Congress report: XV Congreso Panamericano De Infectología the PROGRESS Study

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1 HAART, HIV correlated pathologies and other infections Marco Borderi*, Adriano Lazzarin Congress report: XV Congreso Panamericano De Infectología the PROGRESS Study Infectious Diseases Unit S. Orsola Hospital Bologna Department of Infectious Diseases - San Raffaele Scientific Institute - Milan Following International Guidelines, standard therapy for HIV-1 infected, antiretroviral-naïve patients, consists of two Nucleoside Reverse Transcriptase Inhibitors + a Protease Inhibitor, a Non-Nucleoside Reverse Transcriptase Inhibitor, an Integrase Strand Transfer Inhibitor, or a CCR5 Inhibitor. For those whom NRTI-containing combinations may not be the best option, for example a patient with renal dysfunction, high cardiovascular risk, elder or with comorbidities, a NRTI-sparing regimen may offer an alternative therapeutic approach. An approach that had high expectations was evaluated in ACTG A5262, a single-arm study in which 112 therapy-naive patients received darunavir/ritonavir with raltegravir without NRTIs. Unfortunately the study observed a high rate of virologic failure: 16% at Week 24 and 26% at Week 48. Forty-four percent of participants entered the study with HIV-1 RNA > 1 cp/ml, and these individuals were more likely to fail virologically (hazard ratio for failure in patients with HIV-1 RNA > 1 cp/ml vs lower: 3.76; 95% CI: ; P =.4) and to develop integrase resistance at failure. This was an uncontrolled study and so it is difficult to interpret. A larger comparative study that includes this regimen is ongoing. The SPARTAN study explored the novel approach of combining unboosted atazanavir with raltegravir in an NRTI-sparing regimen. Ninety-four untreated patients were randomized 2:1 to a twice-daily regimen of unboosted atazanavir plus raltegravir or once-daily boosted atazanavir with tenofovir/emtricitabine. Mean HIV-1 RNA at baseline was 4.9 log 1 copies/ml. Again, HIV-1 RNA decline occurred faster in the raltegravir arm, but virologic response rates at 24 weeks appeared comparable between arms (74.6% vs 63.3% had HIV- 1 RNA < 5 cp/ml in the raltegravir vs NRTI arms, respectively). The study was discontinued at this time because of both a higher incidence of grade 4 hyperbilirubinemia and an increased risk of integrase resistance at failure in the unboosted atazanavir plus raltegravir arm. VEMAN is an italian study comparing efficacy and safety of standard ARV treatment with LPV/r+TDF+FTC, vs a novel NRTI sparing strategy with LPV/r+MVC QD 15 mg in naive patients. At 48 wks the NRTI sparing regimen is greater in efficacy to conventional treatment, with a more rapid virological decay and immunological recovery. Due to the high CPE score this new combination could be extremely useful in patients with neurocognitive impairment. For those patients who need to save NRTI- toxicities this new strategy could offer an alternative therapeutical approach. Furthermore from an economic point of view this dual therapy has a comparable cost to the triple therapy due to the half dose of MVC required The PROGRESS study (M1-336) is the first randomized, open-label, multicenter trial specifically designed to compare the safety, tolerability and antiviral activity of lopinavir/ritonavir when administered in combination with raltegravir to lopinavir/ritonavir when administered in combination with tenofovir/emtricitabine in ARV-naïve, HIV-1-infected subjects for 96 weeks. vs. in Treatment- Naive Subjects: PROGRESS Study Design* Inclusion Criteria for PROGRESS (M1-336) HIV-1 infection ARV-naïve Plasma HIV-1 RNA >1 copies/ml Any CD4 + T-cell count LPV/r 4/1 mg BID + RAL 4 mg BID (n=11) Week 48 Primary Screening LPV/r 4/1 mg BID + 3/2 mg QD (n=15) Met Primary Endpoint of Noninferiority Primary endpoint: plasma HIV-1 RNA <4 copies/ml at week 48 (FDA- TLOVR) FDA-TLOVR week 48: =83.2%, =84.8% P=.85, difference -1.6%, 95% exact confidence interval (CI) -12.%, 8.8% Safety and tolerability were similar at week 48 * 3 subjects were randomized but not dosed Efficacy Endpoint Ruth Soto-Malave presented the data at the XV Congreso Panamericano De Infectología in Punta del Este, Uruguay, 7-11 April 211. At first, subjects were randomized in a 1:1 ratio to receive either LPV/r 4/1 mg BID plus RAL 4 mg BID or LPV/r 4/1 mg BID plus a fixed dose combination of 3/2 mg QD. Primary objectives were the proportion of subjects responding with plasma HIV-1 RNA levels <4 cp/ml after 48 weeks of treatment, and compare the safety and tolerability of with. Secondary outcomes include patient-reported outcomes, anthropometric measurements, and measurements from the 419

2 42 Marco Borderi et al ~ Congress report: XV Congreso Panamericano De Infectología the PROGRESS Study ~ pp. 419/423 Dual-Energy X-Ray Absorptiometry scan. First subject was screened on 27 June 28, first subject was enrolled on 11 July 28, and enrollment was completed on October 22, 28. The study was performed in US/Puerto Rico (15 sites), and in 19 sites in 5 countries (Spain, Canada, Poland, France, Italy). Three subject were randomized but not dosed (2 withdrew consent, 1 had acute illness). PROGRESS Main Inclusion Criteria were: HIV-1 infection, ARV-naïve, plasma HIV-1 RNA >1 cp/ml, any CD4+ T-cell count, and susceptibility to LPV/r, TDF and FTC assessed by HIV-1 genotyping at screening. Subjects with LPV/r, TDF, or FTC resistance based on HIV-1 genotyping at screening were excluded. Dr. Soto-Malave stressed that RAL resistance testing was not routinely performed at baseline, nor was RAL resistance at baseline an exclusion criterion, however, baseline samples were archived for RAL baseline resistance testing in the case of virologic failure. Resistance testing was performed at time of virologic failure if any of the three following criteria were met: a) beginning at week 8, if plasma HIV-1 RNA level was 4 cp/ml and at the previous visit the plasma HIV-1 RNA was <4 cp/ml, confirmatory plasma HIV-1 RNA level >4 cp/ml repeated within 4 weeks; b) if plasma HIV-1 RNA increased >.5 log1 cp/ml above study nadir and >4 cp/ml on two consecutive measurements obtained at least 14 days apart; c) if plasma HIV- 1 RNA never reached <4 cp/ml by week 24. Resistance testing for LPV/r, TDF and FTC was performed using ViroSeq HIV-1, and resistance testing for RAL was performed using GeneSeq HIV. Resistance was specified by the 21 IAS-USA panel. After screening, a total of 26 subjects were randomized and dosed: 174 adult males and 32 adult females. Gender, race, ethnicity, age, height, hepatitis co-infection status, and weight, were similar between the lopinavir/ritonavir treatment groups, with no statistically significant differences observed. HIV-1 history variables including years since diagnosis, risk factors, mean baseline plasma HIV-1 RNA levels, distribution of baseline plasma HIV-1 RNA levels, mean baseline CD4+ T cell counts, and distribution of baseline CD4+ T cell counts, were similar between treatment groups, with no statistically significant differences observed. No statistically significant difference was noted in distribution of plasma HIV-1 RNA levels at baseline, and specifically, based on slide kit: <3 cp/ml: =64/11 (63.4%), =65/15 (61.9%), 3 to 1 cp/ml: =22/11 (21.8%), =21/15 (2.%), 1 to 3 cp/ml: =7/11 (6.9%), =12/15 (11.4%), >3 cp/ml: =8/11 (7.9%), =7/15 (6.7%). No statistically significant difference was noted in distribution of CD4+ T-cell counts at baseline, and specifically: <4 cells/mm 3 : =9/11 (8.9%), =6/15 (5.7%), 4 to 2 cells/mm 3 : =15/11 (14.9%), =24/15 (22.9%), 2 to 35 cells/mm 3 : =45/11 (44.6%), =38/15 (36.2%), >35 cells/mm 3 : =32/11 (31.7%), =37/15 (35.2%). Variable Demographics and HIV Disease Characteristics Males, Race White, Black, Other, Mean age ± SD, years Mean BL HIV-1 RNA, log 1 copies/ml (range)* Mean BL CD4 + T-cells/μL (range) 88 (87.1) 74 (73.3) 22 (21.8) 5 (4.9) 39.8 ± (2.-6.) (5 668) 86 (81.9) 81 (77.1) 22 (21.) 2 (1.9) 39.4 ± 11.2 (2.7 6.) (5 743) Total (N=26) 174 (84.5) 155 (75.2) 44 (21.4) 7 (3.4) 39.6 ± 1.6 (2. 6.) (5 743) * Plasma HIV-1 viral loads determined using automated, quantitative RT-PCR assay (Abbott RealTime HIV-1 assay ) Groups were compared using one-way ANOVA for continuous variables and Fisher s exact test for categorical variables. Based on the oral presentation, a total of 34 (16.5%) subjects discontinued during the 96-week trial. There were no significant differences between the treatment groups in the number of subjects who discontinued or in the reasons for discontinuation. The rate of study discontinuation at or before 96 weeks (16.5%) is similar to other clinical trials: CASTLE (ATV + RTV + vs. LPV/r + )=19.5% [Molina et al. JAIDS. 21;53(3): ] ARTEMIS (DRV + RTV + vs. )=2.3% [Mills et al. AIDS. 29;23(13): ] STARTMRK (RAL + vs. EFV + )=15.3% [Lennox et al. JAIDS (1):39-48.] M5-73 ( TDF FTC QD vs. BID)=23.2% [Gonzalez-Garcıa et al. AIDS Res Hum Retroviruses. 21 (8):841-5.] Data presented confirm that the most common reason for premature discontinuation was lost to follow-up, followed by adverse event or HIV-related event and withdrawl of consent. Virologic failure was reported as the reason for discontinuation for 3 (1.5%) subjects overall, 1 (1.%) in the subjects and 2 (1.9%) in the subjects. Both LPV/r + RAL and treatments were generally well tolerated as indicated by the low incidence of discontinuations due to adverse events. 9 subjects (5 and 4 ) prematurely discontinued the study due to adverse events or HIVrelated event. The most common adverse event leading to discontinuation was diarrhea, occurring in remarkably few subjects: 2 in group, 2 in LPV/r + group. Other adverse events leading to discontinuation were: a) in the arm 1 subject discontinued due to sepsis, 1 subject discontinued due to hypercholesterolaemia/hypertriglyceridaemia, and 1 subject discontinued due to increases in ALT/AST/ CPK; b) in the arm 1 subject discontinued due to Fanconi syndrome, and 1 subject discontinued due to vertigo. Subjects who discontinuated study drug are counted under each reason given for discontinuation, therefore, the sum of the counts given

3 Marco Borderi et al ~ Congress report: XV Congreso Panamericano De Infectología the PROGRESS Study ~ pp. 419/423 for the reason may be greater than the overall number of discontinuations. P-value for comparisons between treatment groups using Fisher s exact test. No statistically significant differences between LPV/r treatment groups were observed for any preferred term. Subject Disposition at Total Reasons for (N=26) Discontinuations All Reasons* 19 (18.8) 15 (14.3) 34 (16.5) Lost to Follow-Up 9 (8.9) 12 (5.8) AE/HIV-related Event 5 (5.) 4 (3.8) 9 (4.4) Withdrew Consent 2 (2.) 4 (3.8) 6 (2.9) Virologic Failure 1 (1.) 2 (1.9) 3 (1.5) Other 2 (2.) 1 (1.) 3 (1.5) Noncompliance 1 (1.) () 1 (.5) Pregnancy () 1 (1.) 1 (.5) * P>.5 for RAL vs. comparison for each reason based on Fisher's exact test 1 subject discontinued for two reasons: Noncompliance and Other Dr. Soto-Malave argued that the primary endpoint for this study was plasma HIV-1 RNA <4 cp/ml at week 48 with FDA-TLOVR (Time-to-loss-of-virologic-response), an endpoint recommended by the FDA (FDA Guidance to Industry, October 22). Following the FDA time to loss of virologic response (TLOVR) algorithm, subjects are considered responders when they achieve two consecutive HIV-1 RNA values <4 cp/ml, and are classified as non-responders at all subsequent visits if they demonstrate 2 consecutive rebound HIV-1 RNA values 4 cp/ml, or if they discontinue the study for any reason prior to week 48. Results generally similar to ITT NC=F primary endpoint. FDA-TLOVR at week 48 was =83.2%, =84.8%, with P=.85, difference -1.6%, 95% exact confidence interval [CI] -12.%, 8.8%. Per protocol, noninferiority was assessed by 95% CI for the difference ([] [ ]) using a -2% threshold; if noninferiority with respect to the -2% margin was demonstrated, then noninferiority with respect to a -12% margin was to be evaluated. demonstrated noninferiority to LPV/r + based on the prespecified noninferiority margins of -2% as well as the more stringent -12%. At week 96, using the FDA-TLOVR primary endpoint, 66.3% in the and 68.6% in the TDF were virologically suppressed (HIV-1 RNA <4 cp/ml). These are the slide of the presentation: Proportion of Subjects Responding at (FDA-TLOVR) The proportion of responders at week 96 was also similar between treatment groups for the observed data analysis. Proportion of Subjects Responding at (Observed Data Analysis) FDA-TLOVR response for subjects with baseline HIV-1 RNA level <1 cp/ml was: = 61/86 (7.9%), = 62/86 (72.1%); for subjects with baseline HIV-1 RNA level 1 cp/ml was: = 6/15 (4.%), = 1/19 (52.6%). Week 96 observed data response for subjects with baseline plasma HIV-1 RNA 1 cp/ml was: RAL= 8/1, = 12/15. Statistically significantly more subjects in group achieved virologic suppression (FDA-TLOVR) at weeks 2, 4, 8 and 16 compared with TDF/ FTC group (weeks 2, 4 and 8 P<.1, week 16 P=.38), but early differences in the proportion of subjects achieving HIV-1 viral loads of <4 cp/ ml between treatment groups did not appear to be associated with differences in immunologic recovery as measured by CD4+ T-cell counts. Both treatment groups demonstrated increases in CD4+ T-cell counts over the 96 weeks of treatment, with mean increases of approaching 3 cells / mm 3 at 96 weeks. CD4+ T-cell count increase, from baseline to each visit within each treatment group, was statistically significant at all time points. Similar to results from other studies using RAL, early differences in the proportion of subjects achieving HIV-1 viral loads of <4 cp/ml between treatment group were not associated with differences in immunologic recovery as measured by CD4+ T-cell numbers. Mean CD4 + T-cell Counts Through 96 Weeks of Treatment (Cells/mm 3 ) 421

4 422 Marco Borderi et al ~ Congress report: XV Congreso Panamericano De Infectología the PROGRESS Study ~ pp. 419/423 The data presented at Vienna WAIDS Conference 21 evidenced that at week 48, there were no new protease mutations associated with lopinavir resistance developed on study in either treatment arm, a RAL associated resistance mutation was observed in one subject receiving, and a 3TC associated resistance mutation was observed in one subject receiving. Now, at week 96, thirteen subjects (8 and 5 ) met the protocol-defined criteria for resistance testing: FTC RAM was detected in 1 subject (FTC RAM identified at week 4 was M184V); RAL RAMs without LPV/r RAMs were detected in 1 subject at week 48 (N155H and G163R) and 1 subject at week 65 (Q148H and G14S); RAL and LPV/r RAMs were detected in 1 subject: longitudinal analysis on this subject indicated that RAL RAMs emerged at week 16 (T97A and N155H), an additional RAL RAM emerged at week 84 (D232N), LPV RAM M46I emerged at week 72, and additional LPV RAM, V32I, emerged at week 96. Evidence of LPV/r resistance was more conservatively defined as the presence of one or more of the following mutations: protease I47V/A, G48V, I5V, V82A/F/T/S, I84V, L9M, or the presence of 3 or more of the following mutations: protease L1F/I/R/V, K2M/R, L24I, V32I, L33F, M36I, M46I/L, F53L, any change to I54, A71V/T, and G73S. The 48 weeks presentation in Vienna stressed that safety and tolerability were similar at week 48: no statistically significant differences between groups for the incidence of moderate to severe treatment-related adverse events occurring in 2% in either treatment group. Number and % of Subjects with Moderate or Severe Drug-Related Adverse Events* Any adverse event 31 (3.7) 36 (34.3) Diarrhea 8 (7.9) 17 (16.2) Hypercholesterolaemia 1 (9.9) 7 (6.7) Hypertriglyceridaemia 9 (8.9) 5 (4.8) Alanine Aminotransferase Increased 3 (3.) 1 (1.) Hyperlipidaemia 3 (3.) 1 (1.) Asthenia () Regurgitation () * Occurring in 2.% in either treatment group Hypercholesterolaemia includes blood cholesterol increased, hypertriglyceridaemia includes blood triglycerides increased P>.5 for vs. comparison for each adverse event based on Fisher's exact test In this presentation, the speaker confirmed that there was a trend toward more subjects with moderate or severe treatment-related diarrhea in the LPV/r + treatment group (=7.9%, =16.2%, P=.88). The percent of subjects taking lipid-lowering agents was similar between treatment groups (=23.8%, =25.7%). The only statistically significant laboratory abnormality was creatine phosphokinase, which was greater in the LPV/r+ RAL group ( RAL=19.8%, =8.78%, P=.27); an alternative definition for Grade 3+ CPK is >1x ULN: so number and percent of subjects with CPK >1x ULN was: =1/11 (9.9%) LPV/r + =3/14 (2.9%), P=.47. The creatine phosphokinase increases have been previously de- scribed in subjects taking RAL and optimized background therapy in the BENCHMRK trials [Steigbigel, N Engl J Med, 28; Steigbigel, CID. 21]. Creatinine clearance (ml/min) mean changes from baseline to was specifically: : baseline = 121.3, = 12., Mean Change = -1.43; : baseline = 119.4, = 112., Mean Change = -7.33; P-value for comparison =.35. Lipid abnormalities had been previously described in trials of LPV/r in ARV-naïve and experienced subjects [Gathe, JAIDS, 29; Zajdenverg, JAIDS, 21]. There was one study drug discontinuation due to a laboratory abnormality of high triglycerides in the group. None of the subjects with grade 3+ triglyceride lab abnormalities reported an adverse event of pancreatitis. There was one subject in the group with reported (moderate) rhabdomyolysis who also had grade 3+ CPK elevations. No action was taken for this event and the subject did not discontinue the study. n ( %) Creatine Phosphokinase (CPK) (>4x ULN) 2 (19.8) Creatine Phosphokinase (CPK) (>1x ULN) 1 (9.9) Cholesterol (>7.77 ) 17 (16.8) Triglycerides (>8.475 ) 1 (9.9) Lipase (>2x ULN) 4 (4.) SGPT/ALT(>5x ULN) 5 (5.) SGOT/AST (>5x ULN) 5 (5.) Calculated Creatinine Clearance (<5 ml/min) 1 (1.) Neutrophils (<.75 x 1 9 /L) Calcium (<1.75) 2 (2.) Magnesium (<.5) 2 (2.) * Occurring in 2.% in either treatment group P<.5 for vs. comparison based on Fisher's exact test in Lipid Levels at Variable LDL:HDL ratio HDL LDL Total Cholesterol Triglycerides Number and % of Subjects with Grade 3+ Laboratory Values* N= n ( %) 9 (8.7) 14 (13.5) 5 (4.8) 8 (7.7) 4 (3.8) 4 (3.8) In these slides, we can see that there were no statistically significant differences in the mean change from baseline to week 96 in lipid parameters. The proportion of subjects taking lipid lowering agents at least once through 48 weeks was: =13.9%, =18.1%. The proportion of subjects taking lipid lowering agents at least once through 96 weeks was: =23.8%, =25.7%. N= P>.5 for difference between treatment groups in mean change at all time points using one-way ANOVA

5 Marco Borderi et al ~ Congress report: XV Congreso Panamericano De Infectología the PROGRESS Study ~ pp. 419/423 Through 24 weeks of treatment, subject adherence to lopinavir/ritonavir was assessed using MEMS (Medication Event Monitoring System) caps placed on the Kaletra pill bottle and data recorded at each visit. to 96 week adherence data were available for analysis from 16 (77.7%) subjects (84 [83.2%], 76 [72.4%] TDF/ FTC). There was no significant between-group difference in the proportion of subjects with unavailable adherence data (Chi-square test: P=.1723). Three measures of adherence were assessed: 1) Taking compliance (TAC) = percentage of total doses taken compared to the number prescribed; Taking compliance is calculated as: [number of openings / number of prescribed doses] X 1; If the output from the MEMS monitor for a BID regimen shows 86 openings, and there were 1 prescribed doses (corresponding to a monitored period of 5 days), the percentage of prescribed doses taken, or taking compliance, is 86% [(86/1) X 1]; This measure reflects the average dose received over a given period and hence also the total dose over that period. It accounts for periods of time without drug intake and double dosing. However, it fails to distinguish between a patient who takes their medication regularly and a patient who balances periods of under-dosing with periods of over-dosing, and it captures no information about the timing of drug intake less precise compliance measure. 2) Correct dosing compliance (COD) = percentage of days with correct number of doses taken; Correct dosing compliance is calculated as: [number of days with openings as prescribed / number of monitored days] x 1; If the output from the MEMS monitor for a BID regimen shows 86 openings, but there were exactly 2 openings on only 4 of the 5 monitored days, the percentage of days with the correct number of doses taken, or correct dosing compliance, is 8% [(4/5) X 1]; This statistic captures some measure of the closeness to correct compliance. However, it gives no information concerning the timing of dose intake, and it does not distinguish between days of over-dosing and days of underdosing and thus may not capture deviations most relevant to the drug action, 3) Timing compliance (TIC) = percentage of doses taken within prescribed intervals (24 ± 3 hours for QD dosing, 12 ± 3 hours for BID dosing); Timing compliance is calculated as: [number of openings within ± 3 hours of the prescribed dosing interval / number of prescribed doses 1] X 1; This measure assesses both the periods of over-dosing (interval too short) and periods of under-dosing (interval too long). It is the most precise adherence measure; If the prescribed dosing interval is 12 hours (BID regimen), the number of doses with inter-dose intervals between 9 and 15 hours are calculated. Hence, if the output from a MEMS monitor for a BID regimen shows 86 openings, but only 38 of these openings were within an inter-dose interval of 9 15 hours, and there were 1 openings prescribed (corresponding to a monitored period of 5 days), the % of doses taken within prescribed intervals, or timing compliance, is 38% [38/(1 1) X 1]. These adherence results are similar to those obtained in other studies. Adherence via MEMS Data: 96 Weeks Time Period Adherence was similar between treatment groups regardless of adherence measure Adherence Measure Taking to Week Compliance 96 Correct Dosing Timing Compliance N=76 (Mean %) N=84 (Mean %) P>.1 for each measure based on Wilcoxon rank sum test to test for differences between groups in the distribution of subjects adherence rates In conclusion, in Soto-Malave discussion, at 96 weeks virologic efficacy was comparable to. The proportion of subjects responding [FDA-TLOVR, P=.767] was: : 66.3%, and : 68.6%. Similar mean increases was observed in CD4+ T- cell counts at week 96 (P=.598): : cells/mm 3, and : cells/mm 3. Both regimens were generally well tolerated with few study drug-related discontinuations: the discontinuations for adverse events or HIV-related events was: = 5.% and = 3.8%. Adverse events profile and laboratory abnormalities were generally similar, with the exception of percent of subjects with CPK elevations: = 19.8% and LPV/r + = 8.7%. Although the need for NRTI-sparing regimens in general has not been as urgent as the need for thymidinic and D-drugs-sparing regimens was several years ago based on the overall improved safety profile of newer NRTIs, there are nonetheless safety issues with current NRTIs that become more significant. The toxicities may not be severe, but it is still beneficial to have options that may avoid them. The results of this study are sufficiently promising that one could consider lopinavir/ritonavir plus raltegravir as a viable NRTI-sparing, first-line regimen for a patient with renal dysfunction, high cardiovascular risk, elder, or with an higher rate of comorbidities. It could also be considered as a potent switch option for patients who initiated a tenofovir-containing regimen and developed subsequent renal complications. 423