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Evaluation of nevirapine-switch strategies for HIV treatment
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REVIEW ARTICLE
HIV Medicine
Volume 7 Issue 8 Page 537 - November 2006
CL Cooper1
1Division of Infectious Diseases, University of Ottawa Hospital, The Ottawa Hospital-General Campus, Ottawa, Ont, Canada
Despite the benefits of protease inhibitor (PI)-based HIV treatment, issues of tolerability, dosing frequency, pill count and long-term metabolic complications necessitate evaluation of alternate treatment strategies. The weight of evidence demonstrates that a switch from a PI-based regimen to one containing nevirapine can be accomplished safely while maintaining virological suppression. There is no immunological cost. There is probably an overall benefit in terms of the metabolic milieu.
Introduction
Protease inhibitor (PI)-based combination antiretroviral therapy is well established as a first-line choice in HIV treatment [1]. This practice is based on proven virological potency and durability, reduced opportunistic infection rates, diminished hospitalization and reduced death rates [2,3]. Nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy, for the same reasons, is also considered as standard of care for the treatment of HIV infection [4-6]. Despite the many benefits of PI-based treatment, issues of tolerability, dosing frequency, pill count and long-term metabolic complications necessitate evaluation of alternative treatment strategies.
One approach to address the above concerns is to switch patients to NNRTI-based treatment once virological suppression has been achieved with PI-based therapy. The purpose of this report is to identify a safe and rational approach to this strategy using nevirapine (NVP). Pharmacokinetic issues, switch methodology, and variables impacting NVP switch safety and efficacy are considered in detail.
Methods
A Medline search using the headings 'nevirapine' and 'switch' was utilized to identify published literature of relevance to this report. Abstracts from major international HIV/AIDS meetings were reviewed. Where possible, recommendations are based on peer-reviewed, published material. In the absence of available data, recommendations are opinion-based.
Results
Selected literature
Thirteen published manuscripts and three key review articles [7-9] specifically pertaining to NVP switch studies were identified (Table 1). Several conference abstracts providing additional valuable information were retrieved. These studies were all conducted in economically developed countries, mainly in Europe (the UK, Spain, Italy and France), with one each in the USA and Australia. Seven publications reporting results from randomized switch protocols were reviewed in great detail and are discussed comprehensively [10-17]. Two major retrospective cohort studies are considered [18-20].
Variables determining switch efficacy
General factors influencing switch success A primary concern related to any switch from virologically potent and durable HIV drug therapy is that virological suppression will be lost. Prior switch studies have mandated a minimum period of maximal virological suppression on PI-based therapy prior to initiation of a switch to NVP. This period of time usually ranges from 3 to 9 months. With this approach, the incidence rate of virological failure post-switch generally ranges from 5 to 10%. This rate does not differ from that in patients remaining on their original PI regimen (see 'Virological and immunological outcomes' section). The duration of virological suppression prior to switch probably influences the subsequent success with a NVP switch. A high rate of virological suppression maintenance was achieved in those switched to NVP after a minimum of 9 months of PI-based highly active antiretroviral therapy (HAART) despite the fact that 75% of this cohort had received nonsuppressive therapy [i.e. dual nucleoside reverse transcriptase inhibitor (NRTI) therapy] before HAART [14]. The effect of selection bias influences interpretation of these results, as a history of a demonstrated ability to take antiretroviral therapy predicts future treatment success.
NVP switch was more successful in maintaining virological suppression at 1 year in those who remained on the same nucleoside backbone [relative risk (RR) 0.2, 95% confidence interval (CI) 0.1-0.6] compared with those who switched both PI to NVP and nucleoside backbone to a new combination of NRTIs [20]. Additional changes in therapy subsequent to NVP switch were more likely in patients who underwent treatment change for toxicity-related reasons (RR 2.5, 95% CI 1.7-3.5) as opposed to other issues (i.e. treatment failure or pharmacological indication). Both factors should be considered when a switch to NVP is being contemplated.
Virological and immunological outcomes Switch studies consistently demonstrate that NVP substitution can be performed without excess virological failure (Table 2). In fact, some studies suggest that the risk of virological breakthrough is diminished as a result of improved adherence [17]. In general, published switch studies have involved subjects without prior NNRTI exposure. In such patients, virological suppression is usually maintained. For example, 96% of on-treatment subjects (n=22 of 23) randomized to NVP from PI-based therapy at 12 months remained suppressed [14]. The one failure in this group was attributed to poor adherence. Of interest, a mean CD4 count increase of 115}193 cells/μL was noted, which was comparable to the other arms of this study (i.e. switch to efavirenz (EFV) and continued PI-based therapy).
In subjects with a history of NNRTI exposure prior to initiation of a PI-based regimen (i.e. the regimen that was subsequently switched to NVP-based treatment), the potential for resistance is obvious [21,22]. The issue of prior drug exposure is clinically relevant. The ATHENA database was retrospectively evaluated to compare treatment outcomes of subjects on virologically suppressive HAART (i.e. <500 HIV-1 RNA copies/mL) switched to NVP regimens with those of subjects switched to PI-based treatment. Dieleman et al. [20] reported a high treatment failure rate at 1 year (42%). The 1-year crude relative risk for discontinuation of a nevirapine-based regimen was 5-fold lower than that for those on PI treatments (0.2; 95% CI 0.1-0.3) and the median time to regimen failure was longer for NVP recipients (22 weeks) compared with those receiving PIs (17 weeks) [19,20]. Antiretroviral experience before their first PI-based HAART regimen was a variable predicting treatment failure (N.B. this outcome included both virological failure and treatment discontinuation) in those switched to a second PI or NVP regimen [19]. The negative effect of prior antiretroviral experience on switch outcome has been corroborated [10,23].
Dieleman et al. reported continued increases in CD4 cell count from baseline in both those switching to NVP and those who remained on PIs [19]. The median increase was approximately 100 cells/μL at 48 weeks and did not differ between groups. In a similar population of subjects followed for 1 year, Ruiz et al. reported mean CD4 count increases of 112 cells/μL in NVP switch subjects and 76 cells/μL in those randomized to remain on PIs (the difference was not significant) [11].
Low trough plasma concentrations of NVP have been associated with virological rebounds in HIV-infected patients switched from PI-based therapies [24]. Inadequate NVP concentrations were noted in 85% of subjects with virological failure. As in other studies, the duration of virological suppression prior to switch predicted the relative risk of virological success by multivariate analysis (RR 1.39; 95% CI 1.10-1.76; P=0.006). It is noteworthy that 3 years after the NVP switch, 70% of this cohort remained virologically suppressed, which supports the practice of NVP switch.
The majority of studies suggest that the occurrence of virological breakthrough is not higher in those switched to NVP compared with those switched to EFV or abacavir (ABC) [13-15]. Furthermore, the CD4 count is consistently observed to increase (overall range approximately 50-150 cells/μL) and does not differ among NVP, EFV and ABC switch regimens [13-15].
Metabolic considerations A switch from alternate regimens has been justified on the basis of the premise that NVP regimens are 'lipid friendly' compared with PI-based treatment. In fact, several short-term switch studies have reported improved metabolic profiles [16,17,25-27] (Table 3). There is considerable variation in the results of these short-duration evaluations because of heterogeneous study populations, differing definitions and methods of evaluating metabolic changes, and nonstandardized backbone antiretrovirals. The results of longer duration studies have proven to be more homogeneous. At 12 months of therapy post switch, a mean reduction in low-density lipoprotein (LDL) cholesterol, total cholesterol and triglycerides was reported with NVP which was not observed in efavirenz recipients or those who were randomized to remain on previous PI-based treatment [14]. No change in high-density lipoprotein (HDL) cholesterol or glucose metabolism was observed in any study arm. No change in body habitus in those with predefined lipodystrophy at baseline was identified by anthropometric measurement or dual energy X-ray absorptiometry (DEXA) (n=20 of 26 patients in total). Similar results were reported at 48 weeks in terms of reduced cholesterol and triglycerides and no improvement in body habitus for those randomized to switch to NVP and those who remained on pre-existing PI regimens [11]. Calza et al. also reported greater reductions in plasma triglycerides and total cholesterol levels 12 months after a randomized switch to NVP (n=29) compared with those switched to efavirenz (n=34) [15]. Two other arms were randomized to remain on PI therapy and receive pravastatin (n=36) or bezafibrate (n=31). The percentage of patients achieving normal triglyceride levels after 12 months was 51% in lipid drug recipients compared with 19% of those switched to NNRTI therapy [odds ratio (OR) 4.48; 95% CI 1.5-6.2; P<0.01). Normal cholesterol was achieved in 49% of pravastatin or bezafibrate recipients vs 18% of NNRTI-treated patients (OR 4.62; 95% CI 1.7-6.6; P<0.01). Currently, this is the only study that has evaluated the relative efficacy of lipid-lowering medications compared with NNRTI-switch strategies for correcting PI-related hyperlipidaemia.
Twenty-four-month metabolic data have been provided for NEFA (nevirapine, efavirenz and abacvir). Study subjects randomized to switch from PI-based treatment to NVP (n=29), EFV (n=32) or abacavir (n=29) [13]. The mean HDL cholesterol increased by 21% after 24 months in those switched to NVP. Of note, this increase was similar to that observed in those switched to EFV. No change in HDL cholesterol from baseline was noted in ABC recipients. In contrast, the total cholesterol level decreased in the ABC arm (14%) but not in the NNRTI arms. As a result of these changes in lipid profile, the median total cholesterol to HDL cholesterol ratio decreased in both NNRTI-containing treatment arms (NVP 19%; EFV 14%) at 24 months. There was no significant change from baseline in lipodystrophy measures or peripheral lipoatrophy over the 24-month course of evaluation. This was true for those with and without body habitus changes at the time of switch. One limitation of this study is that 78% of patients were on stavudine, which may have attenuated any beneficial metabolic effects of NVP, EFV and/or ABC treatment.
Liver toxicity In antiretroviral-naive populations, the NVP hypersensitivity reaction (i.e. rash, fever, eosinophilia, increased liver enzymes, etc.) occurs during a period of time in which the immunological milieu is transformed from one of immune hyperstimulation and relative anergy to one of immune reconstitution. This paradigm may help explain why the hypersensitivity reaction is only observed within the first several months of therapy [28]. It is unclear what effect the relative immune stability produced by stable, long-term antiretroviral therapy has on the incidence of hypersensitivity reaction following a switch to a NVP-based regimen. This may result in a reduction in incidence as there is less of a change in the background immune status. This is supported by evaluation of the ATHENA cohort, in which no episodes of clinically overt liver toxicity were observed in 125 subjects with HIV RNA levels <500 copies/mL switched from PI regimens to nevirapine [19]. However, it is theoretically possible that the incidence of hypersensitivity reaction may be increased, as most subjects would have higher CD4 cell counts following a prolonged course of effective antiretroviral therapy compared with those not on therapy when initiating treatment.
Imperiale et al. reported a low incidence of hepatic events in patients switching from PIs to NVP in a composite analysis of 12 studies [29]. Of these patients, 2.9% discontinued therapy as a result of liver-related events. Over one-quarter of these subjects were hepatitis C virus seropositive. The nature of the liver events was not well described. Two of the 22 hepatic events (0.3% of 761 patients in total) were consistent with a NVP hypersensitivity reaction involving the liver. The incidence of hepatic events was 9.2%, which was similar to the rate reported in blinded clinical nevirapine trials. Thus there is no apparent increased risk for switch patients with high CD4 cell counts over patients at other CD4 counts treated with NVP as an initial regimen. However, recent changes to prescribing information, based on naive-patient data, have warned against treatment of high CD4 count patients, particularly women with CD4 counts > 250 cells/μL. In this context, these data (with median CD4 cell counts in all 12 studies examined > 400 cells/μL) should be viewed with caution.
Quality of life Quality of life may be improved in those switching to NVP-based therapy from PI treatment [11,14,16]. Ruiz et al. reported that 70% of those with improved quality of life scores 48 weeks post-switch cited reduced pill burden and side-effect profile as the primary cause [10]. No change in quality of life score was identified in the control group. Selection bias must be considered when interpreting these favourable quality of life results, as those who enrol in switch studies may be particularly motivated to discontinue PI therapy.
Pharmacokinetic considerations
Adequate plasma pharmacokinetics (PK) during the switch period is important in predicting outcome. NVP is extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes 3A4 and 2B6, and is mainly excreted into the urine as glucuronidated and hydroxylated metabolites (80%) and as parent drug (5%) [30]. NVP causes auto-induction of its metabolism, resulting in a 1.5- to 2-fold increase in oral clearance during the first few weeks of dosing. The plasma elimination half-life is about 45 h following a single dose, and 25-30 h during steady-state dosing [30]. The licensed dosage for NVP is 200 mg twice daily (bid), after a starting dose of 200 mg once daily (od) during the first 2 weeks of therapy.
Optimal nevirapine dosing during switch from PI-based therapy has not been established. Patients already on PIs will have already had some degree of CYP 3A4 inhibition depending on the PI(s) used. The CYP 3A4 of patients on ritonavir will be fully inhibited. Therefore, one would predict that an escalating dose approach to the introduction of NVP would be appropriate. This approach may avoid NVP toxicities known to be associated with high drug levels (e.g. rash) [31,32]. Negredo et al. started with NVP 200 mg od and then escalated to 200 mg bid [14]. Using this dosing approach, all but one of the 26 subjects switched to NVP maintained virological suppression over the 12-month period of assessment. Ruiz et al. used a similar approach without increased virological failure compared with those who remained on PI-based therapy [11].
However, low trough levels have been demonstrated to predict the likelihood of virological breakthrough in those switching from PIs to NVP [24]. This argues for full-dose NVP dosing at the time of switch from PI therapy to avoid periods of subtherapeutic drug levels.
As described above, there is a good rationale to support each of the two approaches but few data providing strong support for one over the other. The high rate of maintained HIV RNA suppression and lack of high rates of adverse events irrespective of dosing approach (see above) suggests that this is an academic argument with little, if any, clinical relevance.
Discussion
Although there are theoretical concerns related to the maintenance of therapeutic NVP levels during the switch period, these concerns are not borne out in clinical practice, as virological suppression is maintained at the time of switch and for at least 3 years thereafter. As a conservative approach, the initial dose of NVP should be 200 mg po od followed by dose escalation to 200 mg per month bid after 14 days to ensure an optimal safety profile. This issue requires further evaluation as concerns pertaining to prolonged, subtherapeutic levels of drug with this dosing strategy linger. In patients already demonstrating an ability to remain adherent to therapy and who have achieved and maintained maximal virological suppression, NVP switch can be successfully conducted with minimal risk of virological failure. Most studies suggest that this risk is no higher than that for patients remaining on a PI-based regimen. As with any prescription of HAART, success is diminished with increasing history of antiretroviral exposure. The role of therapeutic drug monitoring in those switching to NVP remains unresolved.
Although there are several short-duration studies suggesting that body habitus changes may be halted or reversed following a switch to NVP from PI therapy [12,17], studies of larger sample size, better design and longer duration suggest that any benefits of this strategy are minimal [13,14]. However, abnormal lipid profiles may be improved by switching to NVP-based therapy. Of importance in interpreting metabolic results is the fact that the backbone nucleosides used in these studies do not general reflect those used currently. The diversity of definitions of this syndrome also complicates interpretation.
The accompanying NRTIs used with nevirapine influence tolerance, adverse event frequency, maintenance of virological suppression, and adherence. Stavudine will probably negate any beneficial metabolic effect of nevirapine inclusion. Reduced pill burden achieved with combination NRTIs (zidovudine/lamivudine or tenofovir/emtricitabine) or once-daily dosed NRTIs (tenofovir/lamivudine or tenofovir/FTC) may complement the benefits of NVP switch (i.e. low pill count and twice daily dosing).
In closing, the weight of evidence demonstrates that a switch from a PI-based regimen to one containing NVP can be accomplished safely while maintaining virological suppression. There is no immunological cost and there is probably an overall benefit in terms of the metabolic milieu and quality of life. This treatment option should be considered for those achieving suboptimal results with PI-based therapy.
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