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Quest Clinical Research, San Francisco, California
South West Infectious Diseases, Dallas, Texas
Elizabeth Taylor Medical Center, Washington, DC
North Broward Hospital District, Fort Lauderdale, Florida
Community Health Initiative of New England, Boston, Massachusetts
Phoenix Body Positive, Phoenix, Arizona
Pennsylvania Oncology and Hematology, Philadelphia
Trimeris, Durham, North Carolina
Roche, Welwyn, United Kingdom
Background.
T-1249 is a 39amino acid synthetic peptide fusion inhibitor (FI) shown to preserve antiretroviral activity in vitro against human immunodeficiency virus (HIV) isolates that have decreased susceptibility to enfuvirtide (ENF).
Methods.
A 10-day phase 1/2 study of the safety and antiretroviral activity of T-1249 was conducted in 53 HIV-1infected adults with detectable viremia while on an ENF-containing treatment regimen.
Results.
From FI-naive baseline levels, the geometric mean (GM) decrease in susceptibility to ENF was 116.3-fold, and the GM decrease in susceptibility to T-1249 was 2.0-fold. Patients continued to administer their failing treatment regimen but replaced ENF with T-1249 at a dose of 192 mg/day. T-1249 was generally well tolerated; injection site reactions, which were generally mild, were the most commonly reported adverse event (64% of patients). The median change from levels of HIV-1 RNA at baseline to levels on day 11 was -1.26 log10 copies/mL (95% confidence interval, -1.40 to -1.09 log10 copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of 1.0 log10 copies/mL was seen in 73% of patients. Antiretroviral activity, as measured by levels of HIV-1 RNA, was not predicted by baseline susceptibility to T-1249 or to ENF; genotypic substitutions that emerged during T-1249 treatment were identified in virus from some patients.
Conclusions.
These results indicate that FIs constitute an expanding class of antiretroviral agents with the potential to be sequenced.
Until recently, only 3 classes of antiretroviral agents (ARVs)namely, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs)were available to treat HIV infection. With the approval of enfuvirtide (ENF), a new class of agentsfusion inhibitors (FIs)was added to this armamentarium. FIs have a novel mechanism of action and can intervene at an earlier stage in viral replication than could previously available ARVs [1]. FIs block a conformational change in the HIV envelope (Env) glycoprotein gp41, which is required for the fusion of viral and target cell membranes. When added to an optimized treatment regimen in patients who had experienced virological failure (VF) with all 3 other classes of ARVs (as did patients in the T-20 vs. Optimized Regimen Only 1 study), ENF demonstrated durable virological and immunological benefits through 48 weeks of treatment [25]. These results support the use of ENF as the standard of care in patients who have experienced VF with all 3 of the conventional classes of ARVs. As with other ARVs, some patients experience VF while on an ENF-containing treatment regimen. In many cases, this VF is associated with substitutions in gp41 aa 3645 that have been closely associated with reduced susceptibility to ENF [68].
T-1249 is a 39-aa peptide composed of sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus. In a 14-day monotherapy study (T1249-101) in patients who were heavily treatment experienced but FI naive, T-1249 was generally safe, was well tolerated, and demonstrated very potent dose-dependent antiretroviral activity [9]. Moreover, analysis of viral Envs in vitro from patients who had experienced VF while on an ENF-containing treatment regimen demonstrated that T-1249 retains antiretroviral activity against Envs that display reduced susceptibility to ENF [10]. Together, these findings provide the rationale for the conduct of T1249-102, a study of the short-term antiretroviral activity of T-1249 in patients who had experienced VF while on an ENF-containing treatment regimen.
PATIENTS, MATERIALS, AND METHODS
Study population.
Eligible HIV-1positive patients were adults enrolled in a clinical trial of ENFa phase 2 study, a phase 3 study (TORO 1), or an early access program (EAP). Patients were required to have had 2 consecutive documented episodes of viremia of >5000 HIV-1 RNA copies/mL while on a stable treatment regimen. Patients must have been on the stable treatment regimen, including ENF, for 8 weeks before the first of the 2 episodes of viremia was documented. Additionally, a screening level of HIV-1 RNA in plasma had to be 5000500,000 copies/mL.
Female patients were ineligible if pregnant or breast-feeding. All patients gave written, informed consent. The protocol, informed consent, and all amendments were reviewed and approved by the Institutional Review Boards of each of the participating centers. The human-experimentation guidelines of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of clinical research.
Study design.
In this multicenter (14 sites) trial, T-1249 replaced ENF in patients' failing treatment regimens. Patients administered their last dose of ENF the night before study day 1 and administered T-1249 at a dose of 192 mg/day the next morning during their study day 1 visit (figure 1). Patients administered T-1249 for a total of 10 days. At commencement of the study, with the exception of the cessation of ENF, the antiretroviral treatment regimen as dictated by each patient's previous study protocol was continued unchanged. Because the formulation of T-1249 used in the present study (48 mg/mL) required 4 injections daily to deliver 192 mg/day, patients were allowed to administer T-1249 once daily (192 mg, taken 1 time each day) or twice daily (96 mg, taken 2 times each day), according to each patient's preference. Patients completed study visits during screening and on study days 1, 5, 8, and 11 and completed a follow-up visit within 14 days of discontinuation of T-1249.
Efficacy evaluation.
Levels of HIV-1 RNA in plasma were measured by use of the Roche Amplicor (version 1.0) and/or the Roche Amplicor UltraSensitive HIV-1 monitor assay (version 1.0). The assay was preformed at Icon Labs, Farmingdale, New York.
Antiretroviral activity was assessed by measurement of (1) change in log10 HIV-1 RNA levels from baseline levels; (2) maximum change in log10 HIV-1 RNA levels from baseline levels; and (3) percentage of patients with decreases of 1.0 log10 HIV-1 RNA copies/mL from baseline levels at each study visit and at any time point. The baseline level of HIV-1 RNA for each patient was defined as the mean of the 2 most recent assessments before administration of the first dose of T-1249. The CD4 cell count for each patient was determined locally from the most recent assessment before administration of the first dose of T-1249. For the purposes of this study, VF while on an ENF-containing treatment regimen used in a previous study protocol was arbitrarily defined as the first documented episode of viremia of >5000 copies/mL that was confirmed in a consecutive measurement.
Genotypic and phenotypic analysis.
Resistance testing on the HIV-1 Env was performed by ViroLogic (South San Francisco, CA); this included genotypic testing on HIV-1 Env and testing of susceptibility to both T-1249 and ENF in baseline and posttreatment (day 11) plasma samples. Genotypic analyses are presented for gp41 aa 3571, which comprise the core HR-1 region, as defined by radiographic analysis of crystallographic structure [11, 12]. The entry inhibitor phenotyping assay was performed with virus particles pseudotyped with HIV-1 Env gp160, which had been amplified from the patient's plasma HIV-1 RNA and ligated into a recombinant test vector [13]. Pseudotyped viruses were tested on cell lines expressing CD4 and either the CCR5 or the CXCR4 cellular coreceptor, and results are reported as the IC50 or as a fold change in IC50 normalized to that of a reference strain (FCIC50; equivalent to viral IC50/reference strain IC50). For data from a single time point, raw IC50 values are used for summaries and comparisons, to allow data from viruses with different cellular tropisms (and thus normalized to that of different reference strains in the calculation of FCIC50) to be combined. For changes in susceptibility between time points, the change in FCIC50 on either the CCR5-expressing or the CXCR4 (and CD4)expressing cell lines was calculated. For dual-tropic viruses, the higher of the changes in FCIC50 from baseline values calculated from either cell line was used for summaries and comparisons.
To examine whether baseline sensitivity to T-1249 or genotypic and/or phenotypic changes observed on treatment during the present study correlated with antiretroviral response, patients were classified, on the basis of levels of HIV-1 RNA during the present study, as responders, rebounders, or nonresponders. Under these arbitrary definitions, responders achieved a 1.0 log10 copies/mL decrease from baseline in levels of HIV-1 RNA, and their level of HIV-1 RNA did not rebound by 0.5 log10 copies/mL above the nadir value; rebounders achieved a 1.0 log10 copies/mL decrease from baseline in levels of HIV-1 RNA but subsequently experienced a rebound of 0.5 log10 copies/mL above the nadir value; nonresponders achieved a nadir decrease of <1.0 log10 copies/mL in levels of HIV-1 RNA from baseline.
Safety evaluation.
Safety was monitored through the reporting of adverse events (AEs), administration of routine physical examinations, monitoring of vital signs, and administration of clinical laboratory testing (including blood chemistry analysis, hematological analysis, and urinalysis, all performed at Icon Labs). AEs were monitored throughout the study, starting after administration of the first dose of T-1249. Severity was graded in accordance with the AIDS Clinical Trial Group toxicity grading scale. Those adverse events not listed on this grading scale were graded as mild, moderate, or severe. AEs were coded by use of the MedDRA dictionary (version 4.0). Injection site reactions (ISRs) were recorded separately from AEs, unless they met the definition of a serious adverse event (SAE).
Pharmacokinetic evaluation.
A predose (trough) plasma sample was obtained from all patients before administration of T-1249, and additional plasma samples were collected on study days 1, 5, 8, and 11. Samples were collected in potassium-EDTAcoated tubes and chilled on ice. Plasma was stored at -70°C until analysis. Samples were analyzed for T-1249 levels by use of a validated high-pressure liquid chromatography/mass spectrometry/mass spectroscopy method.
Statistical analyses.
All analyses were performed on the intent-to-treat (ITT) population, defined as all patients who received 1 dose of T-1249 and, at baseline, either had a reduced susceptibility to ENF of >10-fold or demonstrated genotypic substitutions in gp41 aa 3645 previously associated with resistance to ENF. Data were summarized by use of descriptive statistics for continuous parameters and by use of counts and percentages for categorical parameters. Ninety-five percent confidence intervals (CIs) for the median change between log10 levels of HIV-1 RNA at baseline and those on day 11 were constructed [14].
RESULTS
Study population.
Fifty-three patients were enrolled in the study and received 1 dose of T-1249; these patients constitute the safety population. The ITT population was composed of 51 patients (96%) who received 1 dose of T-1249 and whose virus as examined at baseline demonstrated reduced susceptibility to ENF and/or the presence of genotypic substitutions associated with this susceptibility. All viruses with a >4-fold decrease in susceptibility to ENF, compared with that of viruses at the FI-naive baseline, harbored substitutions in gp41 aa 3645. Of the viruses from the 2 patients excluded from the ITT population, 1 could not be amplified for analysis in spite of viremia with high levels of virus; the other had no apparent resistance to ENF.
The majority of the patients were male (89%), with a median age of 41 years. The median baseline level of HIV-1 RNA in plasma was 5.0 log10 copies/mL (range, 3.55.6 log10 copies/mL), and the median of the most recent CD4 cell count before the first dose of T-1249 was 86 cells/L (range, 1522 cells/L). Patients had enrolled in the present study from a phase 2 study (8; 15%), a phase 3 study (TORO 1) (41; 77%), or an EAP (4; 8%). After VF during the previous study protocol, patients remained on ENF for an additional median duration of 65 weeks (range, 13165 weeks). The median time on the failing treatment regimen was different for patients enrolling from a phase 2 study (100 weeks), a phase 3 study (61 weeks), or an EAP (25 weeks).
Patients were heavily treatment experienced (median exposure to ARVs, 8 years); they had received a median of 8, 5, and 6 years of previous NRTI, NNRTI, and PI therapy, respectively. The failing previous study protocols contained NRTIs (98%), NNRTIs (25%), and PIs (89%) in various combinations.
Antiretroviral activity was also analyzed according to the dosing interval chosen by each patient. Fourteen (27%) patients administered T-1249 twice daily, whereas 37 (73%) patients administered T-1249 once daily. Mean concentrations in trough plasma were 4.9 and 2.5 g/mL for the twice-daily patients and the once-daily patients, respectively. Levels of HIV-1 RNA on day 11 had decreased by a median of -1.03 log10 copies/mL for the twice-daily patients and by a median of -1.30 log10 copies/mL for the once-daily patients (P = .082).
Multiple linear regression (MLR).
To evaluate baseline factors associated with antiretroviral activity, an MLR analysis was conducted. Predictors included, among other factors, demographic characteristics, disease characteristics, ARV experience, baseline susceptibility to ENF and T-1249, and time on a failing ENF-containing treatment regimen. Factors associated with larger decreases in levels of HIV-1 RNA on day 11 (P < .05) included higher baseline CD4 cell counts, shorter time on a failing ENF-containing treatment regimen, higher baseline IC50 of ENF, and administration of T-1249 once daily. Low R2 values demonstrated that each of the prognostic factors made a very small contribution to the overall model, with baseline CD4 cell count making the largest contribution (R2 = 0.167).
Phenotype and genotype of HIV-1 envelope gp41.
Where possible, FI phenotypic testing was performed at baseline of each patient's previous study protocol (FI naive), at or near the time of VF in the patient's previous study protocol, and at baseline in the present study. The geometric mean (GM) increase of FCIC50 of ENF from baseline levels in previous study protocols to baseline levels in the present study was 116.3-fold; in contrast, the GM increase of FCIC50 of T-1249 was 2.0-fold (n = 42). In patients entering this study from TORO 1, the susceptibility to ENF from the time of VF in TORO 1 to baseline in the present study showed a further decrease of 3.7-fold and showed a further decrease of 1.3-fold for T-1249 (n = 28), which suggests an increased resistance to ENF with continued failing treatment.
The relationship between baseline susceptibility to T-1249 and/or ENF and antiretroviral activity was explored by (1) comparing baseline susceptibilities to T-1249 and ENF for responders, rebounders, and nonresponders; (2) comparing FCIC50 of T-1249 or ENF from FI-naive baseline levels (before receipt of ENF) to baseline levels in the present study for responders, rebounders, and nonresponders; and (3) examining the relationship between baseline susceptibility to T-1249 and change in levels of HIV-1 RNA from baseline as a continuous variable. Baseline IC50 levels of T-1249 were similar for all patients, and the same was true for susceptibility to ENF (table 1); the change in susceptibility from baseline in the previous study protocols to baseline of the present study for both T-1249 and ENF was also comparable between study groups (table 1). When baseline susceptibility to T-1249 and antiretroviral activity as a continuous variable were examined, no correlation was found (figure 4A).
In contrast to the lack of correlation between baseline susceptibility and antiretroviral activity, decreases in susceptibility to T-1249 during treatment were strongly correlated with the type of virological response (r = 0.56; P < .0001) (figure 4B). This was also reflected in the GM decreases for the different response groups, with the greatest decrease in susceptibility to T-1249 observed in rebounders and the lowest decrease in susceptibility to T-1249 observed in responders (table 1); changes in GM susceptibility to ENF were similar to those observed for T-1249.
Viral Envs from 10 patients showed a >4-fold decrease in susceptibility to T-1249 between baseline and day 11 (table 2). In each case, 1 substitution was observed in gp41 aa 3571more specifically, within the ENF resistanceassociated region of gp41 aa 3645 [7]. In some instances, substitutions such as Q40K that are known to correlate with resistance to T-1249 [9] were observed, whereas in others additional ENF resistanceassociated substitutions, compared with those seen at baseline in the present study (e.g., G36D), were detected.
Safety and tolerability.
In general, T-1249 was well tolerated throughout the 10-day dosing period. All patients completed the 10-day dosing period without interruption in the administration of T-1249. Excluding nonserious ISRs, an AE was experienced by 42% of patients. AEs reported by >1 patient were arthralgia, diarrhea, fatigue, myalgia, and pyrexia, each occurring in 2 (4%) patients; none of these was severe or treatment limiting. One patient experienced a grade 2 fever concurrent with a diffuse, maculopapular rash consistent with an allergic-like reaction 1 day after completion of the dosing period; after symptomatic treatment, the rash resolved without sequelae in 34 days. Selected hematological and blood chemistry parameters were monitored; 2 (4%) patients had elevated levels of creatinine, whereas elevated levels of aspartate aminotransferase/alanine aminotransferase, elevated levels of blood glucose, neutropenia, and thrombocytopenia were experienced by 1 patient each. The investigators assessed all these events as being unrelated to the use of T-1249.
One patient died after completion of the dosing period. This patient had a longstanding history of chronic obstructive pulmonary disease and was receiving supplemental oxygen at home. On study day 6, he developed an upper respiratory tract illness that progressed to a lower respiratory tract illness and lobar pneumonia. The patient refused life support and died of respiratory failure secondary to pneumonia in the context of multiorgan failure. The event was not considered to be related to the use of T-1249.
Thirty-four (64%) patients experienced 1 ISR. The most common ISRs were pain (65%), subdermal nodule/cyst (65%), induration papule (50%), pruritus (50%), erythema (35%), and ecchymosis (21%). Only 1 patient experienced an ISR with an overall intensity greater than grade 2 (on the basis of severity of pain/discomfort).
DISCUSSION
These results confirm that T-1249 retains potent antiretroviral activity in patients who had experienced VF while on an ENF-containing treatment regimen. Compared with the sample size in other monotherapy studies of the short-term activity of individual ARVs, the 51 ITT patients who received the same dose of T-1249 in the present study represent a relatively large sample size. This accounts for the narrow 95% CI observed for the day 11 level of HIV-1 RNA, which has an upper and lower limit of >1.0 log10 copies/mL decrease from baseline levels.
The criteria for inclusion as an ITT patient were evidence of resistance to ENF, to ensure that results would reflect the activity of T-1249 in patients with true VF while on an ENF-containing treatment regimen and not treatment failure due to other causes. The patient population had extensive ARV experience, viremia with high levels of virus despite treatment with multiple ARVs, and low CD4 cell counts. In addition, these patients had long-term VF while on ENF, as evidenced by the median length of treatment with ENF after VF of 1 year.
One potential bias of the present study is that the patients enrolled in it had continued treatment with ENF after VF. This criterion could have selected for a subset of patients who were healthier than those not included in this study, because they discontinued ENF or died. It could also have selected for patients who continued to have virological or immunological benefit from ENF in spite of the presence of viral replication.
Unexpectedly, MLR analysis suggested that patients who received T-1249 once daily had better antiretroviral responses than did those who received it twice daily. Because this was not a randomized comparison and because dosing frequency was guided by individual patient and physician preferences, the significance of these findings is unclear. One potential bias is that patients who were perceived to be sicker (i.e., more symptomatic or with recent deterioration in clinical status) might have decided to take T-1249 twice daily rather than once daily; the lack of difference between the dosing groups baseline disease characteristics does not allow us to clearly establish clinical status as a confounding factor, and the number of patients who opted for twice-daily administration of T-1249 was small14 (27%) of 51 ITT patients.
Pharmacokinetic analysis was limited to trough plasma samples; patients who received T-1249 twice daily demonstrated trough levels that were twice as high as those of patients who received it once daily. By contrast, using data derived from a study published elsewhere, we could estimate that the area under the curve for T-1249 exposure should have been similar in both dosing groups [9]. However, because the pharmacokinetic parameters critically associated with optimal antiretroviral responses to FIs are unknown, additional studies that incorporate a longer study period will be necessary to better understand the impact of the dosing interval on the efficacy of T-1249.
Importantly, short-term treatment with T-1249 was well tolerated in this extensively ARV-pretreated patient population, and this expands on observations from short-term studies in FI-naive patients [9]. ISRs were the most common AE; similar to those observed with T-1249 in FI-naive patients, they were mild and not treatment limiting.
Of interest, after completion of the dosing period on study day 11, 1 patient experienced a grade 2 fever concurrent with a diffuse, maculopapular rash of moderate severity that resolved several days later. Although this was suggestive of an allergic-like reaction, serum antibody results were nonquantifiable throughout the dosing period for this patient (data not shown). Several months later, the patient was successfully rechallenged with T-1249 as part of a chronic dosing rollover study. In a study of FI-naive patients published elsewhere, reactions that could have been mediated by an allergic mechanism were described in some patients [9]. The findings from the present study suggest that, with short-term exposure to T-1249 in FI-experienced patients, these reactions are infrequent; however, the clinical relevance of these reactions can be better defined only in larger clinical trials [1519].
Baseline susceptibility to T-1249 did not correlate with short-term antiretroviral activity after treatment with T-1249. By contrast, change in FCIC50 from levels at baseline to those on day 11 was strongly correlated with change in levels of HIV-1 RNA. One potential explanation for these findings is that when viruses with reduced susceptibility to T-1249 are selected during treatment with ENF, they have fitness disadvantages that prevent them from becoming prevalent populations. It is only on challenge with T-1249 that these quasispecies rapidly outgrow those that are more sensitive to T-1249. Thus, these quasispecies are evident on day 11 but not at baseline. Alternatively, the range of baseline susceptibilities of these viruses to T-1249 may be well within the therapeutic range of the drug administered at a dose of 192 mg/day; baseline susceptibility would then not have an impact on changes in levels of HIV-1 RNA, because all patients were technically "sensitive" to the compound. From this perspective, viruses that exhibit reduced susceptibility to T-1249 on day 11 could simply represent the outcome of de novo selection of resistant virus subspecies when monotherapy is used, an outcome similar to what was observed in FI-naive patients [9].
Presumably because of the lack of therapeutic alternatives or perceived sustained benefits, patients in the present study continued to take ENF for a median of 65 weeks after VF. Thus, these patients did not experience early VF but had been exposed to ENF for a prolonged interval as part of a failing treatment regimen. Analyses of the time on a failing treatment regimen and subsequent antiretroviral activity after treatment with another ARV of the same class have not been described for other compounds. However, it has been proposed that continued treatment with any ARV after ARV failure can limit the antiretroviral activity after treatment with other ARVs in the same class [20, 21]. Remarkably, length of ENF treatment after VF does not appear to be a strong predictor of decrease in levels of HIV-1 RNA after treatment with T-1249, as demonstrated by the observation that T-1249 causes short-term decreases in levels of HIV-1 RNA in most patients even when they have spent a prolonged period of time on a failing ENF-containing treatment regimen.
In conclusion, T-1249 demonstrated potent short-term antiretroviral activity in patients on a failing ENF-containing treatment regimen. This study provides proof of the concept that FIs have the potential to be an expanding class of ARVs with the possibility of being sequenced. Longer-term studies of T-1249 and/or next generation FIs are needed to assess the potential of FI sequencing as a therapeutic strategy.
Acknowledgments
We extend our thanks to Emily McFalls, for drug safety oversight. Additionally, we recognize Tina Korich at ViroLogic, for help with sample processing. For their work and dedication, we give special thanks to all study site personnel, including the following study investigators and coordinators: April Rosato, Mark Packard, Raul Nunez, Meaghan Morton, Christiane Geisler, Sandra Preston, Joy Edwards, Karlissa Foy, Laurie Wojtusik, Corey Rosmarin, Kerry Upton, Patrick Milne, Vernon Appleby, Kathy Nuffer, Susan Kilcoyne, Beth Zwickl, Eileen Glutzer, Sandy Charles, Toni Kempner, Barbara Casimir, Dawn Chaney, Joy Bautista, and April Rucker. Last, we are greatly indebted to all study participants.
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