Positioning of Protease Inhibitors: First-Line Options
This report was reviewed for medical and scientific accuracy by Mark B. Feinberg, MD, PhD , Associate Professor of Medicine and Microbiology and Immunology, Emory University School of Medicine; Attending Physician, HIV/AIDS Service, Grady Memorial Hospital, Atlanta, Georgia.
Mark Bennett Feinberg, MD, PhD, Emory Vaccine Research Center, Atlanta, Georgia
The advent of potent drugs to treat HIV infection along with the development of increasingly effective treatment strategies have resulted in dramatic improvements in the prognosis and quality of life for HIV-infected persons. However, two major challenges now exist in developing even more effective treatments.
First, treatment regimens typically require the use of three or more antiviral drugs, resulting in complex medication schedules that require patients to take multiple pills at multiple times each day. As the relative complexity and inconvenience of a specific treatment regimen is likely to impact a patient's adherence and their ultimate chance for long-term therapeutic success, the development of effective, but more convenient, antiviral drugs is an essential goal.
Second, there remains a great need to develop alternative antiretroviral treatment regimens for patients who develop resistance to the antiviral drugs included in their initial (or subsequent) antiretroviral therapy combinations. In particular, there is substantial "cross-resistance" seen among different antiretroviral drugs of the same class, including the potent inhibitors of the HIV protease. As a result of the extensive cross-resistance between protease inhibitors (PIs), none of these such drugs currently available have been shown to durably suppress the replication of HIV variants that arise in individuals who had been previously and unsuccessfully treated with other PIs. The development of PIs that select for distinct mutations in the HIV protease gene, in contrast to previously available PIs, would provide one useful path to successful treatment of patients who develop drug resistant HIV variants as a result of prior unsuccessful PI therapy. In addition, growing evidence indicates that strategies to alter the metabolism of PIs can result in substantially increased concentrations of the drug in the blood and appreciably prolonged drug half-lives, thereby achieving greater "drug exposure".
It has been demonstrated that the greater the drug exposure to PIs, the greater the level of suppression of HIV replication and the better the clinical response. Because the antiviral effect of any antiretroviral drug is influenced by its associated resistance pattern and by the level of the drug attained during treatment of HIV-infected persons, maintenance of high concentrations of a potent PI may, in certain instances, be able to successfully inhibit the replication of even those HIV variants that already harbor a number of mutations associated with PI resistance.
For these reasons, the development of Kaletra™, the combined formulation of the potent PI lopinavir (LPV), represents a promising addition to the available antiretroviral treatments for HIV infection. Lopinavir/ritonavir (LPV/RTV) acts as a potent inhibitor of the HIV protease, and its pharmacologic properties yield high levels of the drug in vivo, thereby permitting a simple, twice a day treatment schedule that accomplishes high level drug exposure. Furthermore, this combination drug therapy has proven itself to be an important component in the formulation of successful treatment regimens for patients who have failed prior therapy. While early data on LPV/RTV indicated that it represented a valuable advance in HIV therapy, important questions have been raised concerning how and when to best exploit the drug's favorable properties. It was, for example, unclear whether the drug should become a routine component of initial combination therapy regimens, or alternatively, if it should be reserved for those individuals who fail initial antiretroviral treatments. An important consideration in this regard was in determining whether individuals who experienced viral rebound and the development of resistance to lopinavir and ritonavir could benefit from salvage therapy regimens that included other available PIs. Further, as more potent antiretroviral drugs, such as LPV/RTV, have become available at the same time the plasma HIV RNA viral load assays used in clinical practice are becoming more sensitive, it was not known how long it would take to achieve the desired treatment goal of "undetectable" viral loads using such "ultra-sensitive" plasma HIV RNA assays (detection limits of 50 copies/ml).
While a number of important uncertainties remain, the data presented support the use of LPV/RTV as a PI to be considered in the initial combination antiretroviral treatment regimen to be used in patients for whom such therapy is appropriate. In addition, many treatment-experienced patients who appeared to have run out of options for successful antiretroviral therapy may now be able to obtain substantial benefit through the carefully considered formulation of salvage therapy regimens that include LPV/RTV as an active constituent drug.
With the accelerated FDA approval of lopinavir/ritonavir (Kaletra™) in September 2000, clinicians were given a new potent and useful antiretroviral drug with which to treat HIV infection in adults and children. Lopinavir/ritonavir is a promising new antiretroviral agent with favorable pharmacologic properties, permitting a simplified twice-daily treatment schedule. Through co-formulation of lopinavir with ritonavir, substantial improvements in the pharmacokinetic properties of lopinavir are achieved. As a result of ritonavir's inhibition inhibitor of cytochrome P450 3A-the hepatic enzyme system that is responsible for metabolism of lopinavir-significant increases in total drug exposure to lopinavir are seen in treated patients. Given accumulating evidence concerning the antiviral potency, tolerability, and clinical efficacy of lopinavir/ritonavir, the drug was included as one of the "strongly recommended" protease inhibitors (PIs) to be used in combination antiretroviral therapy regimens for the initial treatment of HIV-infected patients in the recently updated Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults, which were developed jointly by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation (http://hivatis.org/trtgdlns.html).
Reports presented at the 8th Conference on Retroviruses and Opportunistic Infections served to confirm and extend the results presented at other recent meetings concerning the use of lopinavir/ritonavir in initial antiretroviral treatment regimens, as well as its use as a component of salvage therapy regimens. In addition, new results were presented that help define the length of time that it takes for many successfully treated patients to achieve undetectable viral loads using ultra-sensitive plasma HIV RNA assays (detection limit of 50 copies/ml).
Abbott M98-863-a large, randomized study of treatment-naпve patients-compared lopinavir/ritonavir with nelfinavir (Viracept®) as the PI component of treatment regimens that include stavudine (Zerit®) and lamivudine (Epivir®). Previously reported results from this study documented the potent and durable antiviral activity of lopinavir/ritonavir and indicated that it was more effective in durably suppressing HIV replication in treated patients than nelfinavir. At 48 weeks, plasma HIV RNA levels were less than 400 copies/ml in 75% of patients in the lopinavir/ritonavir arm compared with 63% of those in the nelfinavir arm (p < 0.001) Using an ultra-sensitive plasma HIV RNA assay (detection limit of 50 copies/ml), 67% of lopinavir/ritonavir and 52% of nelfinavir-treated patients were below detection (p < 0.001). Follow-up results from this study and an early phase study of lopinavir/ritonavir were also presented that indicate that these favorable lopinavir/ritonavir results are sustained through week 108 in ARV-naпve subjects. Data from this and other studies have indicated that the likelihood of development of resistance on therapy to lopinavir/ritonavir is relatively low. Furthermore, analyses of drug resistant isolates obtained from LPV/RTV-treated patients who have previously been treated with a protease inhibitor or protease inhibitors have indicated that when drug resistant virus variants emerge on lopinavir/ritonavir therapy, cross-resistance to other protease inhibitors is not complete. This suggests that patients might still be able to be treated successfully in regimens that include other PIs such as amprenavir (Agenerase®) or saquinavir (Fortovase®).
Another study presented at the meeting showed that the liquid formulation of lopinavir/ritonavir is safe and effective in HIV-infected children. In all, data presented support the use of lopinavir/ritonavir as a first-line PI to be included in combination antiretroviral treatment regimens for both adults and children.
Time to Achieve Viral Suppression (< 400 copies/ml and < 50 copies/ml)
Abbott M98-863, a large multicenter, international, double-blind, randomized trial, compared the safety and antiviral activity of lopinavir/ritonavir + lamivudine (3TC) + stavudine (d4T) to that of nelfinavir in combination with d4T and 3TC. The study included a total of 653 subjects: 326 patients in the lopinavir/ritonavir (Kaletra™) arm and 327 in the nelfinavir arm. Respective treatments were: lopinavir/ritonavir 400/100 mg bid + d4T + 3TC and nelfinavir 750 mg tid + d4T + 3TC. Placebo formulations of lopinavir/ritonavir and nelfinavir were used such that all patients took the same number of pills according to the same dosing intervals. Eligible patients were required to have an HIV RNA level > 400 copies/ml, no prior exposure to d4T or 3TC, and no more than 14 days' exposure to any other antiretroviral agent. There was no restriction on CD4+ cell count. Eighty percent of the study population was male, and 57% was Caucasian. Data obtained from this study were presented that help define the time needed for many treated patients to achieve undetectable levels of plasma HIV RNA as measured by ultra-sensitive viral load assays (< 50 copies/ml).
The trial showed that almost all patients who ultimately demonstrated viral suppression of HIV RNA below 400 copies/ml had done so by week 24, while a substantial portion of patients (20%) who ever achieved undetectable viral suppression (< 50 copies/ml) did so for the first time only after week 24.
Some patients require more than 24 weeks to achieve HIV RNA < 50 copies/ml, particularly those with baseline viral loads > 100,000 noted Martin S. King, PhD, Abbott Laboratories, Abbott Park, Illinois. Only 1 of 592 patients who ever demonstrated HIV RNA < 400 copies/ml did so for the first time after week 24, while 99 of 507 patients who ever demonstrated HIV RNA levels < 50 copies/ml did so for the first time after week 24. Only 7 patients (1.4%) first demonstrated HIV RNA < 50 copies ml after week 48.
The cumulative proportions of patients achieving HIV RNA values < 400 copies/ml or < 50 copies/ml are presented by treatment group.
Among patients initiating therapy with plasma HIV RNA levels greater than 100,000 copies/ml, viral suppression to below 50 copies/ml was eventually achieved in 84% of patients receiving lopinavir/ritonavir as compared with 60% of those treated with nelfinavir. Among both treatment groups combined, higher baseline viral HIV RNA load was associated with delayed achievement of viral suppression to HIV RNA < 50 copies/ml.
Based on this improved recognition of the time needed to achieve undetectable viral loads in ultrasensitive plasma HIV RNA assays, Dr. King and co-authors suggested that week 48 of treatment may be a more appropriate time than week 24 for assessing the full extent of suppression of HIV replication in treated patients and for distinguishing between potent antiretroviral regimens using a cutoff of HIV RNA < 50 copies/ml.
Decrease in Development of 3TC Resistance Seen with Lopinavir/ritonavir
Another analysis of data obtained from participants in the same comparative study of lopinavir/ritonavir and nelfinavir suggest that lopinavir/ritonavir may have an advantage over nelfinavir in decreasing the risk of development of resistance to the nucleoside analog components used in combination therapy antiretroviral regimens, especially those such as lamivudine (3TC), for which resistance readily emerges in the setting of ongoing HIV replication. In this study, Bernstein and colleagues characterized the resistance patterns in HIV isolates from treatment-naпve patients failing therapy with lopinavir/ritonavir or with nelfinavir. Genotypic analyses to assess the presence of mutations associated with resistance to specific antiretroviral drugs were available for 37 of 58 lopinavir/ritonavir-treated patients with viral loads > 400 copies per/ml at week 48, and for 76 of 102 nelfinavir-treated patients with viral loads > 400 copies per/ml at week 48. None of the patients in the lopinavir/ritonavir group demonstrated resistance to lopinavir; however, 33% of those in the nelfinavir arm displayed genotypic evidence of resistance to nelfinavir (p < 0.001). Mutations associated with 3TC resistance were observed in both treatment groups, but they were significantly more frequent in the nelfinavir-treated patients than in the lopinavir/ritonavir-treated patients-15/37 (41%) versus 62/76 (82%), respectively (p < 0.001). For this reason among others, Dr. Anthony Japour, Medical Director, HIV Franchise, Abbott Laboratories, believes that LPV/RTV is an ideal first-line PI.
"Adherence was similar between subjects for whom genotypic data were available, suggesting that the difference in emerging PI resistance was not due to differing levels of adherence between the two groups," noted B. Bernstein, MD, Abbott Laboratories, Abbott Park, IL, who reported the resistance data.
As expected, responders in both treatment groups reported significantly better adherence compared to non-responders for each adherence category (i.e., under 80% adherence rate or < 90% adherence rate; p < 0.001 for both categories)
After genotypic analysis of samples at week 24, a significantly greater proportion of lopinavir/ritonavir-treated subjects achieved viral suppression compared to nelfinavir-treated subjects-85% versus 32%, respectively (p < 0.001).
"These results suggest that the consequence of detectable viral load may be different for subjects receiving lopinavir/ritonavir-based therapy than for those receiving nelfinavir-based therapy," said Dr. Bernstein.
Patterns of Cross Resistance between Lopinavir/ritonavir and Other PIs
The study reported by Dr. Bernstein confirmed that, to date, 0% of the 326 antiretroviral-naпve patients, all of whom had a viral load > 400 copies/ml, treated with lopinavir/ritonavir for 48 weeks or longer have displayed PI resistance. Another study was undertaken to provide insight into potential treatment options for failures associated with lopinavir resistance, explained Scott Brun, MD, Abbott Laboratories, Abbott Park, Illinois.
In this study, isolates were analyzed from PI-experienced patients prior to treatment with lopinavir/ritonavir, in order to determine the correlation between in vitro phenotypic susceptibility to lopinavir versus other PIs. Further, the phenotypic susceptibility of virus isolates to lopinavir and other PIs was compared using viruses obtained from five PI-experienced patients who experienced viral rebound during lopinavir/ritonavir therapy.
This study showed that decreased susceptibility of viral isolates to lopinavir was highly correlated with decreased susceptibility to ritonavir (Norvir®) and indinavir (Crixivan®), but not with decreased susceptibility to amprenavir (Agenerase®) and saquinavir (Fortovase®). There was an intermediate correlation between lopinavir and nelfinavir. It appears that phenotypic resistance to amprenavir developed more slowly than phenotypic resistance lopinavir, and the accumulation of protease mutations was associated with reduced susceptibility to lopinavir, noted Dr. Brun.
Five PI-experienced patients were identified whose viral isolates developed resistance to lopinavir during rebound while on lopinavir/ritonavir therapy. In these five patients, rebound viruses either remained fully sensitive or demonstrated modestly reduced sensitivity to amprenavir despite the reduced susceptibility to lopinavir. Rebound isolates from the 3 patients with no prior saquinavir treatment remained fully sensitive to saquinavir and 2 isolates that were tested against tipranavir.
These results suggest that amprenavir and saquinavir are reasonable treatment options for patients who develop resistance to lopinavir.
Lopinavir/ritonavir in Children
A preliminary phase I/II open-label study in treatment-naпve and treatment-experienced pediatric patients showed that the liquid formulation of lopinavir/ritonavir was well tolerated by HIV-infected children. Only one drug-related discontinuation was reported in the 60-week, 100-patient study. Lopinavir/ritonavir was safe, with few study-drug-related moderate to severe adverse events or grade 3 or 4 laboratory abnormalities reported at 60 weeks.
Lopinavir/ritonavir demonstrated excellent antiviral activity, according to an intent-to-treat analysis, which showed that 77% of treatment-naпve children and 70% of treatment experienced children had HIV RNA < 400 copies/ml at week 60, said Xavier Saez-Llorens, MD, Hospital del Niсo, Panama City, Panama, who presented the data.
The pediatric study included children between the ages of 3 months and 12 years, with plasma HIV RNA > 400 copies/ml, and no prior non-nucleoside reverse transcriptase inhibitor (NNRTI) experience. Subjects were randomized to receive 2 dosage levels of lopinavir/ritonavir: 230/57.5 mg/m2 every 12 hours (n = 49) or 300/75 mg/m2 every 12 hours (n = 51). In addition to lopinavir/ritonavir, treatment-naпve subjects received d4T and 3TC, and treatment-experienced subjects received nevirapine and 1 or 2 nucleoside reverse transcriptase inhibitors (NRTIs) selected by the individual investigator. Following an analysis of safety and tolerability and week 3 pharmacokinetics, all patients were switched to a dose of lopinavir/ritonavir of 300/75 mg/m2 bid.
For contraindications and other prescribing information, visit http://www.kaletra.com or http://www.rxabbott.com/pdf/kaletrapi.pdf
Other Abstracts of Interest Presented at the 8th Conference on Retroviruses and Opportunistic Infections
Conway B, et al. A Pilot Study of Combinations of Delavirdine (DLV), Zidovudine (ZDV), Lamivudine (3TC) & Saquinavir- SGC (Fortovase, FTV) as Initial Antiretroviral Therapy: Virologic and Pharmacokinetic Considerations. Abstract No. 331.
Erickson-Viitanen S, et al. DPC 681 and DPC 684: Resistance and Cross- Resistance Profiles of Second Generation HIV Protease Inhibitors. Abstract No. 11.
Gulick RM, et al. Durability of Salvage Therapy with Saquinavir SGC (SQV) in Combination with Ritonavir (RTV) or Nelfinavir (NFV) plus Delavirdine (DLV), Adefovir Dipivoxil (ADV), or Both-ACTG 359: 48-Week Final Results. Abstract No. 338.
Harley W, et al. A 24-Week Randomized, Controlled, Open-Label Evaluation of Adherence and Convenience of Continuing Indinavir Versus Switching to Ritonavir/Indinavir 400 mg/400 mg BID (The NICE Study). Abstract No. 334.
Joly V, et al. Assessment of Lipodystrophy in Patients Previously Exposed to AZT, ddI or ddC, but Naive for d4T and Protease Inhibitors (PI), and Randomized Between d4T/3TC/Indinavir and AZT/3TC/Indinavir (NOVAVIR Trial). Abstract No. 539.
Kline MW, et al. A Randomized Trial of Combination Therapy with Saquinavir Soft Gelatin Capsules (SQV) in HIV-Infected Children. Abstract No. 683.
Lalezari J, et al. A Controlled Phase II Trial Assessing Three Doses of T-20 in Combination with Abacavir, Amprenavir, Low Dose Ritonavir and Efavirenz in Non-Nucleoside Naпve Protease Inhibitor Experienced HIV-1 Infected Adults. Abstract No. LB5.
Squires K, et al. Final 48-Week Results of a Phase II, Randomized Study of the Safety, Efficacy, and Pharmacokinetics of BID vs TID Nelfinavir and Saquinavir in Combination with Lamivudine and Stavudine in HIV-Positive Women (Women First Trial). Abstract No. 330.
Van Der Valk M, et al. Nevirapine Containing Potent Antiretroviral Therapy Results in Ananti-Atherogenic Plasma Lipid Profile: Results from the Atlantic Trial. Abstract No. 654B.
Wood R, et al. GW433908, a Novel Prodrug of the HIV Protease Inhibitor (PI) Amprenavir (APV): Safety, Efficacy, and Pharmacokinetics (PK) (APV20001). Abstract No. 333.