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High-dose nevirapine in previously untreated human immunodeficiency virus
type 1-infected persons does not result in sustained suppression of viral
replication
de Jong, M.D.; Vella, S.; Carr, A.; Boucher, C.A.B.; Imrie, A.; French, M.; Hoy, J.; Sorice, S.;
Pauluzzi, S.; Chiodo, F.; Weverling, G.J.; van der Ende, M.E.; Frissen, P.H.J.; Weigel, H.M.;
Kauffmann, R.H.; Lange, J.M.A.; Yoon, R.; Moroni, M.; Hoenderdos, E.; Leitz, G.; Cooper,
D.A.; Hall, D.; Reiss, P.
DOI
10.1086/514002
Publication date
1997
Document Version
Final published version
Published in
The Journal of Infectious Diseases
Link to publication
Citation for published version (APA):
de Jong, M. D., Vella, S., Carr, A., Boucher, C. A. B., Imrie, A., French, M., Hoy, J., Sorice, S.,
Pauluzzi, S., Chiodo, F., Weverling, G. J., van der Ende, M. E., Frissen, P. H. J., Weigel, H.
M., Kauffmann, R. H., Lange, J. M. A., Yoon, R., Moroni, M., Hoenderdos, E., ... Reiss, P.
(1997). High-dose nevirapine in previously untreated human immunodeficiency virus type
1-infected persons does not result in sustained suppression of viral replication. The Journal of
Infectious Diseases, 175(4), 966-970. https://doi.org/10.1086/514002
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2:152 – 7. with dementia. Ann Neurol1995; 38:755 – 62.
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and HIV-1 brain infection: clinical-virological correlations. Ann Neurol stoft J. Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome. AIDS1996; 10:167 – 1995; 38:563 – 70.
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High-Dose Nevirapine in Previously Untreated Human Immunodeficiency Virus
Type 1 – Infected Persons Does Not Result in Sustained Suppression of Viral
Replication
M. D. de Jong, S. Vella, A. Carr, C. A. B. Boucher,* National AIDS Therapy Evaluation Centre, Department of Infectious Diseases, Tropical Medicine, and AIDS, and Department of Virology, A. Imrie, M. French, J. Hoy, S. Sorice, S. Pauluzzi,
Academic Medical Centre, University of Amsterdam, Onze Lieve Vrouwe F. Chiodo, G. J. Weverling, M. E. van der Ende,
Gasthuis, Amsterdam, Dijkzigt Hospital, Erasmus University, Rotterdam, Ph. J. Frissen, H. M. Weigel, R. H. Kauffmann, and Leijenburg Hospital, the Hague, Netherlands; Istituto di Malattie J. M. A. Lange, R. Yoon, M. Moroni, E. Hoenderdos, Infettive, University ‘‘La Sapienza,’’ and Istituto Superiore di Sanita´, G. Leitz, D. A. Cooper, D. Hall, and P. Reiss Rome, and Istituto di Malattie Infettive, University of Bologna, Bologna, Italy; HIV Medicine Unit and Centre for Immunology, St. Vincent’s Hospital, Sydney, and Department of Clinical Immunology, Royal Perth Hospital, Perth, Australia; Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut
High-dose nevirapine treatment has been reported to confer sustained antiretroviral effects, despite a rapid development of resistance. The use of this strategy was evaluated in 20 previously untreated human immunodeficiency virus type 1 (HIV-1) p24 antigenemic persons with CD4 cell counts between 100 and 500/mm3. Treatment consisted of 400 mg of nevirapine, after a 2-week lead-in dose of 200 mg. Rash was the most frequently reported adverse event, occurring in 25%. While sustained declines in p24 antigen levels were observed in the majority, serum HIV-1 RNA load and CD4 cell counts returned to baseline values within 12 weeks in virtually all subjects. The resistance-conferring tyrosine-to-cysteine substitution at reverse transcriptase position 181 was detected after 4 weeks in most subjects. These observations suggest that plasma drug levels attained with high-dose nevirapine were not sufficient to inhibit nevirapine-resistant virus, although they wereÇ2-fold higher than reported IC50values of resistant virus.
Treatment with nevirapine, a nonnucleoside inhibitor of hu- because of a rapid development of nevirapine resistance [1, 2], which is not prevented by concomitant or alternating treatment man immunodeficiency virus type 1 (HIV-1) reverse
tran-scriptase (RT), results in potent antiretroviral effects [1]. How- with zidovudine [1 – 3].
Theoretically, sustained antiviral activity despite the devel-ever, at dosages up to 200 mg/day, these effects are transient
opment of resistance could be achieved by the attainment of active drug levels exceeding concentrations that inhibit drug-resistant virus in vitro. A recent study of nevirapine at a high
Received 22 July 1996; revised 18 October 1996.
Presented in part: X International Conference on AIDS, Yokohama, Japan, dose of 400 mg/day in antiretroviral-experienced patients with August 1994 (abstract PB0847).
advanced HIV disease indeed showed sustained reductions in
Informed consent was obtained from all study participants, and institutional
serum p24 antigen levels and HIV-1 RNA load [4]. In the
human experimentation guidelines were followed.
Financial support: Boehringer-Ingelheim Pharmaceuticals. present study, we evaluated the same principle of treatment Reprints or correspondence: Dr. Menno D. de Jong, National AIDS Therapy
with nevirapine in previously untreated, predominantly
asymp-Evaluation Centre, Academic Medical Centre, F5-108, Meibergdreef 9, 1105
tomatic HIV-1 – infected persons.
AZ Amsterdam, Netherlands.
* Present affiliation: Eijkman-Winkler Institute, Department of Virology,
Academic Hospital, Utrecht University, Utrecht, Netherlands. Patients and Methods
The Journal of Infectious Diseases 1997; 175:966 – 70
Study population and treatment. Previously untreated HIV-1
䉷 1997 by The University of Chicago. All rights reserved.
Table 1. Baseline characteristics of 20 HIV-1 – infected men receiv- was initially reinstituted at a reduced dose for a period of 19
ing high-dose nevirapine. and 33 days, respectively.
Adverse events. Frequently reported nevirapine-associated
Characteristic Value
adverse events were rash and fever, frequently coincident, oc-curring in 25% and 20% of patients, respectively. Four patients
Mean age, years 37.0 (range, 22 – 57)
Mean weight, kg 72.1 discontinued treatment because of adverse events. One patient
Disease stage, no. (%) experienced a mild rash during the lead-in period, which
pro-Asymptomatic 16 (80)
gressed to Stevens-Johnson syndrome on dose escalation. One
AIDS-related complex 3 (15)
patient experienced a severe rash with fever, facial edema, and
AIDS 1 (5)
elevations of plasma transaminase levels during the lead-in
Median CD4 cell count/mm3
250 (range, 69 – 390)
Median non-ICD p24 antigen levels (pg/mL)* 67 (range, 17 – 770) period. Recovery was complete in both patients after therapy Median ICD p24 antigen levels (pg/mL)†
477 (range, 75 – 7427) withdrawal. A third patient developed a rash with mouth ulcers Mean HIV-1 RNA load (log copies/mL) 5.2 (range, 3.8 – 6.0)
on day 24, which resolved after interrupting treatment but im-mediately worsened on reinstitution. The fourth patient
discon-NOTE. ICD, immune complex – dissociated.
* Measured in real time (Abbott [Abbott Park, IL] EIA). tinued therapy at day 98 because of persistent elevations of
†
Measured batchwise (Coulter [Hialeah, FL] ELISA). transaminase levels.
Plasma nevirapine levels. Plasma nevirapine levels were sequentially measured in 19 of 20 subjects while receiving counts between 100 and 500/mm3
were treated with nevirapine at study drug. During the lead-in period, mean trough levels were a single daily dose of 400 mg, after a 2-week period of treatment 12.8{ 4.9mM and 10.9 { 3.8 mM at weeks 1 and 2, respec-with a daily dose of 200 mg. This lead-in dose was aimed at tively. On dose escalation, average trough nevirapine levels reducing the incidence of rash, which is a major dose-limiting increased, ranging from 14.7 { 4.9 to 18.5 { 7.9 mM. Of toxicity of high-dose treatment [4, 5]. The study period was 28
note, in the 2 subjects developing a severe rash early during weeks. The addition of nucleoside analogue therapy was allowed
treatment, nevirapine levels during the lead-in period ranked beyond 6 weeks of treatment, if p24 antigen levels returned to
second and third highest. Nevirapine levels were not measured baseline values.
in the third subject who discontinued treatment because of a
Clinical and laboratory evaluation. Patients were evaluated
rash. weekly up to week 4, biweekly up to week 8, and monthly
thereaf-ter. At each visit, blood was collected for assessment of hematol- Immunologic and virologic responses. The number of CD4 ogy, chemistry, serum p24 antigen level, and lymphocyte subset lymphocytes increased sharply during the first week of treat-enumeration. Serum p24 antigen levels were measured in real time ment but returned toward baseline values at subsequent weeks using the Abbott Enzyme ImmunoAssay and quantitation panels (figure 1A).
(Abbott, Abbott Park, IL). Immune complex – dissociated (ICD) A rapid reduction of ICD and non-ICD p24 antigen levels p24 antigen levels (Coulter, Hialeah, FL) were batch-tested in
was observed in virtually all patients and was sustained stored serum (070⬚C). With the Roche Amplicor assay (Roche
throughout the 28-week study period in the majority of subjects Molecular Systems, Alameda, CA), HIV-1 RNA load was
mea-who continued treatment (figure 1B). When only considering sured in stored serum obtained at screening and at weeks 0, 4, 12,
the 11 subjects who were treated with nevirapine alone for the and 28 for the whole study group and at all time points in a subset
complete study period, a median decline of 59% (range, 8% – of 4 subjects [6]. The relative amounts of HIV-1 RNA containing
94%) was still observed after 28 weeks. the nevirapine resistance – conferring tyrosine-to-cysteine
substitu-tion at RT posisubstitu-tion 181 were measured at baseline and at weeks Changes in HIV-1 RNA load were measured in 18 subjects. 4 and 12, using a primer-guided nucleotide incorporation assay A mean decline of 0.46 { 0.47 log RNA copy numbers was [7]. Trough plasma nevirapine levels were measured in stored observed after 4 weeks of treatment, with a return to baseline plasma [8]. values within 12 weeks (figure 1C). In only 1 subject, a sus-tained reduction at weeks 12 and 28 was observed (0.54 and 0.58 log, respectively), after a maximum decline of 1.34 log
Results
at week 4. Of note, nevirapine levels in this subject were rela-tively low (range, 5.3 – 12.4mM).
Study population. Twenty previously untreated p24
anti-genemic men were enrolled. Baseline characteristics are shown In the subgroup of 4 subjects in whom RNA load was mea-sured at all time points, maximum declines of 1.45 – 1.72 logs in table 1. Fifteen patients completed 28 weeks of treatment.
Zidovudine was added to treatment of 4 of these patients at (mean, 1.52{ 0.19 log) were invariably observed during the first 2 weeks of treatment (figure 1C). During subsequent weeks 8, 8, 16, and 24, respectively. Four patients discontinued
treatment prematurely because of adverse events, and 1 patient weeks, virus load resurged in these subjects and reached base-line values within 6 weeks of treatment.
was lost to follow-up at day 141. Treatment interruptions of
ú1 week occurred in 3 of 15 subjects who completed the study Proportions of 181 cysteine-variant HIV-1 RNA. The rela-tive amounts of 181 cysteine-variant HIV-1 RNA were mea-period (duration 10, 12, and 58 days). In 2 of these, nevirapine
Figure 1. A, Mean changes in CD4 lymphocyte counts { SE; B, median percentage changes in im-mune complex – dissociated (ICD) (ⱓ) and non-ICD (⽧) p24 antigen levels; C, mean changes in log HIV-1 RNA load{ SE in all subjects (l) and in a subgroup of 4 patients (0). Baseline values are defined as mea-surements at week 0 only, to avoid influence of regression to mean ef-fects [9]. Numbers in lower part of each graph indicate number of sub-jects tested at each time point.
sured at weeks 0, 4, and 12 in 15, 15, and 13 subjects, respec- of p24 antigen responses, our conclusion would have been identical. However, at least in previously untreated asymptom-tively. In none of the subjects was 181 cysteine-variant RNA
detectable at baseline. After 4 and 12 weeks of treatment, a atic persons, this conclusion does not seem to hold true when considering the responses in HIV-1 RNA load. This suggests 100% 181 cysteine-variant RNA population was detected in 5
of 15 subjects and 3 of 13 subjects, respectively, while a fully that, although plasma levels were of a similar magnitude as in Havlir’s study (i.e.,Ç2-fold higher than reported IC50values
181 wild type population was observed in 4 of 15 and 6 of 13
subjects, respectively. In the remaining subjects, percentages of resistant virus) [4], they do not seem sufficient to overcome nevirapine-resistant virus. Of note, trough nevirapine levels of 181 cysteine-variant virus ranged from 25% to 95% at week
4 and from 14% to 81% at week 12. were, in fact, relatively low in the only subject who showed a sustained decline in HIV-1 RNA load.
In the 2 patients who added zidovudine to nevirapine
treat-ment at week 8, 181 cysteine-variant populations of, respec- The cause of the discrepancy between responses in HIV-1 RNA load and p24 antigen levels, which has also been observed tively, 100% and 95% at week 4 were reverted to a fully 181
wild type tyrosine population at week 12. The subject with a in other antiretroviral studies [11, 12], remains unclear and requires further research. High levels of anti-core antibody sustained RNA load decline harbored a 55% 181
cysteine-variant virus population at week 12. appear to interfere with p24 antigen detection, even after im-mune complex dissociation of p24 antigen [13]. It can be hy-pothesized that during the period of maximal suppression of
Discussion
viral replication, an excess of anti-core antibodies is attained, which captures circulating p24 antigen for extended periods of The initially potent activity of nevirapine at dosages up to
200 mg/day has encouraged research into strategies to delay time. However, we qualitatively measured anti-core antibodies (Abbott HIVAB p24 EIA) at weeks 2 and 24 in 4 subjects and or circumvent the development of drug resistance, thereby
sus-taining antiviral activity [1, 3]. In theory, the consequences of did not observe a clear pattern in the relationship between anti-core antibody status and p24 antigen levels (data not shown), drug resistance could be circumvented by the attainment of
effective drug levels exceeding concentrations that inhibit drug- which argues against this hypothesis.
An alternative hypothesis for the discrepancy is that nevira-resistant virus in vitro. In a recent study of high-dose nevirapine
treatment in antiretroviral-experienced patients with advanced pine-induced changes in the virus result in a more efficient production of intact virions, reflected by a decreased production HIV disease, sustained reductions in p24 antigen and HIV-1
RNA levels were indeed observed [4]. of circulating free p24 antigen. Finally, the mere presence of nevirapine in serum may have a direct negative influence on In the present study, the same principle of treatment was
evaluated in previously untreated, predominantly asymptomatic the performance of the p24 antigen assay, resulting in the inad-vertent measurement of low p24 antigen levels. An observation HIV-1 – infected persons. Although this study confirms that
high-dose nevirapine results in sustained p24 antigen reduc- that would favor this hypothesis is that the discrepancy between p24 antigen and HIV-1 RNA responses seems unique to high-tions in the majority of patients, declines in serum HIV-1 RNA
load were transient in all but 1 of the patients, similar to what dose nevirapine treatment and is not observed at lower doses [1].
has been observed during treatment at lower doses [1]. As in
the previous study [4], increases in CD4 lymphocyte counts Overall, high-dose nevirapine was well tolerated in our pa-tients, as has been reported in larger studies using the same were also transient and, in our study, mirrored the changes in
RNA load. dose-escalation schedule for nevirapine administration [14, 15]. Although severe rashes were observed in 2 patients, these Previous studies have unequivocally shown a rapid
emer-gence of highly drug-resistant virus during nevirapine treat- rashes occurred during the low-dose lead-in period. Of note, these 2 cases were associated with exceptionally high nevira-ment, regardless of the initial CD4 cell count, virus load, or
nevirapine dose [1 – 3, 10]. Although drug susceptibilities were pine levels during this lead-in period. The development of Stevens-Johnson syndrome in 1 of these patients might have not assessed, it thus seems most likely that the loss of HIV-1
RNA load suppression in our study is due to the development been prevented if the dose had not been escalated after onset of the rash.
of drug resistance, which is substantiated by the detection of
RT codon 181 cysteine-variant virus in the majority of our In conclusion, high-dose nevirapine monotherapy does not result in sustained antiviral effects in previously untreated pa-patients. As previously reported, alternative
resistance-confer-ring mutations are found in a proportion of nevirapine-treated tients. However, the initial suppression of viral replication is substantial. Further attempts to achieve sustained effects by patients [2], which may have accounted for the absence of 181
variant virus in some of our patients. using nevirapine in combination with multiple other antiretrovi-ral drugs may prove worthwhile. Indeed, the addition of nevira-Although Havlir et al. [4] concluded that the development of
nevirapine resistance can no longer be equated with therapeutic pine and didanosine to existing zidovudine treatment shows promising antiviral effects [14], while preliminary results indi-failure, this conclusion appeared to be largely based on the
ciency virus type 1 – infected patients treated with zidovudine. J Med
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