohort B of NRTIs+DRV/r+RAL (B1) versus ETR+DRV/r+RAL (B2) among HBV Ab- participants was performed; HBV Ab+ participants in B received DRV/r + RAL + TDF/FTC or TDF+3TC (B3). Suppression of VL ≤200 copies/mL at 48 weeks and virologic failure (VF, two consecutive ≥1000 copies/mL ≥ 24 weeks) were 1o and 2o endpoints.
From 2013-2015, 545 participants in 10 countries in Africa, Asia, South America and the Caribbean enrolled: 47% females; median age 41 years, median CD4 count 175 cells/mm3. At enrollment, drug resistance (moderate or high-level) to 0, 1, 2, and 3 ARV classes was identified in 22%, 20%, 30% and 27% of participants, respectively. Overall, 64% (95% CI 60, 68%) had VL ≤ 200 copies/mL at week 48. Viral suppression and VF differed across cohorts (Table). By week 48, Cohort A had the most Grade ≥ 3 adverse events (39%) and regimen discontinuations (13%). No differences in VL ≤ 200 copies/mL at week 48 or VF ≥ 24 weeks were observed in the randomized comparison of B1 & B2 cohorts.
Regimens containing DRV/r and RAL with or without ETR were highly effective for participants with LPV/r resistance who presented for 3rd line ART. More than half of participants without LPV/r resistance and who remained on 2nd line ART did not achieve viral suppression at week 48. This subgroup requires additional interventions to achieve viral suppression. Targeted real-time genotyping to select regimens for 3rd line ART can appropriately allocate more costly ARVs to those with greater resistance.

Beatriz Grinsztejn, Michael D Hughes, Justin Ritz, Robert Salata, Peter Mugyenyi, Evelyn Hogg, Linda Wieclaw, Robert Gross, Catherine Godfrey, Nagalingeswaran Kumarasamy, Cecilia Kanyama, John W Mellors, Carole Wallis, Ann Collier

Healio report
CROI 2018 abstract

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