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Case 4: Discussion

Nelfinavir (Viracept) is one of 8 protease inhibitors approved by the U.S. Food and Drug Administration (FDA) for use in combination antiretroviral therapy. Multiple studies have shown that nelfinavir-based regimens provide good virologic and immunologic responses when used as initial therapy in antiretroviral-na?ve patients[1,2]. Subsequent studies, however, have demonstrated superior efficacy of several of the newer protease inhibitors, such as lopinavir-ritonavir (Kaletra) and fosamprenavir (Lexiva). The 2006 DHHS antiretroviral therapy guidelines classify nelfinavir-based combinations as alternative regimens[5]. Nevertheless, because nelfinavir was widely used in previous years and continues to have some current use, important issues remain regarding resistance to nelfinavir and the use of subsequent therapy after development of resistance to nelfinavir. In addition, with the availability of the nelfinavir 625 mg tablets in May 2004, there was some renewed interest in using this protease inhibitor.

Resistance Mutations with Nelfinavir

Among patients who develop virologic failure while taking a nelfinavir-based regimen as initial antiretroviral therapy, the D30N mutation is the most common protease mutation to emerge (Figure 1)[6,7,8,9,10]. The D30N mutation represents a change in the 30 codon position with aspartic acid (D) replaced by asparagine (N). Trials have not shown selection of the D30N mutation by protease inhibitors other than nelfinavir. The next most common mutation generated by nelfinavir is L90M, a mutation that can also emerge with failure of other protease inhibitors and that causes fairly broad cross-resistance within the class. In a double-blind trial that compared lopinavir-ritonavir versus nelfinavir combined with the backbone of stavudine (Zerit) plus lamivudine (Epivir)[2], virologic failure in the nelfinavir arm was associated with the development of the D30N mutation in 29% and the L90M in 15% of cases[7]. In an analysis of 4 clinical trials and 2 cohort studies involving nelfinavir, virologic failure was associated with the D30N mutation in 31% and L90M in 5% of cases[10]. With prolonged nelfinavir failure, additional protease-related mutations (secondary mutations) typically develop. In the California Collaborative Treatment Group 575 study, investigators performed phenotypic analysis of viral isolates from patients who experienced virologic failure on a protease inhibitor-containing regimen and found that patients failing nelfinavir-based regimens remained more susceptible to other protease inhibitors than did patients failing indinavir-based regimens (Figure 2)[11]. Investigators found similar results in the VIRA 3001 study (Figure 3)[12]. These results suggest a high likelihood of response to subsequent protease inhibitor-based therapy after development of virologic failure on a nelfinavir-based regimen. By comparison, resistance testing in patients who develop virologic failure while taking a lopinavir-ritonavir-based regimen as initial antiretroviral therapy has generally shown no evidence of genotypic or phenotypic resistance to lopinavir-ritonavir[7].

Response After Virologic Failure with Nelfinavir

Several studies have demonstrated successful responses to subsequent therapy after virologic failure on a nelfinavir-based regimen. In an analysis of 26 patients who developed virologic failure (2 consecutive HIV RNA values greater than 5,000 copies/ml) on a regimen that contained nelfinavir, patients switched to a regimen that consisted of stavudine plus lamivudine plus ritonavir (Norvir) plus saquinavir (Invirase) and had excellent results[13]. The mean HIV RNA prior to switch was 48,624 copies/ml. Genotype analysis performed prior to the switch showed the D30N in 72% of patients and the L90M mutation in 28%. Excluding 2 patients who discontinued the study at 3 weeks because of gastrointestinal intolerance, the remaining 24 patients achieved an HIV RNA value less than 500 copies/ml, and 17 (71%) of 24 had a sustained HIV RNA value less than 500 copies/ml at week 24 (Figure 4). The response did not correlate with the pre-switch genotype but did correspond with HIV RNA values at the time the switch occurred. In another study, 43 patients who experienced virologic failure while taking a nelfinavir-containing regimen switched to a subsequent regimen of adefovir plus efavirenz (Sustiva) plus indinavir (Crixivan)[14].The genotype performed prior to switch showed 59% had developed the D30N and 38% the L90M mutation. A response with HIV RNA less than 400 copies/ml at week 48 was observed in 56% of patients who had the D30N mutation and in 18% of those with the L90M mutation. Finally, in a study that involved 24 patients who failed a nelfinavir-based regimen and received salvage therapy, 78% achieved at least one HIV RNA level less than 50 copies/ml, and 61% had an HIV RNA less than 50 copies/ml at week 24[9]. In this study, the best responses to salvage therapy occurred in patients who developed the D30N mutation. Taken together, available data suggest effective treatment options exist after virologic failure on a nelfinavir-based regimen, especially when the D30N mutation is the only major protease resistance mutation. The data on response to subsequent therapy following the development of the L90M mutation are conflicting.

Virologic Fitness with Nelfinavir-Induced Mutations

Available data suggest that HIV isolates that have developed a D30N mutation have decreased viral fitness when compared with wild-type HIV. In one study, investigators estimated that virus expressing D30N was 37% less fit than wild type virus, and that the L90M mutant was 10% less fit than wild type[15]. In addition, these investigators speculated that the reduced replicative capacity associated with the D30N mutation would potentially have multiple effects, including shortening the duration that mutant virus would persist following withdrawal of nelfinavir, decreasing the likelihood for transmission of this mutant virus to another person, and diminishing the likelihood that the mutant virus would persist in a newly infected host in the absence of selective pressure by nelfinavir[15]. These issues related to replicative capacity are probably not relevant in most patients since the goal of antiretroviral therapy is to obtain full virologic suppression. The issue of decreased replicative capacity would potentially have more relevance for a patient who had experienced virologic failure with multiple antiretroviral regimens and had reached a point that they could not achieve full virologic suppression with currently available antiretroviral medications.

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    Figure 1. International AIDS Society-USA Fall 2006 Mutation Figures. Mutations of the Protease Gene Associated with Resistance to Protease Inhibitors

    This figure is reprinted with permission from the International AIDS Society-USA. Johnson VA, Brun-V├ęzinet F, Clotet B, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD. Update of the Drug Resistance Mutations in HIV-1: Fall 2006. Topics HIV Med. 2006;14:125-30. The accompanying usernotes, updates of the figure, and additional information available at: www.iasusa.org.


    Figure 1
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    Figure 2. Analysis of HIV Phenotypic Patterns in Patients Failing a Protease Inhibitor-Based Regimen

    This study involved patients who experienced virologic failure (HIV RNA greater than 400 copies/ml) while taking a protease inhibitor-based regimen for at least 3 months. Susceptibility results are shown for multiple protease inhibitors, based on prior virologic failure with indinavir or nelfinavir. Reduced phenotypic susceptibility is defined as a greater than 4-fold increase in the 50% inhibitory concentration compared with drug-sensitive virus. This figure is based on data from Kemper CA, Witt MD, Keiser PH, et al. Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors. AIDS. 2001;15:609-15.


    Figure 2
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    Figure 3. Cross-Resistance to Protease Inhibitors After Virologic Failure with Indinavir or Nelfinavir

    This study involved 225 patients who had HIV RNA greater than 2,000 copies/ml while receiving highly active antiretroviral therapy with 2 nucleoside reverse transcriptase inhibitors and one protease inhibitor. The results are presented based on prior virologic failure (greater than 4-fold phenotypic resistance) with indinavir or nelfinavir. The results show phenotypic susceptibility to 5 different protease inhibitors, with reduced phenotypic susceptibility defined as a greater than 4-fold increase in the 50% inhibitory concentration compared with drug-sensitive virus. This figure is based on data from Cohen CJ, Hunt S, Sension M, et al. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. AIDS. 2002;16:579-88.


    Figure 3
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    Figure 4. Response to Saquinavir plus Ritonavir-Based Regimens after Virologic Failure with Nelfinavir

    The graph shows the virologic response (percentage of patients who achieved an HIV RNA less than 500 copies/mL at 24 weeks) in patients treated with a saquinavir plus ritonavir-based antiretroviral regimen after failing a nelfinavir-based antiretroviral regimen. Patient responses varied depending on whether their HIV RNA at the time of the switch was greater than or less than 30,000 copies/ml. This figure is based on data from Tebas P, Patick AK, Kane EM, et al. Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS. 1999;13:F23-8.


    Figure 4