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HIV UPDATES

INTERNATIONAL CONGRESS ON DRUG THERAPY IN HIV

Glasgow Ι 2012


HIV UPDATES GLASGOW 2012 Regarding etravirin, relevant data about the role of this drug in switch strategies were assessed. These are based on the low frequency of associated adverse events. A review was made of a Phase IV, double-blind, randomised, multicentre trial on the feasibility of switching individuals on efavirenz-based ARVT, who had virological suppression and central nervous system adverse events, to etravirin. This was a pilot study involving 38 male patients. The primary endpoint was the percentage of patients with grade 4 neurological adverse events at 12 weeks. Investigators showed that switching from efavirenz to etravirin led to a significant reduction in grade 2-4 central nervous system adverse events, including insomnia and anomalous dreams1. On the other hand, the switch to etravirin maintained virological suppression, improving metabolic parameters in patients receiving protease inhibitor-based 2

ARVT (and who were undetectable for at least 24 weeks), in a randomised trial conducted in Spain. Participants in the trial – which lasted 48 weeks–, could not have any mutations associated with resistance to nucleoside analogues or non-nucleoside inverse transcriptase inhibitors. All participants must have at least one of the three following conditions: abnormal lipids (low-density lipoprotein [LDL] cholesterol above 130 mg/dl or triglycerides above 350 mg/dl), ARVT-related gastrointestinal disorders, or low satisfaction with the current regimen. Investigators randomised 24 people to switch the PI to etravirin (taken as a 400 mg tablet dissolved in water once a day) and 22 people to maintain their base regimen. Two thirds of participants were male, with a mean age of 47 years. The group on etravirin had taken antiretroviral drugs for an average of 8 years and the control group for an average of 9.2 years. All participants maintained a viral load below 50 copies over the 24-week period. The CD4


count increased non-significantly in both groups. Total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, and triglycerides did not change significantly in the PI group. Among people switching to etravirin, mean total cholesterol dropped from 206 to 186 mg/dl (p=0.037), mean HDL cholesterol dropped from 52 to 48 mg/dl (p=0.004), mean LDL cholesterol increased non-significantly from 110 to 121 mg/dl (p=0.759), and mean triglyceride levels decreased from 168 to 107 mg/dl (p=0.004)2. In this sense, data for darunavir/ ritonavir were also reviewed. One study assessed whether switching virologically suppressed patients from a LPV/r or FPV/r to a DRV/r or ATV/r regimen led to improved plasma triglyceride levels, while maintaining virological suppression. Eligible patients had to have been virologically suppressed for at least 12 weeks and not have any history of resistance to PI. Regarding the baseline ARVT, they received LPV/r (n=46) or FPV/r (n=3) plus nucleosides, and all of them presented with fasting high triglyceride levels (>200 mg/dl). Patients were randomised to a daily dose of DRV/r (800 mg/100 mg) or ATV/r (300 mg/100 mg), keeping the same accompanying nucleosides. The primary endpoint was change in fasting triglycerides at 24 weeks. Of 66 enrolled patients, 49 completed the trial: 25 patients were randomised to DRV/r and 24 to ATV/r. Ninety two percent of subjects were male with a mean age of 47 years. Baseline CD4 count was 569 cells/mm3 and HIV RNA was less than 50 copies in 88% of

subjects. The two arms combined had a reduction in triglycerides after 24 weeks: 113 mg/dl (p<0.001), with a non-significant between arms difference (-126 mg/dl for DRV/ r and -99 mg/dL for ATV/r). On week 24, 48% of those in the DRV/r arm and 50% of patients in the ATV/r arm had triglycerides below 200 mg/dl. No differences were observed on week 24 between groups in CD4 cell counts or HIV RNA levels, and virological control was maintained3. Experience with DRV/r as monotherapy was also reviewed. Significant findings in the MONOI stand out. This was a prospective, open-label, non-inferiority, randomised trial for 96 weeks, to compare DRV/r monotherapy versus DRV/r in the context of triple therapy, as a strategy to maintain virological suppression. Of 225 randomised patients, 219 reached week 48 of follow-up and 211 reached week 96 of follow up (106 patients in the darunavir monotherapy arm and 105 in the triple therapy arm). Baseline characteristics were well balanced between both treatment groups. On week 96, in the intent-to-treat analysis, 91/103 patients (88%) randomised to monotherapy and 87/104 patients (84%) randomised to triple therapy achieved a viral load below 50 copies/mL, with no statistical difference between groups. Over 96 of follow-up, 66/112 patients (59%) and 79/113 patients (70%) maintained less than 50 copies/ml, respectively. The study confirms monotherapy with DRV/r as durable and effective to maintain HIV-1 viral suppression, and it can be considered

a treatment option in selected cases of patients who have had a long viral suppression period4. In the context of monotherapy, there is concern about the emergence of resistance-associated mutations. In the MONET trial, 256 patients with HIV RNA lower than 50 copies/ml on ARVT (57% on PI and 43% on non-nucleoside inverse transcriptase inhibitors) and no history of virological failure were randomised to DRV/r 800/100 mg once a day, whether as monotherapy or with two analogue nucleoside inverse transcriptase inhibitors (triple therapy). All samples with viral load higher than 50 copies/ml were genotyped. During the trial, a total of 63 patients showed viral load levels above 50 copies/ ml at some point, 38 of which were sequenced. No major PIor nucleoside-related mutations were found in 36 (95%) of them. Two patients showed evidence of PI resistance: one patient in the monotherapy group showed a single mutation for DRV (L33F), and one patient previously treated with a PI, currently taking TDF/ FTC/ DRV/r had a reappearance of his pre-existing resistance to nucleosides (M184V) and PI (V82I and L90M). Both patients showed sustained HIV RNA suppression at 48 weeks with the same treatment5. In this context, data from DRV/r monotherapy clinical trials are promising, and confirmed with daily practice experience: in an observational study from 2006 to 2010, 529 patients switched to PI monotherapy, showing an acceptable rate of virological failure6. Moreover, during the conference, 3


relevant data were presented, regarding whether PI monotherapy is associated with a higher risk of neurocognitive impairment (NCI). This assessment included HIV-infected patients with no factors that could be confounders for a neurocognitive assessment, who were in treatment for more than one year with lopinavir/ritonavir (LPV/r) or DRV/r, whether as monotherapy or with two nucleoside analogues, and with prolonged plasma viral suppression. Patients underwent neurocognitive assessment tests by two psychologists, who were blinded to the treatment group. NCI was defined according to the 2007 Frascati criteria, with demographically adjusted normative scores. NCI rates and the association between NCI and monotherapy were analysed, adjusting for relevant confounders. Two monotherapy categories were considered: short-term (1-2 years) and long-term (2-9 years).

The following were assessed as Figure 1

STaR – fixed-dose: FTC/RPV/TDF versus EFV/TDF/FTC in treatment-naïve patients • Multicentre, international, open-label, randomized, Phase IIIb - First single-tablet regimen comparison - 1st primary endpoint Stratified by baseline HIV-1 RNA > or ≤ 100,000 c/ml

Treatment-naïve patients with HIV-1 RNA >2500 c/ml (n=786)

Primary analysis Week 48

Planned follow-up 96 weeks

TDF/RPV/FTC one tablet once a day (n=394) EFV/TDF/FTC one tablet once a day (n=392)

Cohen C, et al. Glasgow 2012. Abstract O425.

4

possible confounders: demographic variables, HIV risk factors, AIDS, CD4 (nadir and current), smoking, alcohol/drug use, prior diseases, neurological and psychiatric factors, HVC co-infection, years of antiretroviral treatment, time with viral suppression, type of PI, lipid profile, and HOMA index. The study enrolled 191 patients (89.5% caucasian). No differences were observed in NCI rates between treatment groups or even between monotherapy durations. In the regression model, confounders for NCI were: years on antiretroviral treatment, ethnicity, education level, transmission mode, and the HOMA index. The authors conclude that PI monotherapy, regardless of duration, is not associated with a higher rate of neurocognitive impairment, compared with triple therapy7. On the other hand, the first study directly comparing the safety and efficacy of two single-tablet treatments was presented: the STAR trial, with FTC/RPV/ TDF and EFV/FTC/TDF in treatment-naïve adults. This was a randomised, multicentre, international, 96-week trial to assess the safety and efficacy of FTC/ RPV/TDF, compared with EFV/ FTC/TDF (both in a single tablet) in HIV-infected patients (see Figure 1). Subjects were randomised 1:1 to FTC/RPV/TDF or EFV/FTC/TDF. Eligibility criteria included: baseline viral load of 2500/ml or higher, genotype sensitivity to EFV, FTC, TDF, and RPV and no prior ARVT. Randomisation was stratified by baseline viral load (<100000 c/ml or >100000 c/ml). The primary endpoint was the proportion of sub-


References 1. 2. 3. 4. 5. 6. 7. 8.

Waters L et al, AIDS 2011. Echeverría P, et al. ICAAC 2011. Skiest D et al, CROI 2011. Valantin MA, et al. J Antimicrob Chemoter 2010. Pulido F, et al. Antivir Ther 2011. Guiguet M et al. AIDS 2012. Pérez-Valeró I et al. Journal of the International AIDS Society 2012, 15(Suppl 4):18179. Cohen C et al. Journal of the International AIDS Society 2012, 15(Suppl 4):18221.

Figure 2

STaR: efficacy of FTC/RPV/TDF versus EFV/TDF/FTC at 48 weeks • FTC/RPV/TDF was non-inferior to EFV/TDF/FTC in the overall

population and in patients with baseline HIV-1 RNA viral load >100,000 c/ml - FTC/RPV/TDF was superior to EFV/TDF/FTC in patients with baseline HIV-1 RNa viral load ≤100,000 c/ml

HIV-1 RNA <50 c/ml (%)

jects with HIV-1 RNA lower than 50 c/ml on week 48. A total of 784 patients were randomised and received at least one dose of the study drug (392 FTC/RPV/TDF and 392 FTC/TDF/EFV). Baseline characteristics were similar between treatment groups, with a mean baseline CD4 count of 390 cells/mm3 and viral load of 4.8 log10 c/ml. FTC/RPV/TDF was non-inferior to EFV/FTC/TDF (86% versus 81%) on week 48, for viral load lower than 50 c/ml. FTC/RPV/TDF was superior for viral load lower than 100,000 c/ml (88% FTC/RPV/TDF versus 81% EFV/FTC/TDF) and non-inferior for more than 100,000 c/ml (80% FTC/RPV/TDF versus 82% EFV/ FTC/TDF). There were fewer interruptions because of adverse events in the FTC/RPV/TDF arm (2%), compared with EFV/FTC/ TDF (8%). The authors concluded that the single-tablet FTC/RPV/ TDF regimen showed non-inferior efficacy and better tolerability, compared with a single-tablet EFV/FTC/TDF regimen, and superior efficacy for subjects with baseline viral load below 100000 c/ml, in treatment-naïve patients (see Figure 2)8.

100 80

Difference: 4.1% (95% CI: -1.1 to 9.2)

86

82

Difference: 7.2% Difference: -1.8% (95% CI: 1.1-13.4) (95% CI: -11.1 to 7.5)

89

82

80

82

Post-hoc analysis

83

82

81/ 98

96/ 117

80

72

60 40 20 0

338/ 320/ 394 392

All

231/ 204/ 260 250

Viral load ≤100K

RPV/TDF/FTC (n=394)

107/ 116/ 134 142

Viral load >100K

26/ 36

20/ 25

Viral load Viral load >100K to 500K >500K

EFV/TDF/FTC (n=392) Cohen C, et al. Glasgow 2012. Abstract O425.

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Data and results presented in this material were obtained from a medical conference and the summarized information can be preliminary and subject to change. These data are included only for medical training and its purpose is solely educational. Opinions presented herein belong to the authors and speakers and do not constitute suggestions by the sponsoring pharmaceutical company. Summary prepared by the Circle Press Staff after attending the Symposium. Cover photo: Shutterstock.


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