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Research Director (HIV and Infectious Diseases)
Hospital La Paz. IdiPAZ.
José R. Arribas, MD, has disclosed that he has received consulting fees from Aelix, Gilead Sciences, Janssen, Merck, Teva, and ViiV Healthcare and funds for research support from Gilead Sciences, Merck, and ViiV Healthcare.
NAMSAL ANRS 12313
One of the most interesting treatment-naive ART studies reported at the recent International AIDS 2020 Conference (AIDS 2020: Virtual) was the NAMSAL ANRS 12313 study conducted in Cameroon and comparing dolutegravir (DTG) (n = 310) with low-dose efavirenz (EFV) (400 mg) (n = 303), each in combination with the NRTI pair of tenofovir disoproxil fumarate (TDF)/lamivudine (3TC). The primary endpoint has been previously reported, and investigators provided a 96-week update at the conference. This trial is interesting because in contrast with many other trials—particularly registrational trials—the patient population was characterized by having overall low CD4+ cell counts (median CD4+ cell count: 281 cells/mm³) and high HIV-1 RNA levels (~ 66% with HIV-1 RNA ≥ 100,000 copies/mL and ~ 30% with HIV-1 RNA ≥ 500,000 copies/mL). At Week 96, 74% of patients receiving DTG and 72% of patients receiving EFV had HIV-1 RNA < 50 copies/mL; the difference between the 2 groups was not statistically significant. Rates of viral suppression per WHO criteria of HIV-1 RNA < 1000 copies/mL were 84% and 82% in the DTG and EFV groups, respectively. This result is particularly surprising because patients in both treatments arms had a relatively high level of primary NNRTI resistance (6.1% in each arm; the majority of these [35/37] had primary resistance to EFV). The findings from this study highlight that we still know relatively little about how to treat patients with advanced HIV infection. Although viral suppression rates were high in both treatment arms, among the subset of patients with baseline HIV-1 RNA > 100,000 copies/mL, the rates of Week 48 viral suppression to HIV-1 < 50 copies/mL were 66.2% with DTG and 61.5% with EFV 400 mg (treatment difference: 4.7%; 95% CI: -4.6% to 14.0%). Results of trials such as this one enrolling a large proportion of patients with high baseline viral load and low baseline CD4+ cell count underscore the need for more data in this patient population. One such ongoing trial is the Late Presenter Treatment Optimization Study (LAPTOP) comparing bictegravir/tenofovir alafenamide/emtricitabine vs darunavir/cobicistat/tenofovir alafenamide/emtricitabine in patients with advanced HIV infection.
In another high-interest report from AIDS 2020: Virtual, investigators presented results from the randomized phase IIb P011 trial comparing dual therapy with islatravir (investigational first-in-class nucleoside reverse transcriptase translocation inhibitor) plus doravirine (DOR) vs DOR plus 3TC/TDF in 120 ARV-naive adults. In this trial, patients were initially randomized to receive DOR plus 3TC plus islatravir at one of 3 doses—0.25, 0.75, or 2.25 mg once daily—or to a control regimen of DOR plus 3TC/TDF. Patients in the islatravir groups with HIV-1 RNA < 50 copies/mL at Week 24 discontinued 3TC and continued on dual therapy with DOR plus islatravir. An FDA Snapshot analysis at Week 48 demonstrated the following rates of protocol-defined virologic failure by treatment arm (HIV-1 RNA > 50 copies/mL):
Two patients in each of the lower-dose islatravir arms and one patient in the triple-therapy control arm experienced virologic rebound; 1 patient in the 2.25-mg islatravir arm experienced nonresponse. Of interest, among those with protocol-defined virologic failure, all had HIV-1 RNA < 80 copies/mL at the confirmatory analysis. Therefore, genotyping for drug resistance mutations could not be performed. Thus, these patients met the criteria for virologic failure but had very low viral levels. This trial is interesting because most initial ART dual therapy studies undertaken to date have included either an INSTI or a boosted PI. In this case, it appears that islatravir is serving as the “backbone” of the regimen. Although DOR appears to have a higher barrier to resistance than EFV or rilpivirine, typically there has been some resistance at virologic failure. I am looking forward to seeing results from the phase III program evaluating dual therapy with DOR plus islatravir 0.75 mg.
The final study to highlight in this commentary is a report from the large GHESKIO cohort in Haiti. In this analysis, investigators included 1017 patients who had experienced virologic failure on a first-line regimen of EFV/3TC/TDF to assess outcomes based on whether the physician followed WHO guidelines regarding modification of the TDF-based NRTI pair in PI-based (atazanavir or lopinavir) second-line regimens. According to WHO recommendations, if a patient experiences virologic failure on a first-line regimen that includes a TDF-containing NRTI pair, the TDF should be replaced with zidovudine in the second-line regimen. The results of this analysis were surprising in that patients who continued to receive TDF/3TC (nonswitchers; 733/1017 [72%]) experienced better outcomes for almost all parameters vs patients who were switched to zidovudine/3TC (switchers). The rate of retention in care was similar between the 2 groups at approximately 83%. However, among those with a viral load measurement at ≥ 12 months, nonswitchers had a significantly higher rate of viral suppression in the first recorded HIV-1 RNA assessment ≥ 12 months than those who switched to zidovudine/3TC (52.7% vs 36.0% with HIV-1 RNA < 200 copies/mL, respectively; P < .001). In a multivariate analysis, the odds ratio for HIV-1 RNA < 200 copies/mL at the first viral load test at ≥ 12 months of treatment in nonswitchers vs switchers was 2.08 (95% CI: 1.46-2.97). The investigators suggested that the difference in viral suppression rates with the 2 strategies may be the result of lower adherence to zidovudine twice daily vs once-daily TDF and lower tolerability of zidovudine vs TDF. The odds ratio for 12-month treatment adherence (by pharmacy refill data) ≥ 90% in nonswitchers vs switchers was 1.53 (95% CI: 1.11-2.11). The results of this analysis highlight the fact that we are still learning more about optimal NRTI selection in subsequent lines of therapy. It has previously been shown that the efficacy of recycled TDF is often similar to the efficacy of switching to a new NRTI. The data from the GHESKIO cohort are interesting because they show that antiviral efficacy is related not only to the activity of the drugs used but also to the convenience and tolerability of the regimen.
What are your thoughts about the findings from these 3 studies? Which studies presented at AIDS 2020: Virtual did you find most compelling? Join the discussion by posting a comment and share your experiences of what your patients are telling you they would most like to see in future HIV treatment strategies.