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A Pilot Study of Nevirapine, Indinavir, and Lamivudine among Patients with Advanced Human Immunodeficiency Virus Disease Who Have Had Failure of Combination Nucleoside Therapy

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A Pilot Study of Nevirapine, Indinavir, and Lamivudine among Patients with Advanced Human Immunodeficiency Virus Disease Who Have Had Failure of Combination Nucleoside Therapy
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  1514 A Pilot Study of Nevirapine, Indinavir, and Lamivudine among Patients withAdvanced Human Immunodeficiency Virus Disease Who Have Had Failure of Combination Nucleoside Therapy M. Harris, C. Durakovic, S. Rae, J. Raboud, S. Fransen,  St. Paul’s Hospital/University of British Columbia, Vancouver, Canada A. Shillington, B. Conway, and J. S. G. Montaner The effects of nevirapine, indinavir, and lamivudine in combination were studied among 22human immunodeficiency virus (HIV)–infected patients with CD4 cell counts  £ 50/mm 3 , whoseoptions for antiretroviral therapy were limited by clinical or laboratory failure or toxicity withprevious regimens. Median plasma HIV RNA was 5.16 log 10  copies/mL at baseline, decreasing bya median of 3.12log 10  copies/mLat 24 weeks. Median baseline CD4cell count was 30/mm 3 ,increasingby a median of 95/mm 3 at week 24. Adverse reactions led to drug discontinuation in 4 cases. Steady-state pharmacokinetic analysis in 17 patients was consistent with an interaction between nevirapineand indinavir. Nevirapine plasma levels were within the expected range, while indinavir levelswere lower than expected. Despite this interaction, the combination of nevirapine, indinavir, andlamivudine was safe and well-tolerated and had substantial antiviral and immunologic effects lastingfor the 24-week study. Combination antiretroviral therapy has been clearly shown concerning the effect of nevirapine on the pharmacokinetics of currently available protease inhibitors. As expected, nevirapineto be superior to monotherapy [1–3]. More recently, triple-drug combinations including two nucleoside analogues plus was found to reduce the area under the curve (AUC) for indi-navir, ritonavir, and saquinavir by Ç 10%–30% when adminis-a nonnucleoside reverse transcriptase inhibitor or a proteaseinhibitor have demonstrated superiority to double-nucleoside tered in combination [13, 14]. However, the clinical and viro-logic implications of this interaction have not been fullytherapy in terms of surrogate marker effect and clinical out-come [4–7]. On the basis of these results, triple-drug combina- characterized.Therefore, we conducted a 24-week pilot study to assess thetion therapy is widely recommended for the treatment of humanimmunodeficiency virus (HIV) infection [8–11]. safety, antiviral and immunologic effects, and pharmacokinet-ics of nevirapine, indinavir, and lamivudine administered inConcomitant use of drugs, however, increases the chance of pharmacokinetic interactions. With the increasing use of prote- combination among patients with advanced HIV disease whohave had failure of combination nucleoside therapy.ase inhibitors and nonnucleoside reverse transcriptase inhibi-tors, concern has arisen regarding possible pharmacokineticinteractions between them [12–14]. Nevirapine is a hepatic Methods enzymatic inducer and as such would be expected to decreasethe effective serum concentrations of protease inhibitors [15].  Patients.  HIV-infected patients with CD4 cell counts  £ 50/  Only recently has preliminary information become available  mm 3 were eligibleif they had demonstratedintolerance, toxicity,ordisease progression with nucleoside analogue–based antiretroviraltherapy. Eligible patients had no prior exposure to nevirapine orindinavir. Prior use of lamivudine was allowed. Study design.  This was a prospective, open-label study con- Received 25 September 1997; revised 19 December 1997.Presented in part: 4th Conference on Retroviruses and Opportunistic Infec-  ducted within the framework of the expanded access programs tions, Washington, DC, 22–26 January 1997; Canadian Association for HIV for nevirapine and indinavir. Patients received a combination of  Research Sixth Annual Conference on HIV/AIDS Research, Ottawa, 22–25 nevirapine, indinavir, and lamivudine in standard doses com- May 1997; 37th Interscience Conference on Antimicrobial Agents and Chemo- menced simultaneously. During 24 weeks of study treatment, pa- therapy, Toronto, 28 September–1 October 1997.Informed consent was obtained from all patients participating in the study.  tients were monitored for safety by assessment of clinical events Ethical approval was obtained from the Institutional Review Boards of St. and standard laboratory parameters, for antiviral response by mea- Paul’s Hospital and the University of British Columbia. surement of plasma HIV RNA, and for immunologic response by Financial support: Boehringer Ingelheim Pharmaceuticals, Ridgefield, Con- measurement of CD4 cell counts. Pharmacokinetics were assessed necticut; Merck Frosst, Montreal; National Health Research Development Pro- by measuring peak and trough plasma levels of nevirapine and gram, Canada, and British Columbia Centre for Excellence in HIV/AIDS,Vancouver.  indinavir on a single day after 6 weeks of study therapy. The Reprints or correspondence: Dr. J. S. G. Montaner, AIDS Research Program, impact of the pharmacokinetic interaction was assessed by compar- St. Paul’s Hospital/University of British Columbia, 667-1081 Burrard St., Van- ison with previously published data, as historical controls. couver, Canada (jmontaner@hivnet.ubc.ca).  Drug therapy.  Patients received treatment with a combination The Journal of Infectious Diseases 1998;177:1514–20 of nevirapine, indinavir, and lamivudine for 24 weeks. Nevirapine   1998 by The University of Chicago. All rights reserved.0022–1899/98/7706–0011$02.00  was given at a dose of 200 mg daily for 2 weeks, escalating to  / 9d46$$ju25 04-16-98 09:24:16 jinfa UC: J Infect   b  y  g u e s  t   on J  ul   y 1 7  ,2  0 1 1  j  i   d . ox f   or  d  j   o ur n al   s . or  gD  ownl   o a d  e d f  r  om   1515JID 1998;177 (June) Nevirapine, Indinavir, and Lamivudine Table 1.  Indinavir, nevirapine, and lamivudine for advanced HIV  Clinical follow-up.  A medical history and physical examina- disease: baseline characteristics of study patients.  tion were completed at the screening visit (4–8 weeks beforestarting study therapy) and again at the baseline visit and at weeks Pharmacokinetic 1, 2, 4, 6, 8, 12, 16, 20, and 24. Information regarding adverse All patients subgroup events and HIV-related illnesses was collected at each clinic visit.  Laboratory monitoring.  Plasma HIV RNA was quantitated Number 22 17 with the Amplicor HIV-1 Monitor assay (Roche Molecular Sys- Male/female 20/2 17/0 tems, Branchburg, NJ) from suitable specimens collected twice at HIV RNA, median (range) baseline and at weeks 1, 2, 4, 6, 8, 12, 16, 20, and 24. Specimens log 10  copies/mL 5.16 (2.58–5.84) 5.17 (2.58–5.84)CD4 cell count, median  having readings õ 500 copies/mL by the standard Amplicor assay (range) cells/mm 3 30 (10–50) 35 (10–50)  were retested with the Ultra Direct assay, which has a lower limit CD8 cell count, median of quantitation of 20 copies/mL [16]. CD4 cell counts were done (range) cells/mm 3 520 (105–1585) 600 (120–1585) twice at baseline and at 2- to 6-week intervals thereafter. Routine Previous protease inhibitor hematology and chemistry testing were done at baseline and every experience 1 (ritonavir) 1 (ritonavir) 4 weeks thereafter. Previous nonnucleoside Pharmacokinetic sampling.  Patients who received study drugs reverse transcriptase for a minimum of 6 consecutive weeks during the first 16 weeks inhibitor experience 2 (loviride) 1 (loviride) of the study were eligible for pharmacokinetic sampling. This was Previous lamivudine 19 16AIDS diagnosis 15 10  done four times on a single day. Patients were requested to taketheir usual oral doses of nevirapine at 8:00  P . M . and indinavir at11:00  P . M . the night before testing, while they continued to takelamivudine on a regular schedule. The following day, a samplewas drawn for trough nevirapine and indinavir levels at 7:00  A . M .200 mg twice daily thereafter. Indinavir was given at 800 mg everyMorning doses of indinavir and nevirapine were taken immediately8 h on an empty stomach. Lamivudine was given at 150 mg twicethereafter, and a sample was obtained for peak nevirapine anddaily. Concurrent use of other antiretroviral therapies was notindinavir levels at 8:00  A . M . A second trough indinavir level wasallowed. No washout period was required before starting studytherapy. drawn immediately prior to the 3:00  P . M . dose, and a second peak  Figure 1.  Median changes in CD4 cell counts and plasma HIV RNA (pVL) versus time in patients during study drug treatment. Barsrepresent 25th and 75th percentiles. CD4 cell counts are not included at 1, 2, and 8 weeks because  n õ 10.  / 9d46$$ju25 04-16-98 09:24:16 jinfa UC: J Infect   b  y  g u e s  t   on J  ul   y 1 7  ,2  0 1 1  j  i   d . ox f   or  d  j   o ur n al   s . or  gD  ownl   o a d  e d f  r  om   1516 Harris et al. JID 1998;177 (June) indinavir level was obtained at 4:00  P . M . Patients continued to take by each patient, was defined as 1  0  NAUC (normalized AUC)[17, 18]. A person with no change from the baseline HIV RNAtheir usual concomitant medications on the sampling day. Plasmawas separated and frozen within 1 h of drawing and stored at value over the 24-week observation period would have a value of  0 70  C for batch testing. 0, while a person whose plasma HIV RNA was reduced to thePlasma samples were analyzed for nevirapine concentrations at quantitation limitof theUltra Direct assayvery quicklywould haveBoehringer Ingelheim Pharmaceuticals (Ridgefield, CT) by use of  a value close to 1. A negative value would result from increases ina validated high-performance liquid chromatographic assay with virus load relative to baseline, if the duration and size of theUV detection (wavelength  Å  280 nm). Standard curves for the increases were large enough to counteract any decreases.analytical method covered the range of 25–10,000 ng/mL. The Results for drug levels are reported as means { SDs. The rela-limit of assay quantitation was 25 ng/mL. Quality control samples tionships between peak and trough levels of nevirapine and indi-analyzed with each analytical run had coefficients of variation for navir and patients’ virologic response to therapy, as measured byprecision and accuracy of  õ 15%. Plasma samples were analyzed 1 0 NAUC, were summarized with scatter plots and Spearman’sfor indinavir concentrations at BAS Analytics (West Lafayette, correlation coefficients. For indinavir, for which two values forIN) by a proprietary validated high-performance liquid chromato- peak and trough were available for each patient, the correlationgraphic assay with a limit of assay quantitation of 12 ng/mL. was examined for 1 0 NAUC and absolute peak or trough levels Statistics.  Median CD4 cellcounts andplasma HIVRNA mea- (i.e., the higher of the two peaks and the lower of the two troughs).surements were calculated at baseline for the entire group and for Lowess (locally weightedscatterplotsmoother) curvesweredrawnthe subset of patients included in the pharmacokinetic analyses. on the plots to summarize the relationships of pairs of variables.At every follow-up visit, the change shown by each person from The lowess curve, which is akin to a moving average, was chosenhis baseline CD4 cell count and plasma HIV RNA level was calcu- instead of fitting a straight line to the data, since the relationshipslated. The median of these changes at each time point is expressed were nonlinear [19].as ‘‘median change.’’ The proportions of patients with plasmaHIV RNA measurements  õ 500 copies/mL and  õ 20 copies/mLwere also tabulated at each follow-up visit. In cases in which  Results Amplicor HIV-1 test results were  õ 500 copies/mL, Ultra Direct Patients.  A total of 22 patients were enrolled, and 17 were results were used in their place. Ultra Direct results below the available for the pharmacokinetic study (table 1). Only 1 patient quantitation limit of this assay (20 copies/mL) were set to 20. had previously used a protease inhibitor (ritonavir), and the The cumulative antiviral treatment effect over 24 weeks, or theproportion of potential improvement in plasma HIV RNA achieved  drug had been discontinued after 14 weeks because of dizzi- Figure 2.  Proportion of patients with plasma HIV RNA below quantitation limit of standard (500 or 2.7 log 10  copies/mL; solid line) andUltra Direct (20 or 1.3 log 10  copies/mL; dashed line) assays, versus time receiving study drug.  / 9d46$$ju25 04-16-98 09:24:16 jinfa UC: J Infect   b  y  g u e s  t   on J  ul   y 1 7  ,2  0 1 1  j  i   d . ox f   or  d  j   o ur n al   s . or  gD  ownl   o a d  e d f  r  om   1517JID 1998;177 (June) Nevirapine, Indinavir, and Lamivudine ness, hot flashes, fatigue, and diarrhea. Two patients had pre-  Immunologic response.  CD4 cell counts increased substan-tially over the 24-week study period (figure 1). The medianviously received loviride (an experimental nonnucleoside re-verse transcriptase inhibitor) as part of their participation in CD4 cell count was 30/mm 3 at baseline. The median changein CD4 cell count was / 30 cells/mm 3 at week 4 and / 95 cells/ the CAESAR trial [3]. All patients except 3 had prior experi-ence with lamivudine. mm 3 at week 24. Changes in CD4 cell counts for the 17 patientseligible for the pharmacokinetic study followed a similar pat-There were no withdrawals attributable to clinical progres-sion or laboratory treatment failure (i.e., increasing plasma vi- tern (data not shown). Pharmacokinetics.  Observed nevirapine plasma levels var-rus load) during the study period. Three patients withdrew forpersonal reasons, unrelated to toxicity or lack of efficacy. ied little between patients and within individuals during thecourse of the day and were not affected by coadministration Safety.  No unexpected clinical or laboratory adverse eventsoccurred during the study. of indinavir (figure 3). Nevirapine peak was 21.6  {  8.3  m  M  and nevirapine trough was 18.3  {  5.7  m  M  . These values didNo serious (grade  § 3) clinical adverse events to the studymedications were encountered during the study. Adverse events not differ significantly from published data for nevirapinemonotherapy [20] ( P Å .074 and .25, respectively).of moderate severity (grade 2) led to the discontinuation of nevirapine or indinavir in 4 patients. In 2 of these cases, the In contrast, observed indinavir plasma levels varied widelybetween patients and within individuals during the course of events (nausea/vomiting and rash) were attributed to nevira-pine, and in the other 2 cases the events (urinary frequency/ the day and appeared to be reduced substantially in the presenceof nevirapine (figure 4). Indinavir peak levels were 6401  { nocturia and nausea/vomiting) were attributed to indinavir. Nocases of nephrolithiasis were observed. A single new AIDS- 4416 n  M   for the morning dose and 3285  {  3373 n  M   for theafternoon dose. These represent 51% and 26%, respectively,defining opportunistic infection occurred during the 24-week follow-up period: a case of   Pneumocystis carinii  pneumonia of the published levels for indinavir when given alone [21]( P  õ .001 and õ  .001, respectively). The observed indinavirdiagnosed during week 3 of the study in a patient with a previ-ous AIDS diagnosis. trough levels were 109 { 66.6 n  M   in the morning and 109 { 56.3 n  M   in the afternoon, representing 43% of published levelsTwo grade § 3 laboratory toxicities occurred during the study.One patient developed hyperbilirubinemia (maximum level, 65 for indinavir monotherapy [21] ( P Å .0075 and .0068, respec-tively). m mol/L Å 3.8 mg/dL), which resolved after a 4-day interruptionof indinavir; therapy was resumed without recurrence. Another  Correlation of pharmacokinetics and virologic responses. The cumulative antiviral effect, represented by 1  0  NAUC forpatient developed worsening of preexisting neutropenia (decreas-ing from 900 at baseline to 300 cells/mm 3 at week 16 during HIV RNA over 24 weeks, did not show a statistically significantcorrelation with nevirapine peak (Spearman’s correlation coeffi-therapy). Thereafter, lamivudine was replaced by stavudine, whileindinavir and nevirapine were continued. Pharmacokinetic sam-pling was done for this patient before the change in therapy. Nocases of chemical hepatitis were observed. Virologic response.  Plasma virus load decreased rapidlyfrom baseline, and this decrease was maintained for the 24-week study period (figure 1). The median plasma virus loadwas 5.16 log 10  at baseline. Median changes in plasma virusload were  0 2.42 log 10  copies/mL at 4 weeks,  0 3.04 log 10 copies/mL at 12 weeks, and  0 3.12 log 10  copies/mL at 24weeks. The plasma virus load changes in the pharmacokineticsubgroup followed a similar pattern (data not shown).Virus load was suppressed to below the limits of quantitationof the HIV RNA assays in a substantial proportion of patients(figure 2). At week 24, 73% of patients (11/15) had plasmavirus load  õ 500 copies/mL, and 40% (6/15) of patients hadplasma virus load õ 20 copies/mL.The patient with prior ritonavir experience and 1 of the patientswith prior loviride experience showed good virologic responsesto the study combination, achieving plasma virus loads of 33 and Figure 3.  Nevirapine peak ( A ) and trough ( B ) plasma levels for õ 20 copies/mL, respectively, at week 24. The other loviride- study patients ( n  Å  17). Solid circles represent individual patient experienced patient withdrew early because of a nevirapine-in- samples; mean value is indicated by horizontal line. Peak and trough duced rash. With regard to lamivudine, 10 of 11 patients with levels (mean  {  SD) are also shown from published data, in which virus load õ 500 copies/mL and all 6 with virus load õ 20 copies/   nevirapine was given alone as single daily dose of 400 mg (peak,27.1 { 5.3  m  M  ; trough, 15.8 { 4.5  m  M  ;  n Å 10) [20]. mL at 24 weeks had received this agent before the study.  / 9d46$$ju25 04-16-98 09:24:16 jinfa UC: J Infect   b  y  g u e s  t   on J  ul   y 1 7  ,2  0 1 1  j  i   d . ox f   or  d  j   o ur n al   s . or  gD  ownl   o a d  e d f  r  om   1518 Harris et al. JID 1998;177 (June) Figure 4.  Indinavir peak ( A ) and trough ( B ) plasmalevels for morning (AM) and afternoon (PM) draws forstudy patients ( n Å 17). Solid circles represent individualpatient samples; mean value is indicated by horizontalline. Peak and trough levels (mean { SD) are also shownfrom published data for indinavir, 800 mg every 8 h asmonotherapy (peak, 12,617  {  4037 n  M  ; trough, 251  { 178 n  M  ;  n Å 16) [21]. cient Å .27,  P Å .29), with nevirapine trough (correlation coeffi- incorporated steady-state peak and trough drug level determina-tions in an attempt to correlate pharmacokinetic variables withcient  Å  .38,  P  Å  .13), nor with absolute indinavir peak levels(correlation coefficient Å .42,  P Å .10). However, a statistically clinical laboratory changes and particularly with virologic ef-fect. We elected to retain lamivudine within the therapeuticsignificantcorrelation wasfound between the 24-week cumulativeantiviraleffectandtheabsoluteindinavirtroughlevels(correlation regimen despite the fact that a majority of the study participantshad previously demonstrated evidence of treatment failure withcoefficient Å .53,  P Å .03) (figure 5).this agent and likely carried drug-resistant virus isolates. Giventhe very favorable safety profile of lamivudine, we felt that Discussion retaining it would not compromise the safety of the combina-tion regimen [3, 22–25]. Furthermore, there has been someThe results of this pilot study demonstrate that standard dosesof nevirapine, indinavir, and lamivudine are generally well- evidence suggesting that HIV strains resistant to lamivudinemay have decreased fitness [26]. In addition, in vitro evidencetolerated and can lead to substantial reductions in plasma virusload and increases in CD4 cell count. This effect was demon- has been generated suggesting that there may be a synergisticinteraction between lamivudine and nevirapine [27].strated among patients with advanced HIV disease who pre-viously had either disease progression or virologic failure while We found that nevirapine, indinavir, and lamivudine givenin combination had very substantial antiviral and immunologicreceiving nucleoside analogue–based combination therapy, of-ten including lamivudine. In addition, our data support the effects. Plasma virus load decreased rapidly on initiation of therapy, leading to a median reduction in plasma HIV RNAexistence of a pharmacokinetic interaction between nevirapineand indinavir, characterized by indinavir peak and trough con- of   ú 3 log 10  copies/mL, which remained for the 24 weeks of the study. This was associated with a median increase in CD4centrations being significantly lower than expected comparedwith historical controls; however, this interaction does not pre- cell count of 95 cells/mm 3 , which remained at 24 weeks. Themagnitude of these immunologic and virologic responses isclude a substantial immunologic and virologic response.The management of HIV-infected persons continues to particularly encouraging when considering the very advancedstage and extensive prior antiretroviral therapy use of our studyevolve at a rapid pace. Now that the single-drug therapy strat-egy is abandoned, multiple-drug combinations are currently group. Previous exposure to a nonnucleoside reverse tran-scriptase inhibitor (2 patients), a protease inhibitor (1 patient),used with the aim of suppressing viral replication as much aspossible for as long as possible [6–11]. Patients who started or lamivudine (19 patients) did not preclude a favorable re-sponse to the combination. Furthermore, unexpected adversetreatment before these guidelines were developed often facedifficult challenges when making therapeutic decisions. It is effects were not encountered within this group of patients.Our pharmacokinetic data support the existence of an interac-within this context that in the late spring of 1996, having gainedaccess to two new promising antiretroviral agents, nevirapine tion between nevirapine and indinavir, as recently reported[13]. This interaction is characterized by plasma concentrationsand indinavir, we offered this combination to persons who hadexhausted conventional treatment approaches. Because of the of indinavir (both peak and trough levels) being significantlylower than expected in comparison to historical controls. Lim-potential for drug interactions, we did so under close clinicaland laboratory monitoring within this pilot study. Further, we ited pharmacokinetic sampling in our study precludes a precise  / 9d46$$ju25 04-16-98 09:24:16 jinfa UC: J Infect   b  y  g u e s  t   on J  ul   y 1 7  ,2  0 1 1  j  i   d . ox f   or  d  j   o ur n al   s . or  gD  ownl   o a d  e d f  r  om 
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