Lopinavir/Ritonavir Combined with Raltegravir or Tenofovir/Emtricitabine in Antiretroviral-Naive Subjects: 96-Week Results of the PROGRESS Study

Abstract

Alternative combinations of antiretrovirals (ARVs) are desired to increase treatment options for HIV-infected patients. PROGRESS was a randomized, open-label, 96-week pilot study comparing a regimen of lopinavir/ritonavir (LPV/r) 400/100 mg twice daily in combination with either raltegravir (RAL) 400 mg twice daily or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily in ARV-naive adults. A total of 206 subjects were randomized and treated (LPV/r+RAL, N=101; LPV/r+TDF/FTC, N=105). Demographics and baseline characteristics were similar across treatment groups. At 96 weeks, 66.3% of subjects receiving LPV/r+RAL and 68.6% of subjects receiving LPV/r+TDF/FTC were responders (plasma HIV-1 RNA levels<40 copies/ml) by the FDA time to loss of virologic response (FDA-TLOVR) algorithm (p=0.767). Mean CD4⁺ T cell increases through 96 weeks were similar between treatment groups (LPV/r+RAL=281 cells/mm³, LPV/r+TDF/FTC=296 cells/mm³, p=0.598). Safety and tolerability were generally similar between groups. The LPV/r+RAL regimen resulted in greater increases in peripheral fat, but not trunk fat, compared with LPV/r+TDF/FTC. There was a statistically significantly greater mean reduction in estimated glomerular filtration rate from baseline to week 96 in the LPV/r+TDF/FTC group compared with the LPV/r+RAL group (−7.33 ml/min vs. −1.43 ml/min; p=0.035). The LPV/r+TDF/FTC group had a statistically significant (p<0.001) mean percent decrease from baseline to week 96 in bone mineral density, which was significantly different from the mean percent change in the LPV/r+RAL group (–2.48% vs. +0.68%, p<0.001). These efficacy and safety observations support further evaluation of the LPV/r+RAL regimen.

Introduction

T he current recommended antiretroviral (ARV) treatment for patients infected with HIV-1 is a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a third agent from another class: protease inhibitor (PI), nonnucleoside reverse transcriptase inhibitor (NNRTI), C-C chemokine receptor type 5 (CCR5) inhibitor, or integrase strand transfer inhibitor (ISTI).¹ Such three-drug regimens have demonstrated antiviral efficacy, as defined by suppression of plasma HIV-1 RNA to <50 copies/ml; however, each has been associated with a different spectrum of adverse events. The study of alternative ARV combination regimens supports an individualized treatment approach.¹ A two-drug regimen consisting of lopinavir/ritonavir (LPV/r) in combination with raltegravir (RAL) may offer an alternative approach for treatment-naive, HIV-1-infected patients when a standard, three-drug regimen may not be ideal.

Lopinavir is an HIV-1 PI that is coformulated with LPV/r; when used in combination with other ARVs, LPV/r has demonstrated durable antiviral activity.^2

–5 RAL is an ISTI that is associated with a rapid reduction of HIV-1 viral load when coadministered with other ARVs.⁶ Both LPV/r and RAL are approved for use in ARV-naive and experienced patients in combination with other ARVs.^2,3,6 A regimen consisting solely of LPV/r+RAL offers two potent ARVs, each with demonstrated antiviral efficacy and durability, with the potential to reduce toxicity associated with the use of NRTIs.

PROGRESS was a pilot study comparing the safety and efficacy of a two-drug regimen (LPV/r+RAL) to that of a traditional three-drug regimen [i.e., LPV/r+two NRTIs (tenofovir/emtricitabine; TDF/FTC)] in ARV-naive, adult HIV-1-infected subjects. The design and primary outcome––the proportion of subjects responding with plasma HIV-1 RNA levels<40 copies/ml after 48 weeks of treatment based on the FDA-TLOVR algorithm—have previously been reported.⁷ At 48 weeks, the efficacy of LPV/r+RAL was determined not to be inferior to that of LPV/r+TDF/FTC⁷: 83.2% in the LPV/r+RAL group and 84.8% in the LPV/r+TDF/FTC group were responders by the FDA time to loss of virologic response (FDA-TLOVR) algorithm (p=0.850, difference −1.6%, 95% exact confidence interval −12.0% to 8.8%).⁷ In addition, LPV/r+RAL also had safety, tolerability, and comparable emergence of resistance similar to LPV/r+TDF/FTC through 48 weeks of treatment.

Given the chronic nature of HIV-1 infection and the need for long-term treatment, this study was designed to continue through 96 weeks of follow-up. The secondary objectives were intended to capture and describe longer term similarities and differences between LPV/r+RAL vs. LPV/r+TFD/FTC in durability of antiviral activity, safety, tolerability, and resistance. Additional planned secondary analyses were also conducted at 96 weeks: renal function, insulin resistance, bone mineral density, and fat distribution.

Materials and Methods

Study design

Subjects in the PROGRESS study were randomized in a 1:1 ratio to either LPV/r 400/100 mg BID plus RAL 400 mg BID or LPV/r 400/100 mg BID plus a fixed dose combination of TDF/FTC 300/200 mg QD.⁷ All subjects were 18 years or older, ARV-naive, and had plasma HIV-1 RNA concentrations ≥1,000 copies/ml at screening; there was no CD4⁺ T cell count restriction. Subjects with resistance to LPV, TDF, or FTC at screening were ineligible for enrollment. RAL resistance testing was not performed at baseline; however, baseline samples were archived for RAL resistance testing in the case of virologic failure.

Statistical methods

Statistical analyses were conducted using SAS, Version 9.1 (Cary, NC). All statistical tests were two-tailed and performed at the 0.05 level of significance. All subjects who were randomized and received at least one dose of the study drug were included in the analyses with two exceptions: (1) for the observed data analysis of plasma HIV-1 RNA levels, subjects with missing data were excluded; (2) for analyses of changes from baseline, only subjects who had both a baseline value and the specific postbaseline value were included.

Virologic efficacy

Virologic efficacy was evaluated as the proportion of subjects with plasma HIV-1 RNA below the limit of quantification (40 copies/ml) using the FDA-TLOVR algorithm, in which time of failure was defined as the earliest of any of the following events: death, permanent discontinuation of the study drug, loss to follow-up, or plasma HIV-1 RNA concentrations ≥40 copies/ml obtained at two consecutive visits or one value ≥40 copies/ml followed by permanent discontinuation of the study drug or loss to follow-up.

Virologic efficacy was evaluated further with five additional (sensitivity) analyses: the FDA snapshot algorithm, in which a subject was considered a responder only if the subject had HIV-1 RNA<40 copies/ml during the visit window (subjects with multiple HIV-1 RNA values in a visit window were categorized according to the last available measurement in the visit window); observed data (OD) in which missing data were not imputed based on other assessments (e.g., death, permanent discontinuation of study drug); noncompleter=failure (NC=F), in which subjects with missing data were considered failures unless values from the visits directly before and after the missing data were <40 copies/ml; missing=failure (M=F), in which a subject with a missing HIV-1 RNA value at a visit for any reason was considered a failure at that visit (subjects with multiple HIV-1 RNA values in a visit window were categorized according to the value closest to the nominal visit day); and last observation carried forward (LOCF), in which missing values were replaced by the preceding nonmissing value. Treatment group differences at each visit were evaluated using Fisher's exact test.

Detectable viremia after reaching plasma HIV-1 RNA<40 copies/ml

Subjects were categorized based on detectable plasma HIV-1 RNA values after achieving plasma HIV-1 RNA<40 copies/ml:

• all plasma HIV-1 RNA values<40 copies/ml

• only one plasma HIV-1 RNA value≥40 copies/ml (subset of this group: only one detectable plasma HIV-1 RNA value≥40 copies/ml but <200 copies/ml)

• more than one plasma HIV-1 RNA value≥40 copies/ml (subset of this group: all detectable plasma HIV-1 RNA values≥40 copies/ml but <200 copies/ml)

Resistance

Resistance mutations were as specified in the IAS-USA panel.⁸ Screening and baseline and on-treatment genotypic resistance testing for LPV/r, TDF, and FTC were performed using ViroSeq HIV-1 (ViroSeq HIV-1 Genotyping System v2.0; Celera, Alameda, CA) and resistance testing for RAL was performed using GeneSeq HIV (Monogram Biosciences, San Francisco, CA). Reverse transcriptase (RT), protease (PR), and integrase (IN) genotyping using population-based sequencing techniques was performed at multiple time points on stored plasma HIV-1 RNA samples from subjects who met the following protocol-defined criteria for resistance testing: (1) Beginning at week 8, if the subject's plasma HIV-1 RNA level was ≥40 copies/ml and at the previous visit the plasma HIV-1 RNA was <40 copies/ml, confirmatory plasma HIV-1 RNA and a sample for HIV-1 drug resistance genotyping were collected within 4 weeks. If the rebound was confirmed by an HIV-1 RNA level >400 copies/ml, genotypic resistance testing was performed on the sample collected for confirmation. (2) For subjects with plasma HIV-1 RNA increased >0.5 log₁₀ (∼3-fold) above the study nadir and >400 copies/ml on two consecutive measurements, genotypic resistance testing was performed on the second consecutive sample. (3) For subjects who failed to achieve plasma HIV-1 RNA<400 copies/ml by week 24, genotypic resistance testing was performed on the sample collected at week 24. Post hoc phylogenetic analysis of the PR/RT (ViroSeq) and IN sequences (using PHYLIP Software v3.5c; J. Felsenstein, University of Washington, Seattle, WA) was performed on one subject with both LPV/r and RAL resistance-associated mutations.

Immunologic efficacy, safety, and tolerability

The mean change from baseline in CD4⁺ T cell counts at each visit was compared between treatment groups using one-way ANOVA. Study discontinuation and baseline characteristics were compared between groups using one-way ANOVA for continuous variables and Fisher's exact test for categorical variables.

The proportion of subjects reporting study drug-related adverse events of at least moderate severity was compared between groups using Fisher's exact test. Proportions of subjects with Grade 3+ laboratory values were also compared between groups using Fisher's exact test.

The mean changes from baseline to week 96 in lipid and renal parameters, homeostatic model assessment-insulin resistance (HOMA-IR), and 10-year Framingham cardiovascular (CV) risk scores [performed post hoc and based on low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC), and including the effect of the 2-year increase in age for each subject] were compared between groups using one-way ANOVA. Proportions of subjects taking concomitant antidiarrheal medication and lipid-lowering agents were compared between groups using Fisher's exact test. Glomerular filtration rate (GFR) was estimated using calculated creatinine clearance (Cockroft–Gault equation).

Dual-energy X-ray absorptiometry (DXA) scans

Full body DXA scans were performed at baseline, week 48, and week 96. The DXA scans were submitted to a central reader, who was blinded to subject treatment. Evaluations of the DXA scan included upper and lower extremity fat, trunk fat, and total bone mineral density. Changes from baseline to week 96 were analyzed using one-way ANOVA. The proportions of subjects with a >10%, >20%, and >30% decrease from baseline in limb fat at week 96 were compared between treatment groups using Fisher's exact test.

Results

Subject disposition and baseline demographics

A total of 206 subjects were randomized and dosed: 101 in the LPV/r+RAL group and 105 in the LPV/r+TDF/FTC group as shown in Fig. 1. Through 96 weeks, 18.8% of LPV/r+RAL subjects and 14.3% of LPV/r+TDF/FTC subjects discontinued treatment. The most common reason for discontinuation overall was loss to follow-up (5.8%). Of note, there were no statistically significant between-group differences in the reasons for discontinuation in this open-label study. Demographic and baseline characteristics were similar between groups.⁷ The mean age of subjects was 39.6±10.6 years; 84.5% were male and 75.2% were white. At baseline, 16.5% of the subjects had plasma HIV-1 RNA≥100,000 copies/ml and 26.2% of subjects had CD4⁺ T cell counts<200 cells/mm³.

FIG. 1.

Subject disposition through week 96.

Virologic efficacy, immunologic efficacy, rebound viremia, and resistance

Figure 2A shows the proportion of subjects with plasma HIV-1 RNA<40 copies/ml using both the FDA-TLOVR and OD analyses by treatment group and Table 1 shows the week 96 results by the FDA Snapshot, NC=F, M=F and by LOCF analyses. At week 96, the proportion of responders in the LPV/r+RAL group was similar to the LPV/r+TDF group regardless of the analysis method used to evaluate antiviral efficacy. Using the FDA-TLOVR analysis 66.3% of LPV/r+RAL subjects and 68.6% of LPV/r+TDF/FTC subjects were responders, and using the OD analysis 88.9% of LPV/r+RAL subjects and 85.2% of LPV/r+TDF/FTC subjects were responders. The between-group differences [(LPV/r+RAL) – (LPV/r+TDF/FTC)] using the FDA-TLOVR and OD analyses were −2.2% and +3.7%, respectively. The proportion of responders by FDA-TLOVR and OD analyses was also analyzed after stratification by baseline plasma HIV-1 RNA level (Fig. 2B). In subjects with baseline plasma HIV-1 RNA≥100,000 copies/ml, the LPV/r+RAL and LPV/r+TDF/FTC groups had comparable proportions of responders, though there were low numbers of subjects available for this analysis. The mean change in CD4⁺ T cell counts from baseline to week 96 was similar between treatment groups (Fig. 2C). The proportion of responders by FDA-TLOVR and OD analyses after stratification by baseline CD4⁺ T cell counts (<200 and ≥200 cells/mm³) is shown in Fig. 2D. There was comparable efficacy between treatment groups with baseline CD4⁺ T cell counts <200 cells/mm³ by the FDA-TLOVR analysis (p=0.584) and the OD analysis (p=0.681). There was also comparable efficacy between treatment groups with baseline CD4⁺ T cell counts≥200 cells/mm³ by the FDA-TLOVR analysis (p>0.999) and the OD analysis (p=0.790).

FIG. 2.

Virologic efficacy through week 96. (A) Proportion of subjects with plasma HIV-1 RNA<40 copies/ml, FDA time to loss of virologic response (FDA-TLOVR), and observed data (OD) analyses. (B) Proportion of subjects with plasma HIV-1 RNA<40 copies/ml at 96 weeks, FDA-TLOVR, and OD analyses stratified by baseline plasma HIV-1 RNA level. (C) Mean CD4⁺ T cell counts (cells/mm³) through 96 weeks of treatment. (D) Proportion of subjects with plasma HIV-1 RNA<40 copies/ml at 96 weeks, FDA-TLOVR, and OD analyses stratified by baseline CD4⁺ T cell count level.

Table 1.

Proportion of Subjects with Less Than 40 Copies of HIV-1 RNA/ml at 96 Weeks Using Different Analyses

	LPV/r+RAL N=101	LPV/r+TDF/FTC N=105	p-value
FDA TLOVR, n/N (%)	67/101 (66.3%)	72/105 (68.6%)	0.767
Snapshot	72/101 (71.3%)	75/105 (71.4%)	>0.999
NC=F	72/101 (71.3%)	75/105 (71.4%)	>0.999
M=F	72/101 (71.3%)	75/105 (71.4%)	>0.999
LOCF	82/101 (81.2%)	85/105 (81.0%)	>0.999
OD	72/ 81 (88.9%)	75/ 88 (85.2%)	0.503

LPV/r, lopinavir/ritonavir; RAL, raltegravir; TDF/FTC, tenofovir/emtricitabine; FDA-TLOVR, FDA time to loss of virologic response; Snapshot, FDA snapshot; NC=F, noncompleter=failure; M=F, missing=failure; LOCF, last observation carried forward; OD, observed data.

Supplementary Table S1 (Supplementary Data are available online at www.liebertpub.com/aid) describes the disposition for each subject with a baseline plasma HIV-1 RNA≥100,000 copies/ml. Nearly half of the subjects with high baseline HIV-1 RNA completed the study (LPV/r+RAL=6/15, LPV/r+TDF/FTC=10/19). Subject dispositions are classified as one of the following: responder, nonresponder (viral rebound), never suppressed, or other (reason for premature discontinuation shown). Additional analyses were performed to investigate the proportions of subjects with detectable viremia in the two groups of the study. A summary of subjects with detectable plasma HIV-1 RNA level after reaching HIV-1 RNA<40 copies/ml is shown in Table 2. The proportions of subjects within each category of detectable viremia were comparable between the treatment groups.

Table 2.

Summary of Subjects with Detectable Plasma HIV-1 RNA Levels After Reaching a Plasma HIV-1 RNA<40 Copies/ml

Proportion of subjects with	LPV/r+RAL N=101 ^a n (%)	LPV/r+TDF/FTC N=105 ^a n (%)
All plasma HIV-1 RNA<40 copies/ml after reaching <40 copies/ml	63 (62.4)	70 (66.7)
One plasma HIV-1 RNA≥40 copies/ml after reaching <40 copies/ml	12 (11.9)	12 (11.4)
One plasma HIV-1 RNA≥40 but <200 copies/ml after reaching <40 copies/ml	9 (8.9)	12 (11.4)
More than one plasma HIV-1 RNA≥40 copies/ml after reaching <40 copies/ml	23 (22.8)	18 (17.1)
More than one plasma HIV-1 RNA≥40 but all <200 copies/ml after reaching <40 copies/ml	11 (10.9)	13 (12.4)

Eight subjects (three LPV/r+RAL and five LPV/r+TDF/FTC) did not have a postbaseline value <40 copies/ml.

A total of 13 subjects (eight LPV/r+RAL and five LPV/r+TDF/FTC) met the protocol-defined criteria for virologic failure. The baseline plasma HIV-1 RNA levels and resistance mutations identified for these subjects are shown in Table 3. Ten of the subjects had baseline HIV-1 RNA<100,000 copies/ml, while three subjects had baseline HIV-1 RNA≥100,000 copies/ml. In the LPV/r+RAL group, an integrase resistance-associated mutation (RAM) was detected in three/eight subjects (two subjects by week 48 and one subject by week 96). One of the subjects with an integrase RAM also had protease RAMs detected (at week 96: integrase N155H, protease V32I, M46I, I47V). Post hoc, longitudinal resistance analysis in this subject revealed that there were no detectable RAMs at baseline, but RAL RAMs were detected first at week 16, followed by LPV/r RAMs at week 72. Post hoc phylogenetic analysis of the PR/RT and IN sequences showed no evidence of multiple HIV-1 strains in this subject. This was the only subject for whom new LPV/r RAMs were detected postbaseline. The two subjects with only detectable integrase RAMs at the time of virologic failure both had protease, but not integrase RAMs detectable at baseline. In the subject who failed at week 48, the L63P protease RAM was detectable at both baseline and week 48. In the subject who failed at week 96, the L63P and M36I protease RAMs were detectable at baseline, though only the M36I RAM was detectable at week 96. A reverse transcriptase (FTC) RAM, M184V, was detected in one/five subjects in the LPV/r+TDF/FTC treatment group at week 40, and this subject did not have PI or RT RAMs at baseline (integrase RAMs were not assessed). No new LPV/r RAMs were detected in the LPV/r+TDF/FTC group.

Table 3.

Baseline Plasma HIV-1 RNA Levels for Subjects Who Had Protocol-Defined Genotype Testing and Resistance Mutations Occurring Through Week 96

	LPV/r+RAL		LPV/r+TDF/FTC
	BL plasma HIV-1 RNA (copies/ml)	Resistance mutations	BL plasma HIV-1 RNA (copies/ml)	Resistance mutations
1	5,350	No resistance detected	14,626	No resistance detected
2	15,758	No resistance detected	25,903	No resistance detected
3	18,069	No resistance detected	37,337	No resistance detected
4	20,821	IN: N155/H, G163/R (day 337)	312,069	RT: M184V (day 281)
5	28,449	No resistance detected	695,767	No resistance detected
6	37,920	IN: N155H, T97A (day 112) D232N (day 588)
		Pr: M46I (day 504), V32I, I47V (day 672)
7	70,618	No resistance detected
8	158,467	IN: G140/S, Q148/H (day 458)

BL, baseline; IN, integrase; Pr, protease; RT, reverse transcriptase.

Adverse events and laboratory abnormalities

Similar proportions of subjects in the two treatment groups reported drug-related adverse events of moderate or greater severity during the 96-week study (Table 4). The most common treatment-related adverse event of at least moderate severity was diarrhea (LPV/r+RAL=7.9%, LPV/r+TDF/FTC=16.2%, p=0.088). A total of nine subjects [LPV/r+RAL=5/101 (5.0%); LPV/r+TDF/FTC=4/105 (3.8%)] discontinued study drug due to a treatment-emergent adverse event through 96 weeks. Through 96 weeks, four subjects [LPV/r+RAL=2/101 (2.0%) and LPV/r+TDF/FTC=2/105 (1.9%)] discontinued treatment due to diarrhea. Of note, similar proportions of subjects in each treatment group were reported to have been prescribed or to have taken at least one dose of antidiarrheal medication during the 96-week study (LPV/r+RAL=26.7%, LPV/r+TDF/FTC=28.6%).

Table 4.

Adverse Events and Grade 3 or 4 Laboratory Abnormalities Occurring in ≥2.0% of Subjects in Either Treatment Group

	LPV/r+RAL N=101 n (%)	LPV/r+TDF/FTC N=105 n (%)
Any adverse event	31 (30.7)	36 (34.3)
Diarrhea	8 (7.9)	17 (16.2)
Asthenia	0	3 (2.9)
Regurgitation	0	3 (2.9)

Laboratory test values	LPV/r+RAL N=101	LPV/r+TDF/FTC N=104
Creatine phosphokinase (>4×ULN)^a	20 (19.8)	9 (8.7)
Creatine phosphokinase (>10×ULN)^a	10 (9.9)	3 (2.9)
Cholesterol (>7.77 mmol/liter)	17 (16.8)	14 (13.5)
Triglycerides (>8.475 mmol/liter)	10 (9.9)	5 (4.8)
Lipase (>2×ULN)	4 (4.0)	8 (7.7)
SGPT/ALT(>5×ULN)	5 (5.0)	3 (2.9)
SGOT/AST (>5×ULN)	5 (5.0)	3 (2.9)
eGFR (<50 ml/min)^b	1 (1.0)	4 (3.8)
Neutrophils (<0.75×10⁹/liter)	0	4 (3.8)
Calcium (<1.75 mmol/liter)	2 (2.0)	0
Magnesium (<0.5 mmol/liter)	2 (2.0)	0

Adverse events are nonlaboratory related, moderate, or severe and possibly or probably treatment related.

p<0.05 for LPV/r+RAL vs. LPV/r+TDF/FTC comparison based on Fisher's exact test.

Calculated using Cockcroft–Gault formula.

SGPT, serum glutamic-pyruvic transaminase; ALT, alanine aminotransferase; ULN, upper limit of normal; SGOT, serum glutamic-oxaloacetic transaminase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate.

The most common Grade 3 or 4 laboratory abnormality was elevation in total cholesterol (LPV/r+RAL=16.8%, LPV/r+TDF/FTC=13.5%; p=0.561). Hypertriglyceridemia combined with hypercholesterolemia resulted in one study drug discontinuation in the LPV/r+RAL group. A comparison of the effect of each regimen on lipid levels and lipid ratios is shown in Table 5. At week 96, there were no significant differences in mean changes from baseline in lipid levels or lipid ratios between the regimens. The mean change from baseline in 10-year CV risk levels was similar between groups. Similar proportions of subjects in each treatment group were reported to have been prescribed or to have taken at least one dose of lipid-lowering medication during the 96-week study (LPV/r+RAL=23.8%, LPV/r+TDF/FTC=25.7%). Elevations in creatine phosphokinase (CPK) occurred more frequently in subjects taking LPV/r+RAL. Of note, an adverse event of rhabdomyolysis of moderate severity was reported for one subject in the LPV/r+RAL group with concurrent grade 3+CPK elevations, which returned to normal levels after a peak level of 29,320 U/liter. This subject did not experience hematuria, renal failure, or muscle pain symptoms. No clinical action was taken for this event, the study drug was not interrupted, and the subject continued participation in the study.

Table 5.

Mean Change from Baseline to Week 96 in Lipid Parameters and Cardiovascular Risk

Variable	LPV/r+RAL N=82	LPV/r+TDF/FTC N=90
LDL:HDL ratio
Baseline	2.64	2.57
Mean change to week 96	−0.04	−0.06
TC:HDL ratio
Baseline	4.51	4.35
Mean change to week 96	−0.21	−0.14
HDL mmol/liter (mg/dl)
Baseline	0.99 (38)	1.07 (41)
Mean change to week 96	+0.35 (+13)	+0.26 (+10)
LDL mmol/liter (mg/dl)
Baseline	2.53 (98)	2.61 (101)
Mean change to week 96	+0.72 (+28)	+0.54 (+21)
Total cholesterol mmol/liter (mg/dl)
Baseline	4.25 (164)	4.40 (170)
Mean change to week 96	+1.11 (+43)	+0.81 (+31)
Triglycerides mmol/liter (mg/dl)
Baseline	1.43 (126)	1.40 (124)
Mean change to week 96	+1.10 (+98)	+0.85 (+75)
CV risk using LDL-C^a (%)
Baseline	6.18	4.91
Mean change to week 96	+0.15	+0.30
CV risk using TC (%)
Baseline	6.35	5.02
Mean change to week 96	+0.60	+0.87

Ten-year Framingham cardiovascular risk scores were based on LDL-C and TC and included the effect of the 2-year increase in age for each subject.

p>0.05 for all comparisons between treatment groups in mean change using one-way ANOVA.

TC, total cholesterol; HDL, high-density lipoprotein (cholesterol); LDL, low-density lipoprotein (cholesterol); CV, cardiovascular.

The impact of the two regimens on insulin resistance was compared. There were no statistically significant difference in mean change from baseline to week 96 in fasting blood glucose (LPV/r+RAL=+ 0.11 mmol/liter, LPV/r+TDF/FTC=–0.01 mmol/liter; p=0.408), total insulin (LPV/r+RAL=+4.44 pmol/liter, LPV/r+TDF/FTC=–6.72 pmol/liter; p=0.236), or HOMA-IR (LPV/r+RAL=+0.198, LPV/r+TDF/FTC=–0.195; p=0.246). Of note, one subject in each treatment group reported hyperglycemia or new onset diabetes mellitus that was reported as possibly/probably related to the study drug.

Renal function was also analyzed in both groups. Baseline mean serum creatinine (LPV/r+RAL=80.1 μmol/liter, LPV/r+TDF/FTC=78.7 μmol/liter, p=0.525) levels were similar between groups. The mean change from baseline to week 96 in serum creatinine was statistically significantly greater in the LPV/r+TDF/FTC group compared with the LPV/r+RAL group (+5.7 μmol/liter vs. +1.6 μmol/liter; p=0.032). Mean estimated GRF (eGFR; estimated by the Cockroft–Gault equation: LPV/r+RAL=124.01 ml/min, LPV/r+TDF/FTC=118.03 ml/min, p=0.278) was also similar at baseline for the two groups.

There was a statistically significantly greater mean reduction in eGFR from baseline to week 96 in the LPV/r+TDF/FTC group compared with the LPV/r+RAL group (–7.33 ml/min vs. −1.43 ml/min; p=0.035). The proportion of subjects with shifts from baseline to week 48 and 96 in the eGFR category (categories defined as ≥90, 60 to <90, and <60 ml/min) is shown in Table 6. A statistically significantly greater proportion of LPV/r+RAL subjects demonstrated improvements in eGFR of at least one category at weeks 48 and 96. Of note, one subject (1.0%) in the LPV/r+RAL treatment group experienced renal failure reported as possibly treatment related. One subject (1.0%) in the LPV/r+TDF/FTC treatment group experienced acute renal failure reported as not related to the study treatment.

Table 6.

Proportion of Subjects with Shifts from Baseline in Estimated Glamerular Filtration Rate (ml/min)

	Week 48, n (%)			Week 96, n (%)
	LPV/r+RAL	LPV/r+TDF/FTC	p-value ^a	LPV/r+RAL	LPV/r+TDF/FTC	p-value ^a
eGFR shifted from BL to worse category	5/96 (5.2)	12/96 (12.5)	0.125	5/81 (6.2)	14/89 (15.7)	0.055
eGFR≥60 at BL and worsened to <60	1/96 (1.0)	0/96	>0.999	0/81	1/89 (1.1)	>0.999
eGFR shifted from BL to better category	11/16 (68.8)	5/17 (29.4)	0.038	9/14 (64.3)	2/15 (13.3)	0.008
eGFR<90 at BL and improved to ≥90	10/16 (62.5)	4/17 (23.5)	0.037	8/14 (57.1)	2/15 (13.3)	0.021

p-value for comparison between treatment groups based on Fisher's exact test.

Categories were defined as ≥90, 60 to <90, and <60 ml/min.

eGFR was calculated using Cockcroft–Gault formula.

DXA analyses were utilized to compare the changes in body fat and bone mineral density between the regimens. At baseline, fat in the arms, legs, and trunk, and bone mineral density were similar between groups. Subjects taking LPV/r+RAL through 96 weeks had statistically significantly larger mean percent increases in fat in the arms and legs, but not in the trunk, compared with subjects taking LPV/r+TDF/FTC (Table 7). The proportions of subjects with limb fat loss >10%, >20%, and >30% at week 96 were similar between groups (>10%: LPV/r+RAL=19.2%, LPV/r+TDF/FTC=14.6%, p=0.528;>20%: LPV/r+RAL=9.0%, LPV/r+TDF/FTC=6.1%, p=0.558;>30%, LPV/r+RAL=2.6%, LPV/r+TDF/FTC=3.7%, p>0.999). No statistically significant between-group differences were observed in mean percent changes from baseline to week 96 for anthropometric measurements of the chest, hips, waist, mid-thigh, or mid-arm. Of note, one subject in the LPV/r+TDF/FTC group experienced lipodystrophy of moderate severity that was reported as possibly treatment related.

Table 7.

Analyses of Body Fat and Bone Mineral Density Changes from Baseline

	LPV/r+RAL			LPV/r+TDF/FTC
	N=78			N=82
	BL	Mean % change from BL to week 96	Within group p-value	BL	Mean % change from BL to week 96	Within group p-value	Between group p-value
Fat index
Arms (g)	1537	+21.5	<0.001	1756	+7.3	0.131	0.040
Legs (g)	5455	+28.8	<0.001	6251	+15.3	0.001	0.041
Trunk (g)	9257	+27.0	<0.001	9694	+13.8	0.022	0.121
Bone index
Total BMD (g/cm²)	1.18	+0.68	0.158	1.19	−2.48	<0.001	<0.001

p-values based on one-way ANOVA.

BMD, bone mineral density.

For subjects who had baseline and week 96 total bone mineral density measurements, the mean baseline total bone mineral density was similar between treatment groups (LPV/r+RAL=1.18 g/cm², LPV/r+TDF/FTC=1.19 g/cm², p=0.762). The LPV/r+TDF/FTC group had a statistically significant mean percent decrease from baseline to week 96 (–2.48%, p<0.001). In contrast, the mean percent change from baseline for the LPV/r+RAL group was not statistically significant (+0.68%, p=0.158). The mean percent decrease from baseline in total bone mineral density for the LPV/r+TDF/FTC group was statistically significantly greater compared to the mean percent change of the LPV/r+RAL group (p<0.001). There were four bone fractures (LPV/r+RAL: hand, LPV/r+TDF/FTC: foot, upper limb, wrist), none of which was reported to be related to the study treatment.

Two subjects in the LPV/r+RAL group died during the study or within the 30-day follow-up after the last study drug dose. Neither death was considered to be related to the study drug: a 58-year-old white male in the LPV/r+RAL group experienced a series of adverse events unrelated to the study treatment, which culminated in sepsis attributed to Klebsiella infection and death; and a 43-year-old white male in the LPV/r+RAL group died of a subarachnoid hemorrhage attributed to viral encephalitis.

Discussion

PROGRESS was a pilot study comparing the safety and efficacy of a two-drug regimen (LPV/r+RAL) to that of a traditional three-drug regimen (i.e., LPV/r+TDF/FTC) in ARV-naive, HIV-1-infected subjects. After demonstrating that LPV/r+RAL had similar efficacy compared with LPV/r+TDF/FTC at week 48, an important question was whether the LPV/r+RAL regimen would also demonstrate durability through week 96. The PROGRESS study showed that the LPV/r+RAL regimen had antiviral efficacy and immunologic recovery comparable to LPV/r+TDF/FTC through 96 weeks (Fig. 2A and C). Overall, tolerability and safety were comparable between the two regimens through week 96. The efficacy results of both regimens observed in PROGRESS were comparable to previous studies of LPV/r+two NRTIs or RAL+two NRTIs through 96 weeks of treatment.^9,10

In considering individual patient traits, current treatment guidelines state that there may be some circumstances in which an alternative regimen may actually be a preferred regimen for a patient.¹ A key reason to investigate a PI+RAL treatment strategy is to determine whether these regimens might result in fewer or a different profile of adverse events while maintaining similar efficacy when compared to more traditional three-drug regimens. A comparison maintaining LPV/r as the anchor PI also allows for a direct assessment of the impact of replacing a two NRTI backbone with an ISTI. PROGRESS was designed in 2007, at which time LPV/r+TDF/FTC was a preferred regimen in the U.S. Department of Health and Human Services HIV guidelines and LPV/r+TDF/FTC remains a preferred regimen in the EACS HIV guidelines. Safety and tolerability were comparable between the two regimens through week 96 in PROGRESS. Gastrointestinal disorders were the most frequently reported study drug-related adverse events of at least moderate severity, particularly diarrhea and nausea. Moderate or severe treatment-related diarrhea was reported more frequently during the 96-week study for subjects in the LPV/r+TDF/FTC treatment group compared with the LPV/r+RAL treatment group, but the difference was not statistically significant. No statistically significant differences between treatment groups in mean changes from baseline to week 96 were observed for any lipid parameter.

However, renal function as estimated by changes from baseline in eGFR showed a greater mean decrease for the LPV/r+TDF/FTC group versus the LPV/r+RAL group. This finding may provide a rationale for the use of a TDF-sparing ART approach given the recent findings from the EuroSIDA Study Group. This cohort study of 6,843 HIV-infected persons with a median follow-up duration of 3.7 years demonstrated that 3.3% of the cohort progressed to chronic kidney disease (CKD) during 21,482 person-years follow-up resulting in an incidence of 1.05 per 100 person-years follow-up. After adjusting for traditional factors associated with CKD and confounding factors, increasing cumulative exposure to tenofovir with an incidence rate ratio (IRR) per year of 1.16 (95% CI: 1.06–1.25, p<0.0001) was associated with a significantly increased rate of CKD.¹¹ The improvement of renal function in subjects on the LPV/r+RAL regimen in PROGRESS could be related to the absence of tenofovir in that arm, even when LPV/r itself may be associated with a worsening of renal function itself.¹¹

Lipoatrophy is also a concern for patients taking ARVs.¹² In PROGRESS, both regimens were associated with a restoration of peripheral body fat, though the LPV/r+RAL treatment group exhibited statistically significantly greater mean percent increases in upper extremity fat and lower extremity fat compared with those observed in the LPV/r+TDF/FTC treatment group. The proportion of subjects with >10%, >20%, or >30% peripheral fat loss did not differ between groups. Previous analysis of RAL+TDF/FTC also showed an increase in trunk fat and appendicular fat at week 96 (21.6% increase and 17.0% increase, respectively).¹⁰ LPV/r+TDF/FTC has also been shown to increase trunk fat and limb fat at week 96 (16% increase and 15% increase, respectively).¹³

Results from the HIV Outpatient Study indicate that the rate of bone fracture is significantly higher in HIV-infected patients compared with the general population.¹⁴ TDF along with other ARVs and HIV infection itself have been associated with reduced bone mineral density (BMD).^15
–17 The reduction of BMD has the potential to be clinically relevant in light of recent studies that have shown an increased rate of osteoporosis, a risk factor for bone fractures, associated with ARV treatment.^14,18 In PROGRESS, the LPV/r+RAL group demonstrated mean BMD at 96 weeks that was essentially unchanged from baseline, while the LPV/r+TDF/FTC group showed a mean reduction of BMD similar in magnitude to the reduction previously observed in ARV-naive subjects taking a three-drug ARV regimen including TDF.¹⁶

Recent studies investigating PI+RAL regimens identified potential shortcomings associated with this treatment approach.^19,20 The ACTG 5262 study was a single-arm, multicenter pilot study of 112 HIV-1-infected, ARV-naive subjects receiving a novel regimen of darunavir (800 mg QD) plus ritonavir (100 mg QD) plus RAL (400 mg BID) for 52 weeks.²⁰ The cumulative week 24 and week 48 proportions of virologic failure were 16% (95% CI: 10%, 24%) and 26% (95% CI: 19%, 36%). After adjusting for age and sex, virologic failure was associated with higher (>100,000 vs. ≤100,000 copies/ml) plasma HIV-1 RNA at baseline (hazard ratio, HR: 3.76, 95% CI: 1.52, 9.31, p=0.004) and lower CD4⁺ T cell count at baseline (HR: 0.77 per 100 cells/mm³ increase, 95% CI: 0.61, 0.98, p=0.037). Five subjects out of 28 that met protocol-defined criteria for resistance testing were found to have integrase RAMs at virologic failure and all five of these subjects had a baseline plasma HIV-1 RNA>100,000 copies/ml.²⁰

The SPARTAN study was a randomized (2:1), controlled, multicenter, pilot study of 94 HIV-infected, ARV-naive subjects who received either an experimental atazanavir dose of 300 mg BID plus RAL (400 mg BID) or atazanavir (300 mg QD) plus ritonavir (100 mg QD) plus TDF/FTC (300/200 mg QD) for 24 weeks.¹⁹ Of the 11 subjects who experienced virologic failure in the ATV+RAL group, eight (72%) had baseline plasma HIV-1 RNA>250,000 copies/ml. Of the six subjects who qualified for protocol-defined resistance testing, RAL genotypic or phenotypic resistance, but not ATV resistance, was found in five/six (83.3%) subjects.¹⁹ A total of 38/63 (60.3%) subjects in the ATV+RAL group experienced grade 3–4 total bilirubin abnormalities and 13/63 (20.6%) in the ATV+RAL group experienced grade 4 total bilirubin abnormalities through 24 weeks of treatment.¹⁹

The emergence of resistance during treatment with a PI+ISTI is an important topic that should be studied further. A retrospective study of 39 treatment-experienced subjects suggested that the number of preexisting PI RAMs at baseline and the adherence to a PI+ISTI regimen predicted virologic failure.²¹ The presence of baseline RAMs and the adherence to drug regimen are known to predict virologic failure with traditional three-drug regimens.^22,23 Further study is needed to understand the relationship between baseline RAMs and adherence with virologic failure in PI+ISTI regimens when compared with three-drug regimens.

The findings in the PROGRESS study are limited by the size of the study. The study was designed to determine whether larger studies of an LPV/r+RAL treatment regimen would be justified and to limit the potential risk for subjects (i.e., resistance) if the investigational regimen demonstrated less robust antiviral activity than anticipated. PROGRESS also was not designed to specifically address the impact of baseline plasma HIV-1 RNA on response and emergence of resistance. Thus, the finding that subjects in the PROGRESS study with high baseline levels of plasma HIV-1 RNA who initiated treatment with LPV/r+RAL were not at higher risk for the emergence of resistance mutations compared with subjects who initiated treatment with LPV/r+TDF/FTC should be confirmed through studies enrolling more subjects with high baseline viral load. While HIV-1 RNA from all 13 subjects with virologic failure was analyzed for resistance mutations, five subjects who tested negative for resistance had plasma HIV levels below the 2000 copies/ml lower limit of analysis for the resistance assays. Moreover, the study was not powered to detect differences in infrequent adverse events. CT scanning, a more informative method for the determination of visceral fat accumulation, and site-specific DXA measurement, a more informative method for spine and total bone mineral density, were not used.

In conclusion, there is a continuing need to evaluate alternative ARV regimens in ARV-naive patients for whom NRTI-containing regimens may not be optimal. The PROGRESS study showed that the LPV/r+RAL regimen has safety, tolerability, and efficacy comparable to LPV/r+TDF/FTC. Additionally, the LPV/r+RAL regimen provided potentially clinically relevant benefits compared with LPV/r+TDF/FTC through 96 weeks: LPV/r+RAL had less impact on bone mineral density, restored more peripheral body fat compared with LPV/r+TDF/FTC, and was not associated with a decline in renal function. Thus, the results of this study support the further evaluation of the LPV/r+RAL regimen, particularly in patients at risk for long-term adverse events associated with NRTI-containing regimens.

Footnotes

Acknowledgments

The authors would like to thank all participating investigators: United States: Dr. Laveeza Bhatti, Dr. Larry M. Bush, Dr. Frederick A. Cruickshank, Dr. Edwin DeJesus, Dr. Robin H. Dretler, Dr. Joseph Gathe, Dr. Cynthia A. Mayer, Dr. Lewis McCurdy, Dr. Ighovwerha Ofotokun, Dr. Gerald Pierone, Jr., Dr. Moti Ramgopal, Dr. Louis M. Sloan, Dr. Lawrence F. Waldman. Poland: Dr. Brygida Knysz. Canada: Dr. Jonathan B. Angel, Dr. François Laplante, Dr. Mona Loutfy, Dr. Anita Rachilis. France: Dr. Laurent Cotte, Dr. Pierre-Marie Girard, Dr. Jacques Reynes, Dr. Dominique Salmon-Ceron. Puerto Rico: Dr. Ivan Melendez-Rivera, Dr. Ruth Soto-Malave. Italy: Dr. Franco Baldelli, Dr. Antonio Di Biagio, Dr. Fiorella Di Sora, Dr. Adriano Lazzarin, Dr. Claudio Viscoli. Spain: Dr. Jose R. Arribas, Dr. Bonaventura Clotet, Dr. Pere Domingo, Dr. Daniel Podzamczer, Dr. Federico Pulido, Dr. Jesús Sanz, Dr. Pompeyo Viciana.

The design, study conduct, and financial support of the PROGRESS study were provided by Abbott. The authors acknowledge the Abbott clinical team of Mary Woulfe, Sara Gibbs, Christian Naylor, and Christal Marincic. The authors also acknowledge Sarah Kopecky-Bromberg (Abbott) for assistance in writing and editing the article. Merck provided the raltegravir. Clinical Trial Registration: ClinicalTrials.gov identifier NCT00711009.

Portions of these data were presented at the XV Pan American Congress on Infectious Diseases, April 7–11, 2011, Punta del Este, Uruguay (SO3-17); the International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies, June 7–11, Los Cabos, Mexico (65); the 6th International Conference on HIV Pathogenesis, Treatment, and Prevention, July 17–20, Rome, Italy (4756); the 13th International Workshop on Adverse Drug Reactions and Co-Morbidities in HIV, June 14–16, Rome, Italy; and the 49th Annual Meeting of the Infectious Diseases Society of America, October 20–23, Boston, Massachusetts (406).

Author Disclosure Statement

J.R. has received honoraria for lectures or advisory boards, research support, and/or travel grants from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, Schering-Plough, Tibotec, and ViiV Healthcare. R.T., R.Q., M.T., L.F., T.P., M.N., and A.N. are Abbott employees and may own Abbott stock or options. F.P. has received consulting and lecture fees from Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, and Pfizer. R.S. received consulting and lecture fees from Abbott and Tibotec. J.G. has received speaker fees and/or honoraria from Abbott, Tibotec, Merck, Boehringer-Ingelheim, and Schering-Plough.

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