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Lopinavir/Ritonavir (LPV/r) Combined With Raltegravir (RAL) Provides More Rapid Viral Decline Than LPV/r Combined With Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) in Treatment-naïve HIV-1 Infected Subjects
  Reported by Jules Levin
Thomas Podsadecki, M.D., Min Tian, M.S., Linda Fredrick, M.S., Adebayo Lawal, M.D., Barry Bernstein, M.D. Abbott Laboratories, Abbott Park, IL, USA Corresponding author: Thomas Podsadecki; Abbott Laboratories, 200 Abbott Park Road, Dept. R48U, AP-30, Abbott Park, IL 60064,
15th Annual Conference of the British HIV Association (BHIVA) • 1-3 April 2009 • Liverpool, UK
• Subjects in the LPV/r + RAL group were more likely to have HIV-1 RNA levels below the limit of quantifi cation (<40 copies/mL) at 2, 4, and 8 weeks of treatment compared with subjects administered LPV/r + TDF/FTC.
- The rapid viral suppression observed for LPV/r + RAL is consistent with a previous study in which RAL was administered with NRTIs.3
- The response to LPV/r + TDF/FTC mirrors that seen in a previous trial,14 suggesting that the results observed here are not simply due to underperformance of the control arm.
• While the mean increase in CD4+ T-cell count was numerically greater for LPV/r administered with RAL versus NRTIs, there was no statistically signifi cant difference in immune recovery between treatment groups through week 8.
• LPV/r + RAL was safe and well-tolerated, with diarrhea being the most commonly-reported adverse event in both treatment arms.
- Moderate-to-severe, drug-related diarrhea occurred in 4.0% of subjects in the LPV/r + RAL group group and 8.6% of subjects taking LPV/r + TDF/FTC.
- Elevations in triglycerides, total cholesterol, and HDL cholesterol were greater in the LPV/r + RAL treatment group; however, only a small number of subjects in either treatment group experienced Grade 3 or greater elevations in these parameters.
• Through 8 weeks of treatment, an NRTI-sparing dual-agent regimen of LPV/r + RAL is well tolerated and enabled a greater proportion of antiretroviral-naïve, HIV-1-infected individuals to achieve viral loads <40 copies/mL compared with LPV/r + TDF/FTC.
• Lopinavir (LPV) is an HIV-1 protease inhibitor (PI) that is co-formulated with ritonavir (r), which functions as a pharmacokinetic enhancer.
• Durable antiviral activity of LPV/r has been demonstrated in antiretroviral-naïve and PI-experienced patients.1, 2
• Raltegravir (RAL) is an inhibitor of the HIV-1 integrase with potent antiviral activity.
- In combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs), RAL results in more rapid viral decline than efavirenz + 2 NRTIs in treatment-naïve patients over the fi rst 8 weeks of treatment.3
- Results of a Phase III randomized clinical trial demonstrate rapid and sustained suppression of HIV-1 RNA levels in treatment-naïve subjects through 48 weeks with RAL + TDF and lamivudine.4
- RAL provides enhanced antiviral activity when added to an optimized background regimen in treatment-experienced patients.5
Treatment Simplification
• In many HIV-infected patients, initiating a regimen that spares the use of NRTIs may be desirable to achieve a reduced pill burden and avoid NRTI-associated toxicity.
• Clinical trials have demonstrated that dual-agent NRTI-sparing regimens can produce similar response rates to standard combination therapy in antiretroviral-naïve subjects.6, 7, 8
• The availability of newer classes of antiretroviral drugs (i.e. integrase inhibitors) offers additional options for NRTI-sparing treatment regimens. HIV-1 RNA Dynamics
• Decay of HIV-1 RNA in response to antiretroviral therapy is biphasic. - The first phase occurs within the initial week of treatment and represents clearance of activated, virus-producing CD4+ T-cells.9
- A second, sustained phase is thought to represent elimination of other longer-lived cellular compartments.9
• Rapid viral decay is associated with improved therapeutic outcomes.
- Faster viral suppression may minimize the development of resistance.10
- Virus levels at weeks 4 and 8 are indicative of treatment response at weeks 24 and 48, and are superior to pretreatment RNA levels as predictors of response.11, 12
• Study M10-336 was designed to compare the safety, tolerability and antiviral activity of an NRTI-sparing regimen of LPV/r + RAL to LPV/r + TDF/FTC.
• This analysis explores the differences between treatment groups in viral decay through week 8.
• Study M10-336 is an ongoing Phase III, open-label, randomized study.
• The primary endpoint is to compare the antiviral effi cacy of LPV/r + RAL and LPV/r + TDF/FTC after 48 weeks of treatment.
Study Design
• Following screening, subjects were randomized 1:1 to LPV/r + RAL or LPV/r + TDF/FTC (Figure 1).
• LPV/r tablets were administered at 400/100 mg BID with either the integrase inhibitor RAL (400 mg BID) or fi xed-dose NRTI combination tablets of TDF/FTC (300/200 mg QD).
Study Population
• Inclusion criteria:
- HIV-1-infected adults at least 18 years of age providing informed consent
- naïve to antiretroviral treatment
- plasma HIV-1 RNA ≥1,000 copies/mL
- any CD4+ T-cell count
• Exclusion criteria:
- genotyping at screening indicated resistance to LPV/r, TDF, or FTC
- history of allergy or sensitivity to LPV/r, TDF/FTC, or RAL
- history of medical or psychiatric illness that would interfere with adherence to the protocol
- hemoglobin ≦8.0 g/dL, absolute neutrophil count ≦750 cells/_L, platelet count ≦50,000/mL, ALT (SGPT) or AST (SGOT) ≥3.0X Upper Limit of Normal (ULN), calculated creatinine clearance <50 mL/min, or positive for Hepatitis B surface antigen


Efficacy Analysis
• The proportion of subjects with HIV-1 RNA levels below the limit of quantifi cation (<40 copies/mL) based on on-treatment analysis at weeks 2, 4, and 8 was compared between treatment groups using Fisher's exact test. • The mean change from baseline to weeks 4 and 8 in CD4+ T-cell count was analyzed using one-way ANOVA with treatment group as the factor.
Safety Analysis
• The proportion of subjects reporting treatment-emergent adverse events (AEs) through week 8 was compared between treatment groups using Fisher's exact test.
• The incidence of Grade 3+ laboratory abnormalities (according to NIAID Division of AIDS Adverse Event Grading13) was compared between treatment groups using Fisher's exact test.
• Mean changes in lipid parameters and chemistry values from baseline to weeks 4 and 8 were compared between treatment groups using one-way ANOVA with treatment group as the factor.
• The study randomized 209 subjects.
- 3 subjects were randomized but not dosed.
- 101 subjects received LPV/r + RAL.
- 105 subjects were administered LPV/r + TDF/FTC.
• Through week 8, a total of 3 subjects from the LPV/r + TDF/FTC treatment group discontinued prematurely: 2 withdrew consent, and 1 subject discontinued due to pregnancy. There were no discontinuations through week 8 for subjects in the LPV/r + RAL arm.
• Subjects' baseline demographic and disease characteristics were similar between groups and are displayed in Table 1.


Virologic Efficacy
• By observed data analysis, statistically signifi cantly greater proportions of subjects had HIV-1 RNA levels <40 copies/ mL at weeks 2, 4, and 8 when treated with LPV/r + RAL compared with LPV/r + TDF/FTC (Figure 2).
- At week 8, nearly twice as many subjects receiving RAL achieved viral suppression below the limit of quantifi cation compared with those receiving NRTIs (p<0.001).
- Through week 8, on-treatment results are consistent with outcomes using intent-to-treat analysis.


Immunologic Efficacy
• Both treatment groups had statistically significant mean increases in CD4+ T-cell count from baseline to weeks 4 and 8 (p<0.001 for both).
• While mean increases in CD4+ T-cell count from baseline to week 4 or 8 were numerically greater for LPV/r + RAL compared to LPV/r + TDF/FTC, the differences between groups were not statistically significant (Figure 3).


Safety Analysis
• Overall, the incidences of treatment-emergent AEs were not different between treatment groups.
- The most commonly-reported events occurring in ≥10% of subjects, regardless of severity or relationship to study drug, were gastrointestinal in nature, including diarrhea, nausea, and fl atulence. Headache was also commonly reported and did not differ between groups. • Moderate-to-severe, study drug-related AEs were also similar between groups.
- Diarrhea, which occurred in 4.0% (4/101) of LPV/r + RAL subjects and 8.6% (9/105) of subjects taking LPV/r + TDF/FTC, was the only event occurring in ≥5.0% of subjects in either treatment arm. This difference was not statistically signifi cant.
• Clinically signifi cant laboratory abnormalities were infrequent. - Incidence of Grade 3+ laboratory abnormalities13 occurring in ≥5.0% of either treatment arm:
- The proportion of subjects showing cholesterol elevations (>7.77 mmol/L [>300 mg/dL]) was not statistically signifi cantly different between groups; elevations occurred in 6.9% (7/101) of LPV/r + RAL subjects and 2.9% (3/102) of LPV/r + TDF/FTC subjects (p>0.100).
- The proportion of subjects showing triglyceride elevations (>8.475 mmol/L [>750 mg/dL]) was statistically signifi cantly different between groups; elevations occurred in 5.9% (6/101) of LPV/r + RAL subjects, but were not observed in LPV/r + TDF/FTC subjects (p=0.014).
• Lipid analysis
- Mean changes in lipid levels from baseline to week 8 were statistically significantly greater for triglycerides, total cholesterol, and HDL cholesterol in the LPV/r + RAL arm, but not signifi cantly different between treatment groups for LDL cholesterol and the HDL:LDL ratio (Table 2). • Changes in laboratory chemistry values
- From baseline to week 8, mean changes in chemistry values were statistically signifi cantly different between the LPV/r + RAL and LPV/r + TDF/FTC groups for creatinine, BUN, sodium, magnesium, and alkaline phosphatase (Table 3).



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