This report was reviewed for medical and scientific accuracy by Susan E. Boruchoff, MD, Associate Professor of Medicine, Division of Allergy, Immunology and Infectious Diseases, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

The introduction of highly active antiretroviral therapy (HAART) was a major advance for patients with HIV-1 infection, often changing the prognosis of AIDS from a death sentence to that of a chronically managed disease. Continuing gains in pharmacologic treatment come in small increments, and the current focus of researchers is to develop more simplified treatment regimens and novel agents that will enhance adherence and provide potent viral suppression and immune reconstitution. One of the encouraging studies reported at this meeting demonstrates the potential for a regimen containing once-daily lopinavir/ritonavir (LPV/r; Kaletra®, Abbott Laboratories) in treatment-naпve patients for whom a simplified treatment regimen is preferred.¹ Though preliminary, these are encouraging results for naпve patients in whom a once-daily protease inhibitor is preferred. A second study demonstrated that patients achieve durable viral suppression from LPV/r regardless of baseline CD4 cell count and baseline viral load, while response to nelfinavir is dependent on these two parameters.² Further, LPV/r demonstrated a significantly longer time to loss of virologic response as compared to nelfinavir. Other positive news for patients with HIV-1 infection is that several novel agents in various stages of development hold promise as additional or alternative options in both treatment-naпve and treatment-experienced patients.

Regimen Simplification

LPV/r QD vs. BID

A once-daily LPV/r based regimen achieved similar viral suppression at 48 weeks compared to the standard twice-daily LPV/r-based regimen in antiretroviral (ART)-naпve patients, according to results of a study presented at the meeting.¹ Although this was a small study that included 38 patients, the results suggest that once-daily LPV/r is an option for treatment-naпve patients for whom a once-daily regimen is preferable. Potential benefits of a once-daily regimen include not only dosing simplification but also improved adherence, which is associated with a lower risk of disease progression.^3,4

"Although this study is exploratory and further study is needed, the results are nevertheless encouraging. The study suggests similar efficacy and safety results in treatment-naпve patients taking once-daily Kaletra and twice-daily Kaletra with two NRTIs," said Joseph Eron, MD, Associate Professor of Medicine, University of North Carolina, Chapel Hill, North Carolina, and Director of Clinical Care at the UNC Center for AIDS Research. "The tolerability profile and once-daily dosing of Kaletra may promote patient adherence, a critical factor in achieving long-term viral suppression," he added.

The primary objective of the pilot study (M99-056) was to compare the pharmacokinetics of LPV/r 400/100 mg administered twice daily (n = 19) to LPV/r 800/200 mg administered once daily (n = 19). The once-daily dose involved six capsules of LPV/r taken with food, whereas the twice-daily regimen utilized three capsules per dose taken with food. Patients in each treatment arm also took 2 nucleoside reverse transcriptase inhibitors (NRTIs), d4T (30 mg or 40 mg twice daily) and 3TC (150 mg twice daily). In addition to being ART-naпve, patients' entry criteria included plasma HIV RNA levels > 50 copies/mL with no minimum CD4 cell count.

Pharmacokinetic data showed that the once-daily and twice-daily regimens achieved similar steady state lopinavir C_max (µg/mL) (mean ± standard deviation (SD), 10.94 ± 2.81 vs. 9.81 ± 3.66 , respectively) and 24-hour area-under-the-curve (AUC₂₄) (µg-h/mL) (mean ± SD, 164.9 ± 67.5 vs. 185.2 ± 73.4, respectively). Overall median lopinavir Inhibitory Quotient (IQ) [C_tough/IC₅₀] (protein binding-adjusted) was 40 (range 3.6-220) for the once-daily treatment group and 84 (range: 36-174) for the twice-daily regimen. Higher and more consistent lopinavir trough levels were observed with the standard twice-daily LPV/r regimen; however, median trough concentrations over 48 weeks exceeded the protein binding-adjusted IC₅₀ of wild-type HIV by 40 and 84 fold in the once-daily and twice-daily regimens, respectively. (See Table 1)

"The trough concentrations, or the lowest values of lopinavir, were more variable with the 24-hour dosing compared to the [twice-daily] dosing, which I think is predictable. But in these treatment-naпve patients, the level of the drug still remained significantly higher than what's required, at least in the test tube, to suppress the virus," Dr. Eron commented.

Both regimens exhibited a potent antiviral effect over 48 weeks. Intent-to-treat analysis showed that once-daily LPV/r achieved an undetectable viral load [HIV-RNA < 50 copies/mL] in 74% of patients compared to 79% of patients taking LPV/r twice daily (see Figure 1). Among patients on study at week 48, the mean CD4 cell count increases from baseline were 235 cells/mm³ and 248 cells/mm³ for once-daily and twice-daily LPV/r, respectively (see Figure 2).

Figure 1.

Figure 2.

"In this very small study, there didn't seem to be any clinical difference between [virologic] suppression with the once-daily and twice-daily regimens. In other words, although there were only 19 patients per arm, the proportion of patients below 50 copies [at week 48] is virtually identical. But further study is needed," Dr. Eron said.

Safety and Tolerability of LPV/r QD vs. BID

Both LPV/r regimens were well tolerated over the 48-week study. Only 2 of 38 patients discontinued the study due to adverse events related to study drug. Side effects were similar to those reported in other studies of LPV/r in ART-naпve patients.⁵ The most common study-drug related adverse events of at least moderate severity were nausea (3 vs. 1), asthenia (0 vs. 2), and diarrhea (1 vs. 1), in once-daily vs. twice-daily LPV/r respectively. "Both regimens were well tolerated. More nausea was seen initially in the once-daily LPV/r because of the pill burden, but the nausea abated in almost all patients. We have patients who continue to tolerate once-daily Kaletra at two years out," Dr. Eron noted. Grade 3 elevation of triglycerides (> 750 mg/dL) was observed in two patients taking once-daily LPV/r and one patient taking twice-daily LPV/r. Grade 3 elevation of cholesterol (> 300 mg/dL) was observed in one patient each from both the once-daily LPV/r and twice-daily LPV/r treatment arms.

Adherence to LPV/r QD vs. BID

Adherence data was measured using Medication Events Monitoring System (MEMS). A similarly high rate of adherence was observed for both treatment groups. The mean percentage of days with the correct number of LPV/r doses taken was 90% for the once-daily group and 87% for the twice-daily group (p = 0.88).

Summary LPV/r QD vs. BID

In summary, Dr. Eron said that the key message from this study is that twice-daily LPV/r provides tighter pharmacokinetics compared to a once-daily regimen. "But these data suggest that Kaletra can be taken once a day, which is important for treatment-naпve patients in whom you believe once-daily therapy is the key to success--for example, a patient in methadone maintenance or a patient with a particularly chaotic life," he concluded.

Impact of Baseline CD4 Cell Count and Viral Load on Durability of Virologic Response

The ability to achieve viral suppression and/or the duration of virologic response with a protease-inhibitor regimen has been shown to be affected by baseline CD4 cell count and baseline viral load.^6-9 A Phase III comparative study analysis presented here demonstrated that the effects of lower baseline CD4 cell counts and higher baseline viral load levels on the durability of virologic response to a LPV/r-based regimen were generally nonsignificant.² Conversely, in nelfinavir-treated patients, the durability of virologic response was highly statistically significantly associated with lower baseline CD4 cell counts and higher baseline viral load levels.

This Phase III, controlled, double blind study randomized 653 ART-naive patients to receive either LPV/r 400/100 mg twice daily plus nelfinavir placebo 3 times daily plus d4T/3TC (n = 326) or LPV/r placebo twice daily plus nelfinavir 750 mg 3 times daily plus d4T/3TC (n = 327). There were no minimum CD4 cell counts or maximum viral load restrictions per protocol.

"Differences between treatment groups in the time to loss of virologic response were largest among patients most likely to initiate treatment based on current treatment guidelines. For example, among patients with baseline CD4 counts < 200 cells/mm³--a group among whom initiation of therapy is universally recommended¹⁰--74% of the LPV/r group maintained response through week 96 versus 44% of the nelfinavir-treated group (p < 0.001)," stated Dr. Martin King, lead author on the abstract.

Overall, LPV/r-treated patients (79%) demonstrated significantly longer time to loss of virologic response compared to nelfinavir-treated patients (58%) up to 96 weeks (p < 0.001, Cox proportional hazards model). Multivariate analysis showed that lower baseline CD4 cell count and higher baseline viral load were significantly associated with a higher risk of failure in the nelfinavir-treated patients, but not in the LPV/r-treated patients. Specifically, the risk ratio for baseline CD4 cell counts (per 100 cells/mm³ decrease) for nelfinavir was 1.15 (95% Confidence Interval (CI), 1.01,1.30, p = 0.035) compared to 1.05 for LPV/r (95% CI, 0.90,1.22, p = 0.543). The risk ratio for baseline viral load (per 1.0 log₁₀ copies/mL increase) for nelfinavir was 1.70 (95% CI, 1.28,2.26, p = 0.0002) compared to 1.27 for LPV/r (95%CI, 0.84,1.91, p = 0.265). Kaplan-Meier response rates through Week 96 are shown for each stratum for nelfinavir-treated patients (see Figure 3) and for LPV/r-treated patients (see Figure 4). These results were also demonstrated by univariate analysis.

Figure 3.

Figure 4.

"Neither variable [baseline CD4, baseline viral load] was significantly associated with response in the lopinavir/ritonavir group," Dr. King stated.

Dr. King indicated that his data suggest that protease-inhibitor (PI) resistance is found in nelfinavir-treated patients but not in LPV/r-treated patients. A recent study presented by Bernstein et al at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in December 2001 documented protease inhibitor resistance in 43% of nelfinavir-treated patients versus 0% in LPV/r-treated patients.¹¹

The analysis results suggest that in addition to the less durable virologic response observed in the nelfinavir-treated patients compared to the LPV/r-treated patients, response to subsequent treatment regimens for nelfinavir-treated patients may be undermined due to the higher rate of PI resistance.

According to Dr. King, results from this, and other studies, that do not reflect current guidelines for treatment initiation of ART may either underestimate treatment effects by including patients with higher-than-recommended CD4 counts or overestimate treatment effects by excluding patients with more advanced disease and CD4 counts below 50 cells/mm³.

Investigational Agents

Several presentations focused on promising investigational agents representing next generations of established drug classes or new drug classes.

Gazzard et al reported the results of a small Phase IIA study of TMC125, a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), in 16 HIV-infected experienced patients (median baseline: CD4 cell count: 389 cells/mL, HIV-1 RNA 10,753 copies/mL) who failed on efavirenz or nevirapine-containing regimens and presented with documented resistance to efavirenz.¹² In a 7-day proof-of-concept study, TCM125 900 mg administered twice daily along with the patient's baseline NRTI regimen demonstrated significant antiviral potency (median decrease in viral load was 0.9 log₁₀ from baseline) and was well tolerated (11 patients reported Grade 1 adverse events), although the study period was inadequate to fully evaluate side effects, Dr. Gazzard noted.

DPC 083 is another next generation NNRTI designed to improve upon the side-effect profiles of efavirenz and nevirapine, explained Nancy Ruiz, MD, from Bristol-Myers Squibb. "One of the unmet needs of patients who fail NNRTI therapy is a back-up drug for patients resistant to currently available NNRTIs," Dr. Ruiz told listeners.

Two studies of DPC 083 were reported here, one in ART-naпve patients and the second study in patients who failed on other NNRTI regimens. The first Phase II double blind study of 134 treatment-naпve patients (median baseline: CD4 cell count 367 cells/mm³, viral load 33,113 copies/mL) compared three different (50, 100, and 200 mg) once-daily doses of DPC 083 with the standard 600 mg once-daily dose of efavirenz.¹³ Each regimen was given in combination with lamivudine/zidovudine. At 24 weeks, no statistically significant differences in response rates were seen across treatment groups (p > 0.05). The incidence of dizziness was lower in those patients receiving DPC 083 (11-18%) compared with efavirenz (32%). Rash was less frequent in the 50 mg (15%) and 100 mg (33%) doses of DPC 083 compared with efavirenz (38%), but the DPC 083 200mg dose had the highest frequency (53%).

"Based on this study, the dose of 100 mg was selected for ART-naпve patients," Dr. Ruiz told listeners.

A second Phase II study compared once-daily DPC 083 100 mg and 200 mg plus two individually selected NRTIs in 51 patients (mean baseline: CD4 473 cells/mm³, viral load log₁₀ 3.85 copies/mL) failing an NNRTI-containing regimen and in whom testing revealed viral resistance to a NNRTI drug.¹⁴ At eight weeks, 57% [pooled 100 and 200 mg on-treatment response rate] of patients had significant suppression of viral replication (< 400 copies/mL). The mean change in viral load from baseline was -1.28 log. Greatest viral suppression was observed when DPC 083 was used with at least one new NRTI, Dr. Ruiz noted. The discontinuation rate due to adverse experiences was 16% (8/51).

Data were unveiled on a novel HIV entry inhibitor that blocks HIV-1 access into cells by binding to the viral envelope glycoprotein (gp 120) and inhibiting gp120/CD4 receptor interaction suggesting that this compound--or others like it--may find a role in the treatment of HIV infection.¹⁵ The investigational compound has shown potent inhibitory effect against HIV-1 in the test tube, explained Richard Colonno, PhD, Bristol-Myers Squibb Pharmaceutical Research Institute.

"This drug may become an option for patients experiencing treatment failure due to resistance to one or more of currently available ART drugs. Agents like this can reset the clock for failing patients," Dr. Colonno told listeners. "Viruses that are not resistant to entry inhibitors are resistant to other classes of drug, and vice-versa," he added.

Novel drugs that may become available in a year or several years from now will provide different options for patients after they fail first- or second-line regimens. "These compounds represent a new wave. The drugs we have are getting better; some new drugs allow once-daily dosing which leads to better adherence and improved quality of life. Novel drugs will provide new options for the future," Dr. Colonno commented.

References

1. Eron J, Bernstein B, King M, et al. Once-Daily vs. Twice-Daily Kaletra (lopinavir/ritonavir) in Antiretroviral-Naпve HIV + Patients: 48-Week Follow-Up. 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002, Seattle, WA. Poster #409W.
2. King M, Bernstein B, Cernohous P, Moseley J, Bauer E, Sun E. Impact of Baseline CD4 Cell Count and Viral Load on Durability of Virologic Response Through 96 Weeks for Lopinavir/ritonavir and Nelfinavir in a Phase III Clinical Trial. 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002, Seattle, WA. Poster #470-M.
3. Bartlett J, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the Effectiveness of Triple Combination Therapy in Antiretroviral-Naпve HIV-1 Infected Adults. AIDS 2001;15(11):1369-1377.
4. Cahn P. Potential Advantages of a Compact Triple Nucleoside Regimen: Efficacy and Adherence with Combivir/Abacavir versus Combivir/Indinavir in an Open-Label Randomized Comparative Study (CNAB3014). 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada, 2000. Abstract 695.
5. Kaletra Professional Prescribing Information. Abbott Labs. Available at http://www.rxabbott.com. Accessed March 3, 2002.
6. Paredes R, Puig T, Arno A, et al. High-Dose Saquinavir Plus Ritonavir: Long-Term Efficacy in HIV-Positive Protease Inhibitor-Experienced Patients and Predictors of Virologic Response. J Acquir Immune Defic Syndr 1999;22(2):132-138.
7. Le Moing V, Chene G, Carrieri MP, et al. Predictors of Virological Rebound in HIV-1-Infected Patients Initiating a Protease Inhibitor-Containing Regimen. AIDS 2002;16(1):21-29.
8. Staszewski S, Miller V, Sabin C, et al. Virological Response to Protease Inhibitor Therapy in an HIV Clinic Cohort. AIDS 1999;13(3):367-373.
9. Grabar S, Pradier C, Le Corfec E, et al. Factors Associated with Clinical and Virological Failure in Patients Receiving a Triple Therapy Including a Protease Inhibitor. AIDS 2000;14(2):141-149.
10. US Department of Health and Human Services and Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Published online at: www.hivatis.org February 4, 2002. Accessed March 3, 2002.
11. Bernstein B, Kempf D, King M, et al. Comparison of the Emergence of Resistance in a Blinded Phase III Study with Kaletra (lopinavir/ritonavir) or Nelfinavir plus d4T/3TC from Week 24 Through Week 96. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL December 16-19, 2001. Poster No.1768.
12. Gazzard B, Pozniak A, Arasteh K, et al. TMC125, A Next Generation NNRTI, Demonstrates High Potency After 7 Days Therapy in Treatment-Experienced HIV-1-Infected Individuals with Phenotypic NNRTI Resistance. 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002, Seattle, WA. Abstract 4.
13. Ruiz N, Nusrat R, Lazzarin A, et al. Study DPC 083-201: A Phase II Double Blind Comparison of 3 Once-Daily Doses of the NNRTI DPC 083 vs. 600mg Efavirenz in Combination with 2 NRTIs in HIV Antiretroviral Treatment-Naпve Patients. 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002, Seattle, WA. Abstract 7.
14. Ruiz N, Nusrat R, Lavenroth-Mai E, et al. Study DPC 083-203: A Phase II Comparison of 100 and 200 mg Once-Daily DPC-083 and 2 NRTIs in Patients Failing a NNRTI-Containing Regimen. 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002, Seattle, WA. Abstract 6.
15. Lin PF, Guo K, Fridell R, Ho HT, Yamanaka G, Colonno R. Identification and Characterization of a Novel Inhibitor of HIV-1 Entry - II: Mechanism of Action. 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002, Seattle, WA. Abstract 10.

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Disclosure
Susan E. Boruchoff, MD: Has no significant relationships to disclose.

Alice Goodman: Has no significant relationships to disclose.

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved. Lopinavir/ritonvir and investigative agents are not included in the labeling approved by the US FDA for the treatment of HIV-infection.

This report is supported by an educational grant from Abbott Laboratories.

Medical Writer
Alice Goodman, Freelance Medical Writer, Millennium Medical Communications, Inc., Hampton, NH

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This HIV/AIDS Express Report(tm) includes discussion of treatment and indications outside of current approved labeling. This HIV/AIDS Express Report(tm) was made possible through an unrestricted educational grant from Abbott Laboratories.

© 2002 Millennium Medical Communications, Inc. and UMDNJ--Center for Continuing and Outreach Education