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Seven Year Follow-up of a Lopinavir/ritonavir (LPV/r)-Based Regimen in Antiretroviral (ARV)-Naive Subjects
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Robert Murphy (Northwestern University, and colleagues) presented these data at EACS.
This report includes coverage of two interesting posters at EACS. Poster Poster PE7.9/3 reports the 7 year followup of Kaletra from the phase II study reported by Rob Murphy. The second poster (#PE7.3/4) reports response to Kaletra regimens from 4 studies in patients with low CD4 counts of <25 cells.
Summary of 7-year followup study:
Through 7 years (360 weeks) of follow-up, antiretroviral-naive subjects receiving LPV/r-based therapy exhibited sustained virologic responses, with 61% of subjects demonstrating HIV-1 RNA <400 copies/mL and 59% demonstrating HIV-1 RNA <50 copies/mL by intent-to-treat (NC=F) analysis. Corresponding on-treatment response rates were 98% and 95%, respectively.
Mean CD4 cell count increased 501 cells/mm3 over 360 weeks of follow-up with consistent CD4 cell count increases regardless of baseline CD4 cell count.
Through 360 weeks of follow-up, no primary protease inhibitor resistance mutations have been observed in subjects with HIV-1 RNA >500 copies/mL any time at or after Week 24.
Safety and Side effects
As expected nausea, GI side effects, elevated lipids were all associated with use of the regimen of Kaletra plus d4T & 3TC. Of note, the new Kaletra tablet is forthcoming, which will likely be associated with less GI side effects & other side effects. Of particular note was an abstract presented at the Lipodystrophy Workshop Nov 205 Dublin, which I forwarded a report to you. This abstract found patients who switche from d4T to tenofovir had reductions in lipids & glucose & other lab parameters suggesting d4T was associated with many of these side effects & elevations in lipids. See the report I sent out for interesting details.
In a separate study reported at EACS: Martin King of Abbott conducted a combined analysis of 4 studies of LPV/r-based regimens to assess response in subjects with baseline CD4 cell count <25 cells/mm3. Studies: M97-720 (n=100); M98-863 (n=326); M99-056 n=38); M02-418 (n=190).
"Antiviral Activity of Lopinavir/ritonavir-Based Regimens in Subjects with CD4 Cell Counts Below 25 Cells"
M King1, M Johnson2, M Youle2, S Brun1, G Hanna1
1Abbott, Abbott Park, IL, United States of America; 2Royal Free Centre for HIV Medicine, London, United Kingdom
The authors concluded: Studies of antiretroviral-naive subjects often exclude subjects with very low CD4 counts. In one study with no lower bound on entry CD4 cell counts, NNRTI-based regimens demonstrated a higher risk of virologic failure among subjects with baseline CD4 cell count <25 cells/mm3.
- In contrast, in the current analysis of LPV/r-treated subjects, no significant reduction in efficacy was observed among subjects with very low CD4 cell counts.
- Similarly, antiviral activity of LPV/r-based regimens was not associated with baseline HIV-1 RNA level.
- These findings may have implications for the choice of initial treatment of patients who present with advanced HIV disease.
Background from authors: Studies of antiretroviral-naive subjects sometimes exclude those with the lowest CD4 cell counts (1, 2) or do not enroll large numbers of such subjects. Thus, the antiviral activity of HAART in antiretroviral-naive subjects with very advanced HIV disease is not well characterized. One study has demonstrated higher virologic failure rates in efavirenz- or nevirapinetreated subjects with baseline CD4 cell count <25 cells/mm3 (3). Studies of lopinavir/ritonavir (LPV/r)-based regimens have suggested no reduction in efficacy in antiretroviral-naive subjects with baseline CD4 cell counts <200 cells/mm3 compared to those with higher baseline CD4 cell counts through 2 or more years of therapy (4, 5). Further, a large comparative study indicated good antiviral activity among subjects with baseline CD4 cell counts <50 cells/mm3, in contrast to significantly poorer responses among nelfinavir-treated subjects with such low CD4 cell counts (6). Sample sizes of individual studies of LPV/r-based regimens in antiretroviral-naive subjects have not been sufficient to examine CD4 cell count cutoffs lower than 50 cells/mm3. Therefore, we conducted a combined analysis of 4 studies of LPV/r-based regimens to assess response in subjects with baseline CD4 cell count <25 cells/mm3.
Antiviral Activity
At week 48, no significant differences in response to therapy between baseline CD4 cell count categories (Figure 1) or baseline HIV-1 RNA categories (Figure 2) were observed.
Figure 1. Week 48 HIV-1 RNA <50 copies/mL
by Baseline CD4 Cell Count
Immunologic Response
The change from baseline to Week 48 in CD4 cell count was generally comparable across baseline CD4 cell count categories (Figure 5). With the exception of the group with baseline CD4 cell count 50-199 cells/mm3, mean increases in CD4 cell counts were not significantly different from those in the reference group.
At Week 48, 44% of those with baseline CD4 cell count <25 cells/mm3 had CD4 cell count >200 cells/mm3, as did 62% of those with baseline CD4 cell count between 25-49 cells/mm3. No subject had CD4 cell count <50 cells/mm3 at Week 48.
p-values represent
comparison with reference
group (baseline CD4 cell
count 500 or more)
Sensitivity Analyses
To ensure that the finding of no statistically significant differences was not due to the choice of reference group, we assessed the time to loss of virologic response by all possible pairwise comparisons of the baseline CD4 cell count and HIV-1 RNA level categories
- CD4 cell count: Each of the 6 categories was compared to each other category, resulting in 15 possible pairwise comparisons. None of the 15 comparisons demonstrated a statistically significant difference between categories (p>0.14 for all comparisons)
- HIV-1 RNA level: Each of the 4 categories was compared to each other category, resulting in 6 possible pairwise comparisons. None of the 6 comparisons demonstrated a statistically significant difference between categories (p>0.18 for all comparisons).
To ensure that observed results were not a manifestation of insufficient sample size, we combined adjacent categories and assessed the time to loss of virologic response. Specifically, subjects were dichotomized and compared by various
CD4 cell counts (<25 vs. 25 or more cells/mm3, <50 vs. 50 or more cells/mm3, <200 vs. 200 or more cells/mm3, etc.) and baseline HIV-1 RNA levels (<30,000 vs. >30,000 copies/mL, <100,000 vs. >100,000 copies/mL, <300,000 vs. >300,000 copies/mL). No statistically significant differences were observed for any of these comparisons (p>0.20 for each).
Kaletra 7 Year Followup Study
The M97-720 study was a phase II trial of LPV/r in combination with stavudine (d4T) and lamivudine (3TC) in antiretroviral-naive HIV-1-infected subjects. This study began in 1997 and was closed in 2005. This was the first trial of LPV/r in HIV-1-infected subjects and hence provides the longest duration of follow-up for subjects treated with LPV/r. This poster presents data on antiviral activity, immunologic parameters, and safety through 7 years (360 weeks).
Entry Criteria
- Antiretroviral-naive subjects with confirmed HIV-1 infection.
- Plasma HIV-1 RNA 35,000 copies/mL with no CD4 cell count restriction.
- Exclusion criteria included ALT or AST >2.5x Upper Limit Normal (ULN) and creatinine >1.5x ULN.
Study Design and Analysis
- One hundred antiretroviral-naive HIV-1-infected subjects were randomized to receive one of three dosage levels of LPV/r (200/100 mg BID, 400/100 mg BID or 400/200 mg BID), together with d4T (40 mg BID) and 3TC (150 mg BID) given either after 3 weeks of monotherapy (Group I) or from study entry (Group II).
- Enrollment into Group II began following an evaluation of preliminary efficacy and safety of LPV/r in Group I.
- After 48 weeks, all subjects converted to open-label LPV/r 400/100 mg BID dosing.
- Subjects were evaluated every 2-4 weeks for the first 24 weeks and every 12 weeks thereafter.
- At Year 6, 37 subjects treated with LPV/r + stavudine + lamivudine substituted stavudine with tenofovir disoproxil fumarate (tenofovir DF).
RESULTS
Baseline Characteristics
1. Ninety-six male and 4 female subjects: 65% White, 29% Black, 6% Hispanic.
2. Mean age: 35 years (range 21-69).
3. Among all 100 subjects enrolled, the median baseline HIV-1 RNA and CD4 cell count were 4.8 log10 copies/mL and 326 cells/mm3, respectively.
Efficacy
Viral Load Suppression Below the LOQ
- Based on the ITT NC=F analysis through Week 360, 61% of subjects had HIV-1 RNA <400 copies/mL (on-treatment analysis: 98%) (Figure 2) and 59% of subjects had HIV-1 RNA <50 copies/mL (on-treatment analysis: 95%) (Figure 3).
Analysis of Genotypic and Phenotypic Drug Resistance
- A total of 33 samples from 29 subjects were submitted for resistance testing
- 18 subjects met criteria for loss of virologic response, and 11 patients had at least 1 "blip" (single HIV-1 RNA value >500 copies/mL bracketed by HIV-1 RNA values <400 copies/mL) after Week 24.
- Genotypic drug resistance testing failed for 10 subjects whose median HIV-1 RNA was 575 copies/mL.
- In 19 subjects with available results, no lopinavir or stavudine resistance was observed, and 4 subjects demonstrated lamivudine resistance.
Correspondingly, no evidence of phenotypic resistance to any PI was observed.
- 6 subjects demonstrated a substitution at a new position in protease during viral rebound (1 each at amino acids 15, 36, 43, 57, 63, 70).
However, as demonstrated previously, none of these substitutions are primary protease inhibitor mutations, no impact on protease inhibitor phenotypic resistance was observed, and all 3 of these subjects who completed the study demonstrated HIV-1 RNA <50 copies/mL at the final visit.
Figure 5. Study 720: No Change in Susceptibility to any Protease Inhibitor Between Baseline and Rebound
CD4 Cell Count Response
- Among subjects with values at both baseline and Week 360 (N=60), the mean CD4 cell count increased from 275 cells/mm3 at baseline to 776 cells/mm3 at Week 360, an increase of 501 cells/mm3 (Figure 6).
- CD4 cell count response appeared to be consistent regardless of baseline CD4 cell count (Table 1). Among subjects with baseline CD4 cell count <50 cells/mm3, mean CD4 cell count increased from 23 cells/mm3 at baseline to 556 cells/mm3 at Week 360, an increase of 533 cells/mm3.
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