THLBB2 Late Breaker Track B – 2

This late breaker session was extremely interesting with many important clinical trials and cohorts presented.

Eron, et al. addressed the “when to start” question using data from the CASCADE cohort of HIV seroconverters. Using a novel method of sequential nested cohort analysis combined with inverse probability weighting, initiation of ART at CD4 <500 appears to reduce risk of death compared to deferring at baseline. At CD4 500-799, there was no apparent benefit to initiation for the population of patients with CD4s in this range. Eron discussed limitations to using observational data to address the question of “when to start”.

Quinson, et al. presented results of a RCT of nevirapine 400 mg QD in an extended release formulation versus NVP 200 mg BID that found the QD formulation to be non-inferior, and with a similar safety and tolerability profile to BID dosing of the immediate release formulation.

Portsmouth, et al. presented the 24 week results of a pilot, open label RCT comparing MVC 150mg daily with ATV/r versus TDF/FTC/ATV/r in 112 treatment naïve patients. At week 24, VL<50 achieved in MVC arm: 80% versus TDF/FTC arm: 89%. Of the 5 participants with virologic failure who could be evaluated for drug resistance, no resistance was detected. A phase III study is now planned.

There is interest among clinicians to have available an antiretroviral regimen which is both ritonavir and nucleoside sparing. Before this conference several uncontrolled studies had suggested that unboosted Atazanavir 300 mg BID plus Raltegravir 400 mg BID could be a useful regimen in antiretroviral naive patients to avoid at the same time nucleosides and ritonavir associated toxicities. Kozal and colleagues (THLBB204) have reported the results of SPARTAN which is a multicenter, randomized, open-label, non-comparative pilot study to evaluate the efficacy and safety of atazanavir 300mg BID plus RAL 400mg BID in treatment-naïve HIV-infected patients. Subjects were randomized 2:1 to ATV+RAL (n=63) or a reference regimen of ATV/RTV 300/100mg QD + tenofovir/emtricitabine (TVD) 300/200mg QD (n=31). By the primary analysis at week 24 (HIV-RNA < 50c/ mL) that used confirmed virologic response (CVR NC=F) 74.6% of the patients randomized to ATV+RAL had undetectable viral load compared to 63.3% of patients receiving the control regimen.

Through week 24, 7 patients on ATV+RAL and one on ATV/RTV +TVD met criteria for resistance testing. 57.1% of the virologic failures on ATV +RAL developed RAL resistance. No ATV resistance was observed in either arm.  Grade 4 hyperbilirubinemia were 20.6% and 0%, respectively. The study supports the antiviral efficacy of the combination but poses the question if the risk of resistance to RAL is increased with this nucleoside and ritonavir sparing combination. Based on these data Dr. Kozal informed the audience that the study has been stopped. 

 GSK1349572 (ING572) is an integrase inhibitor in preclinical development which is administered once daily and without boosting. At this conference Arribas et al (THLBB205) communicated the results of a phase IIb dose-ranging, partially-blinded trial which included 205 antiretroviral naïve HIV-infected patients. All patients received a 2 drug NRTI backbone given once daily and were randomized to receive ING572 10 mg QD, ING572 25 mg QD, ING572 50 mg QD or EFV 600 mg QD. Mean baseline viral load was 4.46 log₁₀ copies/mL and mean baseline CD4 cell count was 324 cells/µL. After 16 weeks, proportions of patients with less than 50 copies/mL (TLOVR) were 90-96% in the three ING572 groups and 60% in the EFV group. At week 16 only two confirmed virologic failures were identified (one in each arm). There were not severe adverse events related to ING572. Treatment-emergent laboratory abnormalities of grade 3 or higher were rare. Changes from baseline in lipids were more favorable in the ING572 groups than in the EFV group. Based upon this data, 50mg has been selected for Phase 3 studies of integrase inhibitor naïve subjects

 Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor which had shown promising results in dose-finding studies. In this conference Cohen and colleagues have reported (THLBB206) two important phase III trials of rilpivirne (ECHO and THRIVE) in antiretroviral naïve patients

These two trials include patients receiving (1:1) rilpivirne 25mg qd or efavirenz 600mg qd, plus either tenofovir (TDF)/emtricitabine (ECHO) or TDF/emtricitabine, lamivudine/zidovudine or abacavir/lamivudine (THRIVE). The primary objective was to demonstrate non-inferiority of TMC278 to efavirenz in confirmed virologic response (viral load < 50 copies/mL ITT-TLOVR algorithm) at Week 48. A total of 1368 patients were randomised to the study arms. Median baseline viral load was 5.00 log10 copies/mL and median CD4 256 cells/mm3. Rilpivirine showed non-inferior efficacy versus efavirenz. At week 48 proportion of patients with less than 50 copies/mL were 84.3% in the Rilpivirine groups and 82.3 % in the Efavirenz groups. The virologic failure rate was 9.0% in the TMC278 group and 4.8% in the efavirenz group. This difference was compensated by a lower rate of discontinuations due to side effects in the Rilpivirine groups. Lipid changes were more favorable with Rilpivirine than with Efavirenz. Half of the patients who failed rilpivirine with resistance were also cross-resistant to etravirine. This results support the use of Rilpivirine in antiretroviral naïve patients but also support the high efficacy of efavirenz based combinations.

 Toxicities associated with TDF and Abacavir have increased the interest for nuc-sparing regimens. A “middle way” to avoid these toxicities would be to use dual therapy using 3TC or FTC as the only nucleoside. Both 3TC and FTC have a very benign toxicity profile. In this conference De Luca and collaborators have presented (THLBB207) an interesting single-arm study about the safety and efficacy of treatment simplification to atazanavir/ritonavir plus lamivudine in patients on two NRTIs plus atazanavir/ritonavir with optimal virologic control (ATLAS study).

Patients receiving atazanavir/ritonavir + 2NRTI, without previous treatment failure or resistance to PI and/or lamivudine, with HIV-RNA< 50 copies/mL for >3 months, CD4>200cells/µL for >6 months, HBsAg-negative and with atazanavir plasma levels above efficacy thresholds were eligible. At baseline, regimens were simplified to atazanavir/ritonavir + lamivudine at recommended doses.

Study enrolled 40 patients with prolonged HIV suppression (medina 663 days) and high CD4 cell counts (98cells/µL). Thirty-nine patients discontinued tenofovir and one abacavir. At the time of analysis, 36/40 patients had reached week 24 visit. All patients maintained an HIVRNA< 50 copies/mL. Atazanavir concentration and total bilirubin did not show significant modifications. Median change from baseline total cholesterol was +19mg/dL and  LDL +15mg/dL, HDL +4mg/dL without significant modification of Total cholesterol/HDL ratio. A significant increase of GFR was observed. This is an interesting preliminary finding that should be confirmed in larger studies.

Clinical trials have suggested that abacavir might be less efficacious than tenofovir in patients with baseline viral load above 100.000 copies/mL. Partially for this reason ABC/3TC is now an “alternative” NRTI option for treating ART-naïve patients in the DHHS guidelines. In this conference Loufty and colleagues (THLBB208) present a cohort study looking at time to virologic suppression (two consecutive VL< 50 copies/mL>1 month apart) and time to switch or stop of ABC/3TC or TDF/FTC (not due to virologic failure) in ART-naïve patients who started HAART. 783 patients were included in the analysis. Investigators did not find a difference between the time to virologic suppression and stopping or switching first time use of ABC/3TC and TDF/FTC. Main limitation of the study is that is not randomized

 Rieger and colleagues communicated the 96 weeks results of the MONET clinical trial (THLBB209). To be included in the trial patients have to be naïve to Darunavir/ritonavir and had to be virologically suppressed (less than 50 copies/mL) for more than 6 months while receiving HAART (NNRTI or PI based). Patients with prior virological failures were excluded.

Patients were randomized to receive darunavir/ritonavir QD monotherapy or Darunavir/ritonavir QD plus two nucleosides. At 48 weeks (primary endpoint) this clinical trial demonstrated the non-inferiority of darunavir/ritonavir monotherapy. At this conference investigators have presented the 96 week update. At this time point in the switch = failure analysis (TLOVR) 80.6% of the patients randomized to triple therapy had less than 50 copies/mL compared to 74.8% of the patients randomized to monotherapy. The lower limit for the 95% CI for this difference is -16.0% and consequently the monotherapy arm did not achieve non-inferiority.

Authors performed a multivariate analysis looking for predictors of failure during the trial and interestingly Hepatitis C co infection was significantly associated with failure in both arms. One possible explanation for the lower efficacy of monotherapy at 96 weeks is that the proportion of patients with HCV/HIV co-infection at baseline was higher in the monotherapy group (19%) than in the triple therapy group (12%). After 96 weeks of follow up protease inhibitor resistance was found only in one patient per group.