 |
|
|
| |
Long-Term Outcome of Individuals Experiencing a Phenotypic Switch in HIV-1 Co-receptor Use in the MERIT Study
|
| |
| |
Reported by Jules Levin
ICAAC Sept 14 2010
SD Portsmouth1, M Lewis2, C Craig2, D Chapman1, LC Swenson3, J Heera4
1Pfizer Inc, New York, NY, USA; 2Pfizer Global Research and Development, Sandwich, UK; 3BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada; 4Pfizer PGRD, New London, CT, USA
Conclusions
There were no observed adverse clinical or immunological consequences related to the emergence of CXCR4-using virus associated with virologic failure on maraviroc therapy
Individuals switching tropism during maraviroc-containing therapy had good immunological outcomes and responded to subsequent therapy
Tropism change reversed on stopping maraviroc in 2 patients with persistent viremia and reportable post-maraviroc tropism data
Five of the 15 treatment failures would have been excluded from the study had population genotyping been used at screening
INTRODUCTION
- CCR5 tropism predominates in early HIV infection with increased CXCR4 use noted over time.1 More frequent detection of CXCR4-using HIV coincides with more marked immune dysfunction and disease progression
- Virologic failure in individuals treated with CCR5 antagonist-containing ART can occur with emergence of CXCR4-using virus. This is most frequently observed when resistance to other ART in the regimen is present and fewer active drugs are used. Alternatively, this can be observed if an insensitive tropism determination method is employed to screen patients for CCR5 antagonist therapy.2
- Unlike natural disease progression which coincides with increasing CXCR4 use, the emergence of CXCR4-using virus during therapy with maraviroc has been shown to be reversible on withdrawal of maraviroc and is not associated with declines in CD4+ counts. Therefore, it is uncertain whether drug-related emergence of CXCR4-using virus has similar clinical relevance as that arising under untreated conditions. Virologic failure on CCR5 antagonist therapy with emergence of CXCR4-using virus usually occurs because undetected CXCR4-using virus was present pretreatment.
- The immunological and clinical outcome of virologic failure with the emergence of CXCR4- using virus after ART administration, in particular when combined with a CCR5 antagonist, is not well described
- This analysis describes the immunological and clinical outcomes of virologic failure with emergence of CXCR4-using virus in treatment-naïve individuals receiving twice-daily maraviroc.
METHODS
- The ongoing MERIT study compares maraviroc with efavirenz, each combined with lamivudine/zidovudine, in treatment-naïve patients with R5 HIV-1 infections3
- This analysis included individuals in the MERIT study who experienced virologic failure, which was defined as discontinuation for lack of efficacy, with a documented phenotypic change in co-receptor use. These individuals were selected for maraviroc therapy using the original Trofile assay, which was subsequently replaced with the more sensitive enhanced Trofile (ESTA) assay
- Baseline characteristics, changes in CD4+ count after tropism change, response to subsequent therapies, and occurrence of significant clinical events were assessed
- Pre-treatment predictors of subsequent tropism change were explored
- Co-receptor tropism in MERIT screening samples was retrospectively assessed by ESTA and genotypically by population sequencing and ultra-deep sequencing (UDS: sensitivity 2% X4, 3.5 FPR)
RESULTS
Baseline Characteristics
360 individuals with R5 tropic HIV-1 by the original Trofile assay were treated with maraviroc in the MERIT study
Fifteen individuals (4%) enrolled in MERIT experienced virologic failure on maraviroc-containing regimens, with emergence at failure of CXCR4-using virus by the original Trofile assay
- Lamivudine resistance mutations were also present in all 15 individuals
- Male gender: 10/15
- Age: 26-63 years
- Median baseline CD4+ count: 220 cells/mm3 (range 12-475)
- Median baseline CD4+ in full maraviroc Trofile arm = 241 cells/mm3
- Median baseline HIV-1 RNA: 117,000 copies/mL (range 2360-993,000)
Median baseline HIV-RNA in full maraviroc Trofile arm 92000 copies/mL (range 1700 to 4,076,666)
Co-Receptor Tropism at Screening
HIV-1 was CCR5-tropic (R5) in all 15 individuals at screening by the original Trofile assay that was used for study entry
Re-analysis of screening samples with the enhanced Trofile assay (ESTA) identified 8/15 individuals as having R5 virus and 7/15 with dual/mixed (DM) virus (Table 1)
Genotypic analysis of screening samples by 454 "deep" sequencing, using a 2% X4-using cutoff, identified 10/14 individuals as having R5 virus
Genotypic analysis at screening using population sequencing and geno2pheno with a 5.75 FPR identified 10/15 as having R5 virus
Therefore, at screening 5 individuals would have been excluded from the study by population genotyping, 7 individuals would have been excluded by ESTA and 4 by 454 sequencing
Follow-Up Analyses
Emergence of CXCR4-using HIV-1 (by the original Trofile assay) was detected after a median 85 days (range 14-504)
The median time to treatment switch was 183 days (range 74-548)
Follow-up plasma HIV-1 RNA and CD4+ cell count data are available for 8 individuals at 192 weeks; mean follow-up was 192 weeks (range 12-240)
The median CD4+ gain for all 15 individuals was 218 cells/mm3
There were two serious adverse events (secondary syphilis and TB); neither was considered related to therapy
Nine individuals have subsequent therapy data
- 5 received NNRTI-based therapy, 3 PI-based, and 1 triple NRTI
-- All but one (an NNRTI recipient) were virologically suppressed at week 96
Figure 1. Follow-up Through 192 Weeks
- Figure 1 shows follow-up HIV-1 RNA data, CD4+ counts, treatment changes, and tropism test results for the 8 individuals with 192-week data
- Five individuals were lost to follow-up before week 48, and 2 individuals between weeks 48 and 96
- Tropism test results are indicated as R5 (CCR5-tropic), X4 (CXCR4-tropic), DM (dual/mixed tropic), or NR (not reportable); indicates when maraviroc therapy was stopped
- At screening, DM virus was detected by ESTA in 5 of these 8 individuals, and X4 virus was detected in 4 of these individuals (all were R5 at screening by original Trofile)
References
1. Goetz MB, Leduc R, Kostman JR, et al. J AIDS 2009; 50:259-266.
2. Lewis M, Simpson P, Fransen S, et al. XVI International HIV Drug Resistance Workshop. Bridgetown, Barbados, 12-16 June 2007. Abstract 56.
3. Cooper DA, Heera J, Goodrich J, et al. J Infect Dis 2010; 201:803-813.
|
| |
|
|
|
|
|
