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ICAAC 2013: Stribild Is Effective and Well-tolerated in Older People with HIV

The Stribild single-tablet regimen matched both Atripla and boosted atazanavir (Reyataz) in efficacy among people age 50 and older, who responded as well as younger patients, researchers reported at the recent 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy in Denver. Related studies showed that Stribild had durable efficacy through 3 years and caused fewer central nervous system (CNS) side effects than Atripla.

While modern antiretroviral therapy is safe and highly effective, there is always room for new drugs that are more convenient or better tolerated. The 4-in-1 Stribild pill contains the HIV integrase inhibitor elvitegravir, the boosting agent cobicistat, and tenofovirand emtricitabine (the drugs in Truvada). U.S. treatment guidelines recently added Stribild as an "alternative" option for first-line therapy.

Joel Gallant from the Southwest Care Center in Santa Fe presented findings from an analysis of the safety and tolerability of Stribild in older individuals, who make up a growing proportion of the HIV positive population in the U.S. and Europe.

As reported at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this past July, Gilead Sciences' Phase 3 Study 102 showed that that Stribild was non-inferior to Atripla (efavirenz/tenofovir/emtricitabine) at 96 weeks, with 84% vs 82% of previously untreated patients, respectively, having undetectable viral load (<50 copies/mL). Likewise, Study 103 showed that Stribild worked as well as ritonavir-boosted atazanavir plus Truvada, with 83% vs 82%, respectively, having undetectable HIV RNA.

Gallant and colleagues' analysis compared response rates and side effects between people age 50 and older and those younger than 50 years, using 96-week data from these 2 trials. In Study 102, 49 people (14%) randomly assigned to receive Stribild and 56 (16%) assigned to Atripla were age 50 or older. In Study 103, 48 (14%) randomized to Stribild and 48 (14%) on atazanavir were in the older age group.

In both studies about 90% of participants were men, between two-thirds and three-quarters were white and the mean CD4 T-cell count was approximately 375 cells/mm³.

Results

• In Study 102, 82% of patients older than 50 had undetectable viral load at week 96 in both the Stribild and Atripla arms.
• Within the younger group, rates were 85% and 81%, respectively -- not a significant difference.
• While 1 older person in each treatment arm developed drug resistance during the first year, no additional patients did so during the second year.
• Response rates were also comparable in Study 103: 90% of people over 50 achieved undetectable viral load with both Stribild and boosted atazanavir.
• In the younger group, response rates were 82% and 81%, respectively.
• In this study no older patients developed resistance during either the first or second year.
• Older patients did see somewhat smaller CD4 cell gains:

o   In Study 102, T-cells increased by 233 cells/mm³ with Stribild and 250 cells/mm³ with Atripla at 96 weeks in the over 50 group, compared with 305 and 278 cells/mm³, respectively, in the younger group.

o   In Study 103, gains were 226 cells/mm³ with Stribild and 231 cells/mm³ with atazanavir in the older group, and 261 and 266 cells/mm³, respectively, in the younger group.

• Turning to adverse events in Study 102, in the older group there was significantly less dizziness and fewer abnormal dreams among Stribild recipients compared with Atripla recipients.
• In the younger group, Stribild again caused less dizziness and fewer abnormal dreams, but also significantly less rash and more nausea. 
• Looking only at those taking Stribild, diarrhea was less common among older compared with younger patients, but none of the other side effects differed significantly by age.
• In Study 103, there were no statistically significant differences in adverse events between older recipients of Stribild vs boosted atazanavir.
• In the younger group, Stribild recipients had significantly less yellowing of the eyes (a sign of elevated bilirubin) and less diarrhea, but more back pain, than atazanavir recipients.
• Within the Stribild arm older people had slightly less nausea but significantly more depression than younger patients.
• Older and younger people had similar serum creatinine levels at baseline and experienced similar changes at 96 weeks of treatment. In both age groups, however, increases were higher with Stribild (older 0.14-0.16 mg/dL; younger 0.12-0.13 mg/dL) than with Atripla (older 0.05 mg/dL; younger 0.01 mg/dL) or atazanavir (older 0.12 mg/dL; younger 0.07 mg/dL).
• Total cholesterol, LDL ("bad") cholesterol, and HDL ("good") cholesterol increased significantly less with Stribild than with Atripla among younger patients.
• Increases in total cholesterol, LDL, and triglycerides were also smaller with Stribild in the older group, though here the differences did not reach statistical significance due to small numbers.
• In contrast, cholesterol levels rose more with Stribild than with boosted atazanavir in both age groups, though differences again were not significant.

People age 50 and older "had high and similar rates of virological suppression as subjects age <50 years," the researchers concluded. Median CD4 cell increases were similar with all 3 regimens, but were smaller for older patients.

Older people had "blunted" immune recovery indicated by "less pronounced gains" in CD4 cells across the board, Gallant explained.

Other Stribild Studies

In a late-breaking poster, researchers reported outcomes out to 144 weeks in the Stribild vs Atripla trial described above. Looking at participants of all ages, they found that "high rates of virologic success were maintained" at 3 years, with 80% and 75%, respectively, having undetectable viral load in a "snapshot" analysis. No Stribild recipients developed resistance after week 96.

Response rates were similar in the 2 treatment arms regardless of baseline viral load or CD4 count (above or below 350 cells/mm³). CD4 cell counts continued to increase with longer time on therapy, with gains of 321 and 300 cells/mm³, respectively.

Rates of treatment discontinuation were "low and similar" in both arms (Stribild 6%; Atripla 7%); 4 people in the Stribild arm and 2 in the Atripla arm stopped due to adverse events after week 96. Again, CNS side effects, rash, and lipid increases were less common with Stribild, while Atripla caused less change in kidney biomarkers and fewer people stopped treatment for this reason.

A third study looked more closely at side effects at 96 weeks among participants in Study 102 and 103. Most treatment-emergent adverse events were mild in severity and occurred within the first few weeks after starting treatment, the researchers noted.

Focusing on side effects that continued at 96 weeks, the CNS symptoms of insomnia, abnormal dreams, and dizziness occurred less often among Stribild recipients compared with Atripla recipients, but were a bit more common with Stribild than with ritonavir-boosted atazanavir (abnormal dreams: 4% vs 14% vs 1%). People taking Stribild reported more nausea (4% vs 3%) and headaches (5% vs 2%) than those taking Atripla, but less diarrhea (5% vs 9%) and yellowing of eyes (0% vs 7%) than those taking atazanavir. Overall, adverse events rates were low after 2 years, with only abnormal dreams in the Atripla arm exceeding 10%.

Finally, Calvin Cohen and colleagues presented a poster looking at switching from Atripla to Stribild. This could potentially be a concern because residual efavirenz in the body might reduce elvitegravir levels due to a drug-drug interaction.

But in a small study of 14 people who switched from Stribild to Atripla with full viral suppression, all maintained undetectable viral load 2 weeks after switching. At 24 weeks post-switch, 12 of 14 still had undetectable HIV RNA (1 was lost to follow-up, another had a 1-time "blip" of 54 copies/mL).

A pharmacokinetic analysis of 32 healthy HIV negative volunteers found that elvitegravir levels at 2 week post-switch were lower than those seen in people who did not switch from Atripla (29% lower for AUC; 55% lower for trough concentration). However, both elvitegravir and efavirenz levels remained above known therapeutic levels.

10/1/13

References

JE Gallant, D Hardy, F Bredee, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF) demonstrates comparable efficacy and favorable tolerability
to efavirenz (EFV)/FTC/TDF and to ritonavir-boosted atazanavir (ATV+RTV) plus FTC/TDF in subjects 50 years and older at week 96. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-1459.

D Wohl, C Cohen, J Gallant, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB) has durable efficacy and differentiated long-term safety and tolerability versus efavirenz/emtricitabine/tenofovir DF (ATR) at week 144 in treatment-naive HIV patients. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-672a.

P Shalit, J Gallant, A Mills, et al. Long-term tolerability of elvitegravir/cobicistat/emtricitabine/tenofovir DF compared to efavirenz/emtricitabine/tenofovir DF or ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF in treatment-naive HIV-1 infected subjects. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-671.

C Cohen, R Elion, P Ruane, et al. Switch from efavirenz/emtricitabine/tenofovir DF to elvitegravir/cobicistat/emtricitabine/tenofovir DF: efficacy
and pharmacokinetics. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-658.