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Case 3: Discussion

Principles of Resistance to NNRTIs

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) exert their antiviral effect against HIV by binding to reverse transcriptase in a hydrophobic pocket located next to the active site of the enzyme, causing a conformational change in this enzyme that blocks the process of DNA polymerization (Figure 1). The region of binding predominantly involves amino acid codons 98-108 and 179-190 in the hydrophobic pocket[2]. Resistance to NNRTIs occurs as a result of mutations that inhibit effective binding of the NNRTI, thus allowing DNA polymerization to proceed in an unrestricted manner (Figure 1). The specific mutations associated with resistance to NNRTIs correlate with amino acid changes in the pocket where the NNRTI drug preferentially binds. Although the three NNRTI drugs--efavirenz (Sustiva), nevirapine (Viramune), and delavirdine (Rescriptor)--bind to the same general area, subtle differences exist in the interaction of the specific drug and the hydrophobic pocket, and as a result drug-specific mutations can develop. Unfortunately, the emergence of characteristic NNRTI-associated mutations correlates with rapid virologic rebound and high-level phenotypic resistance. These characteristic mutations presumably exist at low levels in all antiretroviral therapy-naive patients. When an NNRTI is used in a sub-optimal regimen, or when patients do not adhere to therapy, NNRTI-resistant mutants can be selected within 1-4 weeks[2,3].

NNRTI Resistance Profiles

Among patients who fail combination antiretroviral therapy that includes efavirenz, the NNRTI mutations most often associated with early virologic failure are K103N, Y188L, and G190 S/A (Figure 2). The K103N mutation is the most common to emerge and it correlates with high-level resistance to efavirenz. The patient in this case study experienced virologic failure on an efavirenz-base regimen with the emergence of the K103N mutation and we would expect the patient to have high-level phenotypic resistance to efavirenz. Although early virologic failure with efavirenz characteristically involves a single mutation, such as the K103N mutation (or dual mutations), persistent virologic failure leads to the accumulation of multiple mutations that may include L100I, V108I, Y181C/I, and P225H; the development of these multiple mutations enhances the level of NNRTI resistance[2,5]. Among patients who fail combination antiretroviral therapy that includes nevirapine, approximately 80% of patients with early virologic failure develop the K103N or Y188C/L/H mutation (Figure 2). In about 20% of patients, the mutations V106A/M or Y181C/I emerge as the initial mutation[6]. Patients treated with nevirapine monotherapy most commonly develop the Y181C mutation[3]. It appears that the Y181C is less likely to emerge in persons taking a thymidine analogue, namely zidovudine (Retrovir) or stavudine (Zerit). With early delavirdine failure, the K103N or Y181C is generally observed as the initial mutation (Figure 2).

NNRTI Cross Resistance

The single point K103N mutation is the most common mutation to occur in patients who fail an NNRTI-based regimen and this mutation clearly confers cross-resistance to efavirenz, nevirapine, and delavirdine[2,6]. Because the patient in this case study developed the K103N mutation while on efavirenz, we would not expect a significant virologic effect from using nevirapine or delavirdine in a subsequent salvage regimen. Conflicting data exist regarding cross-resistance and the Y181C mutation. Early data from ACTG 241 suggested that the Y181C mutation conferred resistance to nevirapine and delavirdine, but not necessarily to efavirenz[8]. In one small retrospective study, nevirapine-treated patients who developed the Y181C mutation had good responses to a subsequent efavirenz-based regimen[9]. Other reports, however, have not shown consistently good virologic responses with the use of efavirenz in the setting of the Y181C mutation[10,11,12]. Based on available data, there is no clear evidence that patients failing one NNRTI could sequence to another FDA-approved NNRTI. Thus, we believe it is generally inadvisable to try to rescue patients who have failed an NNRTI-based regimen on a new NNRTI-based regimen, even if the new regimen involves a different NNRTI. Currently, clinical development is ongoing with several second generation NNRTIs that retain significant activity against viral strains that have developed common NNRTI-associated mutations. Future availability of true second-generation NNRTIs could lead to sequencing strategies for use of drugs in this class.

Archived Resistance

In this case study, although the K103N mutation observed on the initial genotype was not detected on the second genotype a year later, the results of the first genotype remain clinically relevant. Among chronically-infected persons who develop resistance in response to antiretroviral therapy, populations of wild-type and resistant strains of HIV will likely co-exist. Antiretroviral drug pressure selects for the preferential replication of resistant strains that eventually dominate the circulating viral population and genotypic resistance assays can detect these resistance mutations. In the absence of drug therapy that selects for resistance mutations, however, the balance of wild-type populations versus resistant populations may shift over time, with wild-type virus potentially re-establishing the position as the predominant circulating strain of HIV. Because resistance assays do not reliably identify strains of HIV that constitute a low percentage (generally defined as less than 10 to 20%) of the overall viral population, minority resistant strains may evade detection by resistance assays in chronically infected persons who discontinue therapy. Unfortunately, resistance mutations that have developed on a previous antiretroviral regimen generally remain 'archived' at low levels in the body, and typically re-emerge to confer resistance when these agents are re-introduced[13]. Hence, it is best to think of resistance as the cumulative sum of all resistance that has developed in the patient's past, recognizing that a recent resistance assay may not detect all of these resistance mutations. When considering a salvage regimen, the clinician should consider the patient's past clinical responses to prior treatment regimens as well as the results of past resistance assays when designing a salvage regimen.

Resistance with NNRTIs and Viral Fitness

All resistance mutations have the potential to impair viral replication. Mutations in the NNRTI class appear to have markedly less impact on viral replication than do protease inhibitor-related mutations[1,13]. Taken together, data from multiple studies suggest the K103N mutation has minimal impact on viral fitness and thus virus that contains the K103N mutation can exists as a highly resistant and highly fit virus[2]. Accordingly, most experts do not recommend continuing NNRTI medications in the setting of the K103N mutation.

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    Figure 1. NNRTI Mechanism of Action and Mechanism of Resistance

    With drug-sensitive virus, drugs in the NNRTI class bind to the hydrophobic pocket near the active site of reverse transcriptase and block DNA polymerization. With NNRTI-resistant virus, the NNRTI binding is blocked and DNA polymerization can proceed normally. This figure is from Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350:1023-35. The figure was reproduced with permission from the Massachusetts Medical Society. Copyright © 2004 Massachusetts Medical Society. All rights reserved.


    Figure 1
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    Figure 2. International AIDS Society-USA Fall 2006 Mutation Figures. Mutations of the Reverse Transcriptase Gene Associated with Resistance to Reverse Transcriptase Inhibitors: Nonnucleoside Reverse Transcriptase Inhibitors

    This figure is reprinted with permission from the International AIDS Society-USA. Johnson VA, Brun-Vézinet 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 2