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Novel Four-Drug Salvage Treatment Regimens after Failure of a Human Immunodeficiency Virus Type 1 Protease Inhibitor-Containing Regimen: Antiviral Activity and Correlation of Baseline Phenotypic Drug Susceptibility with Virologic Outcome

  1. Steven G. Deeks,
  2. Nicholas S. Hellmann,
  3. Robert M. Grant,
  4. Neil T. Parkin,
  5. Christos J. Petropoulos,
  6. Mark Becker,
  7. William Symonds,
  8. Margaret Chesney and
  9. Paul A. Volberding
  1. University of California, San Francisco, San Francisco General Hospital, ViroLogic, Inc., and Gladstone Institute of Virology and Immunology, San Francisco, and Agouron Phamaceuticals, La Jolla, California; Glaxo-Wellcome, Research Triangle Park, North Carolina
  1. Reprints or correspondence: Dr. Steven G. Deeks, UCSF, 995 Potrero Ave., San Francisco General Hospital, San Francisco, CA 94110 (sdeeks{at}sfaids.ucsf.edu).

  1. Presented in part: 12th World AIDS Conference, Geneva, July 1998 (abstract LB22490); 2d International Workshop on HIV Drug Resistance and Treatment Strategies, Lago Maggiore, Italy, June 1998 (abstract 82).

 
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Abstract

Twenty human immunodeficiency virus—infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n = 10) or nevirapine (n = 10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P = .04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change = −2.24 log and −0.35 log, respectively; P = .01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

The goal of antiretroviral therapy is to maintain health and prolong life. According to current US guidelines, the optimal manner of achieving this goal is to suppress viral replication to below the level of quantitation by the most sensitive virus load assay available [1–3]. By definition, virologic failure occurs in any patient who is unable to achieve this goal. Although the clinical significance of virologic failure remains unclear, a detectable virus load implies a higher degree of viral replication and a more rapid selection for drug resistance. Since cross-resistance among antiretroviral drugs is common, failure of one regimen may reduce the efficacy of subsequent treatments.

Virologic failure in the presence of indinavir or ritonavir is often associated with well-characterized mutation patterns [4, 5]. In vitro, these mutations may confer high-level phenotypic cross-resistance to other protease inhibitors, including nelfinavir and saquinavir [4]. As a result, simply switching to a second protease inhibitor-containing regimen frequently fails to produce durable viral suppression [1, 2, 6, 7]. Therefore, treatment guidelines recommend 4-drug regimens containing 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 2 protease inhibitors, using, whenever possible, drugs to which the patient is naive [1]. Clinical experience, however, suggests that these regimens may have limited effectiveness [6, 7].

Non-NRTIs (NNRTIs), such as nevirapine, delavirdine, and efavirenz, are potent antiretroviral agents that generally have no cross-resistance with NRTIs or protease inhibitors. We designed a prospective pilot study to evaluate the role of NNRTIs in patients for whom a protease inhibitor-containing regimen failed. All subjects received a combination of nelfinavir, saquinavir soft-gel capsules, and abacavir (a potent NRTI undergoing clinical evaluation). The first 10 subjects received these three drugs with an additional NRTI, which was chosen on the basis of the patient's prior treatment experience. The second 10 subjects received these three drugs with nevirapine.

There is growing interest in the use of genotypic and phenotypic assays of antiretroviral drug resistance for patient management. Data evaluating the role of these assays in identifying effective drugs for salvage therapy are limited [8]. Therefore, after conducting the pilot intervention trial, we analyzed stored specimens in a blinded manner to evaluate baseline drug resistance as a predictor of subsequent response.

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Methods

Study design

This was an open-label, nonrandomized, single-center, prospective study. Subjects must have received at least 24 weeks of continuous therapy with a regimen containing 2 NRTIs and either indinavir or ritonavir immediately prior to study entry. Subjects were required to have a screening virus load > 2500 copies/mL (Amplicor HIV Monitor test; Roche Diagnostic Systems, Branchburg, NJ) and to be naive to nelfinavir, saquinavir (in either the hard- or soft-gel formulations), abacavir, and all NNRTIs. Subjects with a documented history of treatment nonadherence were excluded.

Subjects discontinued all antiretroviral therapy 7 days before initiation of study medications. The first 10 subjects enrolled (nucleoside arm) received a combination of nelfinavir (1250 mg twice daily), saquinavir soft-gel capsules (1200 mg twice daily), abacavir (300 mg twice daily), and an additional NRTI. The NRTI was selected on the basis of the subject's therapy history; an attempt was made to use a new NRTI to which the patient was naive. The selected NRTI was administered at the standard recommended dose. The second 10 subjects enrolled (nevirapine arm) received nelfinavir (1250 mg twice daily), saquinavir soft-gel capsules (1200 mg twice daily), abacavir (300 mg twice daily), and nevirapine (200 mg once daily for 2 weeks and then 200 mg twice daily).

The planned duration of the study was 24 weeks. All subjects were offered long-term therapy beyond 24 weeks with their originally assigned regimen.

Measurements

Safety evaluations (including hematology and serum chemistries) were performed, and virus load and T cell levels (CD4, CD8) were determined at baseline and every 4 weeks there-after. Plasma virus load was measured by use of a standard assay (Amplicor HIV Monitor test) that has a lower limit of quantitation of 500 RNA copies/mL. Samples that were undetectable using this assay were evaluated with an experimental polymerase chain reaction-based assay that has a lower limit of quantitation of 50 RNA copies/mL (Amplicor Ultrasensitive; Roche Diagnostic). Adherence was monitored prospectively using a standardized questionnaire developed by the Recruitment, Adherence, and Retention Subcommittee of the Adult AIDS Clinical Trials Group [9]. The questionnaire was administered at baseline and at every study visit.

Resistance testing

Viral genotyping and phenotypic drug susceptibility testing were done retrospectively in a blinded fashion on plasma samples obtained at baseline (day —7). Genotyping by direct sequencing of reverse transcriptase (codons 1–305) and protease (codons 1–99) was done on amplification products or pooled resistance test vectors (see below) by use of an automatic sequencer (Applied Biosystems, Foster City, CA). All sequences were proofread manually and aligned with a human immunodeficiency virus type 1 (HIV-1) strain (NL4-3; GenBank accession no. M19921) as a consensus sequence.

A novel recombinant virus-based assay (ViroLogic, Inc., South San Francisco) was used in phenotypic testing. In brief, resistance test vectors are constructed by inserting amplified patient-derived HIV-1 reverse transcriptase and protease sequences into a modified retrovirus vector derived from the pNL4-3 molecular clone of HIV-1. Resistance test vectors also contain a luciferase indicator gene, which is used to monitor the ability of the virus to replicate in the presence or absence of antiviral drugs. The virus vector is restricted to a single replication cycle by inserting the indicator gene within the env gene region.

The phenotypic assay is performed by cotransfecting 293 cells (human embryonic kidney cells) with resistance test vector DNA and an expression vector that produces amphotropic murine leukemia virus envelope protein. Pseudotyped virus particles are harvested after transfection and used to infect fresh 293 cells. Protease inhibitors are added to cells during transfection, and reverse transcriptase inhibitors are added to cells during infection. After infection, cells are lysed, and luciferase activity is measured. Drugs that inhibit reverse transcriptase or protease reduce the amount of luciferase activity in the target cell. The concentration of drug that inhibits luciferase activity by 50% (IC50) is used as a measure of drug susceptibility (data on file, ViroLogic). In reproducibility studies with the phenotypic assay, 195% of replicate IC50 results varied by < 2-fold, suggesting that larger increases in IC50 indicate reduced drug susceptibility.

For this study, duplicate phenotypic assays were done on each tested patient sample, and five replicate phenotypic tests were done on the drug-sensitive control virus: IC50 values for each study drug varied by < 2-fold across replicate tests for both the patient and control viruses (see footnote to table 1). Sequences from all patients who completed 24 weeks of therapy (n = 16; see table 1) have been provided to GenBank (accession nos. AF124541–56).

Figure 1
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Figure 1

Median change (25%–75% interquartile ranges) in baseline phenotype and virologic response over first 24 weeks of therapy for HIV-infected patients receiving novel 4-drug salvage treatment after failure of HIV-1 protease inhibitor-containing regimen. Virus was considered susceptible to assigned drug if IC50 was < 2-fold control virus. Subjects were categorized in 1 of 2 groups on basis of no. (0 or 1 [0/1] or 2 or 3 [2/3]) of drugs in treatment regimen to which baseline virus was susceptible. Only subjects who completed 24 weeks of therapy are shown; 1 subject could not be phenotyped at baseline due to presence of internal restriction enzyme cleavage site.

Table 1
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Table 1

Baseline HIV genotype, phenotype, and week-16 and week-24 virologic responses to therapy for 16 patients who received treatment with nelfinavir, saquinavir, and abacavir plus a nucleoside reverse transcriptase inhibitor (NRTI) or nevirapine (NVP) through week 24.

Before evaluating the results of phenotypic drug-susceptibility testing in this trial, we defined virus as being phenotypically sensitive to a specific drug if the IC50 of the subject's virus was < 2-fold greater than the IC50 of the drug-sensitive control virus. One subject's baseline virus was not phenotyped due to the presence of an internal restriction enzyme cleavage site within the amplified protease and reverse transcriptase fragment. For purposes of analysis, subjects were categorized according to the number of drugs in the treatment regimen to which the patient's baseline virus was sensitive (i.e., 0–4 drugs). Due to the small sample size in each phenotypic category, subjects with virus sensitive to 0 or 1 drug were grouped together and those with virus sensitive to 2 or 3 drugs were grouped together to avoid bias from the differential distribution of baseline phenotypes and virologic responses between treatment arms.

Statistical analysis

Median values (with interquartile ranges) were determined for baseline and outcome variables. The primary outcome measure was virus load change at week 24. Differences in week-24 virus load changes between groups were analyzed by use of the Wilcoxon rank sum test. Differences in categoric variables between patient groups were analyzed by use of Fisher's exact test. The predictive value of baseline phenotypic drug susceptibility for virologic outcome was analyzed by use of the Wilcoxon rank sum test and Fisher's exact test. Simple linear regression was utilized to analyze the correlation between number of baseline resistance mutations and change in virus load.

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Results

Baseline characteristics

A total of 20 subjects were enrolled (10 in each treatment group). As shown in table 2, the 2 groups were well matched in terms of baseline CD4 T cell count, baseline virus load, and prior exposure to NRTIs. All patients had previously received indinavir. Two subjects had received prolonged ritonavir after brief exposure to indinavir. One subject in the nucleoside group had received prior therapy with efavirenz, an NNRTI. Of note, all subjects had evidence of ongoing viral replication in the presence of indinavir or ritonavir for an extended period before switching to the study medications (median, 12.4 months; range, 4.1–25.2 months; data available for 17 subjects). Due to prior exposure or concern for potential side effects, only 4 subjects in the nucleoside group initiated a new NRTI.

Table 2
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Table 2

Baseline characteristics for 2 groups (n = 10 each) of HIV-infected patients receiving nelfinavir, saquinavir, and abacavir plus a nucleoside reverse transcriptase inhibitor (NRTI; another nucleoside analog) or nevirapine (NVP).

Drug safety, tolerability, and adherence

Sixteen subjects completed 24 weeks of study drug therapy. Three subjects in the nucleoside group discontinued therapy between weeks 4 and 8: 1 because of an increase in hepatic transaminase levels (a subject with hepatitis C), 1 because of abdominal pain, and 1 because of bacteremia related to an indwelling intravenous catheter. One subject in the nevirapine group discontinued therapy after 3 days due to diarrhea. Nineteen subjects treated with study drugs for ⩾4 weeks completed the self-administered treatment-adherence questionnaire. Through study week 24, measured treatment adherence was 95%–100% in 14 subjects, 90%–95% in 3 subjects, and 85%–90% in 2 subjects. Adherence was similar in both groups.

Plasma HIV-1 RNA and CD4 T cell levels

The median change in plasma HIV-1 RNA levels in each group is shown in tables 1 and 3. At week 24, the median decrease in virus load in the nucleoside group was −0.39 log10 copies/mL (range, −2.21 to 0.50; n = 7). The median decrease in the nevirapine group was −2.67 log10 copies/mL (range, −3.21 to −0.36; n = 9), which was significantly greater than in the nucleoside group (P = .02). At week 24, the plasma virus load was < 500 copies/mL in 1 of 7 subjects in the nucleoside group and in 7 of 9 in the nevirapine group (P = .04); virus load was < 50 copies/mL in 1 of 7 and 5 of 9 subjects in the 2 groups (P = .15). Baseline variables, including age, sex, CD4 cell count, plasma virus load, duration of prior protease inhibitor therapy, number of prior nucleoside agents used, and CD4 cell count before administration of protease inhibitors, did not predict virologic outcome (P > 0.05 for each baseline predictor, bivariate analysis).

Table 3
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Table 3

Virologic outcome at week 24 for 2 groups of HIV-infected patients receiving nelfinavir, saquinavir, and abacavir plus a nucleoside reverse transcriptase inhibitor (NRTI; another nucleoside analog) or nevirapine (NVP).

By week 36 of therapy, 1 subject in each group with an undetectable virus load (< 500 copies/mL) at week 24 experienced virologic rebound despite continued adherence with therapy. The remaining 6 patients (all in the nevirapine group) had < 500 copies/mL at week 36.

Correlation of baseline phenotype and genotype with virologic response

Baseline virus genotypes and virologic response for all 16 subjects who remained on therapy for at least 24 weeks are presented in table 1. The correlation between the number of primary resistance mutations at baseline [10] and the degree of virus load reduction at week 24 was not significant (r = .28, P = .30).

Fifteen subjects completed 24 weeks of study therapy and had results from baseline viral phenotypic drug susceptibility testing. As shown in figure 1 and table 1, subjects with virus sensitive to 0 or 1 drug at baseline generally had a transient virologic response to their treatment regimen. In contrast, subjects with virus sensitive to 2 or 3 drugs in their treatment regimen had a sustained antiviral response through week 24. The median change in plasma virus load at week 24 was −0.35 log copies/mL in subjects with baseline virus sensitive to 0 or 1 drug and −2.24 log copies/mL in subjects with virus sensitive to 2 or 3 drugs (P = .01). The correlation between baseline phenotypic drug susceptibility and virologic outcome was observed in both treatment arms (see table 1).

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Discussion

Although combination therapy has significantly decreased the morbidity and mortality associated with HIV disease [11, 12], a growing number of patients are unable to achieve durable virus suppression with current treatment regimens. Consistently effective salvage strategies for such patients have not been elucidated. For patients who experience virologic failure with an indinavir- or ritonavir-containing regimen, current treatment guidelines recommend regimens containing 2 new NRTIs and either ritonavir-saquinavir or nelfinavir-saquinavir [1]. In a retrospective analysis of patients followed at San Francisco General Hospital, the first option (ritonavir-saquinavir with 2 NRTIs) was rarely successful [6]. In the current study, the second option (nelfinavir-saquinavir with 2 NRTIs) had limited efficacy in suppressing viral replication.

After failure of an initial regimen, the goal of therapy is to switch to a new regimen of sufficient potency to durably suppress viral replication [1]. Due to broad cross-resistance, which can exist within each class of antiretroviral drugs, simply switching to new drugs within the same class may not provide sufficient potency. On the basis of our results, we believe that salvage regimens for patients experiencing virologic failure with an indinavir- or ritonavir-containing regimen should include at least one agent from a class of antiretroviral agents to which the patient is naive. Most subjects in this study who initiated a drug from a class to which they were naive (NNRTI) achieved an undetectable virus load through week 24 of therapy. Similar results with NNRTI-based salvage regimens were seen in a much larger observational study of protease inhibitor therapy recently performed at San Francisco General Hospital (13 of the 20 subjects in this study contributed to that observational study) [13]. However, the decision to use an NNRTI in a salvage regimen needs to be weighed against the concern that subsequent failure will likely exhaust the patient's therapeutic options. The optimal timing of when to use NNRTIs after failure of protease inhibitor-based therapy is unclear and merits further study.

As a class, NNRTIs are potent and generally well tolerated. Recent data suggest that these drugs, in combination with 2 NRTIs, may be an effective first-line option for treatment-naive patients [14]. The activity of the NNRTIs in patients for whom protease inhibitor therapy has failed has not been reported. Due to the rapid high-level resistance that can occur with these agents, NNRTIs are unlikely to be effective unless other active agents can be initiated concurrently. In this study, 2 nevirapine-treated patients had baseline virus that was sensitive only to nevirapine. Both patients experienced rapid drug failure. Therefore, aggressive regimens combining the NNRTI with drugs that retain at least some antiviral activity are likely to be required.

Due to the complexities of selecting effective salvage treatment regimens and the high prevalence of drug-resistant virus in previously treated patients, the use of drug-resistance assays to evaluate a patient's virus has potential clinical benefits for patient management [8]. Currently, both genotypic and phenotypic assays are undergoing clinical development. Recognizing the lack of a consensus on the significance of specific genotypic mutations [8], we made no attempt in this study to correlate baseline genotype with virologic response. Larger studies evaluating the role of genotyping in the setting of salvage therapy are currently underway.

Phenotypic assays may provide a more direct measure of drug activity than genotypic assays; however, phenotypic assays are generally more costly, take longer to perform, and require specialized facilities [8]. New high-throughput, rapid turnaround recombinant vector-based phenotypic assays are being developed [15, 16]. In this pilot study, the predictive value of one such phenotypic assay was tested retrospectively. Subjects with a baseline virus phenotypically sensitive to at least 2 of the 4 drugs in the treatment regimen had a potent virologic response through week 24 of therapy, while those subjects whose baseline virus was sensitive to 0 or 1 drug had a transient response or no response. This observation suggests that phenotypic susceptibility testing may play a role in designing patient-specific salvage regimens. Prospective studies are necessary to validate this approach.

This study has several limitations. First, the study was not randomized. Due to the unknown safety of these 4-drug combinations, safety data on nelfinavir-saquinavir and abacavir was necessary before adding the NNRTI. Second, the sample size was small. Although the difference between the 2 groups was statistically significant, larger studies are necessary to confirm our conclusions. Third, pharmacokinetic studies were not done. It is possible that the doses used in this study were not optimal. Nelfinavir increases saquinavir levels ∼5-fold and, thus, potentially allows reduced twice-daily dosing of saquinavir soft-gel capsules [17]. Nevirapine, an inducer of cytochrome P-450 CYP3A, reduces saquinavir levels [18] but probably not nelfinavir levels [19]. The effect of nevirapine on the combination of nelfinavir and saquinavir has not been studied and is difficult to predict. Clinicians should therefore view the data presented with caution. Future studies may indicate that the dose of nelfinavir or saquinavir (or both) may need to be adjusted when used with nevirapine. Fourth, 18 patients had received indinavir only, while 2 had received prior ritonavir. Considering the nearly overlapping resistance patterns of these 2 drugs [4, 5], we believe that response to salvage therapy would be similar for patients not responding to therapy with either drug [1]. Finally, all patients in this study switched to a salvage regimen long after initial indinavir- or ritonavir-containing regimens failed. Response rates to either treatment arm may have been better if patients switched soon after treatment failure, as is currently recommended [1,2]. Theoretically, continued therapy with a failing regimen selects for high-level resistance and cross-resistance.

In summary, our data suggest that potent viral suppression may be possible after failure of an indinavir- or ritonavir-containing regimen and that NNRTIs may be an important component of salvage treatment regimens in NNRTI-naive patients. Also, novel phenotypic drug susceptibility assays hold promise as valuable tools to assist clinicians in selecting optimal salvage regimens.

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Acknowledgments

We acknowledge Laurent Fischer for his assistance in designing and implementing this study. We would also like to acknowledge Kory McGuire and Dorrie Heeren for coordinating the clinical study, Don Chambers for analyzing the adherence data, and Kay Limoli, Jeannette Whitcomb, Terri Wrin, and Tina Tian for performing the phenotypic and genotypic testing.

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Footnotes

  • ↵N.S.H., N.T.P, and C.J.P. are employed by ViroLogic, Inc., which is developing the phenotypic assay described herein; M.B. is employed by Agouron Pharmaceuticals, the manufacturer of nelfinavir; and W.S. is employed by Glaxo-Wellcome, the manufacturer of abacavir.

  • This study was approved by the Institutional Review Board of the University of California, San Francisco. Informed consent was obtained from all subjects.

  • Grant support: NIH (AI-27763 to University of California, San Francisco Center for AIDS Research); Agouron Pharmaceuticals; Glaxo-Wellcome; Hoffmann—La Roche.

  • Received October 27, 1998.
  • Revision received February 2, 1999.
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  1. J Infect Dis. (1999) 179 (6): 1375-1381. doi: 10.1086/314775
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