 |
|
|
| |
Kaletra-NFV (study 863): using 1 copy viral load test may predict viral outcomes
|
| |
"The Level of Persistent Viremia Below 50 copies/mL Is Associated with Subsequent Rebound to Above 50 HIV RNA copies/mL for Nelfinavir-Treated Subjects, But Not Lopinavir/Ritonavir-Treated Subjects"
XIV International HIV Drug Resistance Workshop
June 7-10, 2005, Quebec City, Quebec, Canada
M. King1, S. Palmer2, A.Wiegand2, F. Maldarelli2, S. Brun1, D. Kempf1, G. Hanna1, J. Coffin2, and J. Mellors3
1Abbott Laboratories, Abbott Park, IL; 2HIV Drug Resistance Program, NCI, NIH, Frederick, MD; 3University of Pittsburgh, Pittsburgh, PA
These study results were reported at the Workshop by Abbott.
BACKGROUND
The clinical significance of persistent viremia below 50 copies/mL in subjects on suppressive antiretroviral therapy is not known.
In Study 863, antiretroviral-naive subjects were treated with stavudine, lamivudine, and lopinavir/ritonavir (LPV/r, n=326) or nelfinavir (NFV, n=327). At week 60, HIV RNA was <50 copies/mL in 64% of subjects receiving LPV/r and 52% of subjects receiving NFV, by intent-to-treat, noncompleter=failure analysis (p<0.01).1
In a subset of the subjects with sustained HIV RNA <50 copies/mL, we examined the relationship between the level of plasma HIV RNA, measured using a real-time RT-PCR assay with single-copy sensitivity, and subsequent virologic outcomes beyond the week 60 evaluation.
Assay
--An internally controlled real-time RT-PCR assay with single-copy sensitivity (single-copy assay, SCA)2 was used to test all samples.
--Based on sample volumes available in this study, the lower limit of assay sensitivity was 0.63 copies/mL.
Subjects
--Samples were selected from among subjects with HIV RNA <50 copies/mL at all visits from week 24 to week 60 (Figure 1). Among 237 such subjects, we selected a convenience sample of 163 subjects (85 LPV/r, 78 NFV), representing those with archive samples in storage in North America.
--Baseline samples were tested with the single-copy assay to ensure suitability of primers and probes. 145 of 163 subjects (71 LPV/r, 74 NFV) with successful amplification of baseline samples had week 60 samples tested by SCA.
Outcomes After Week 60
Sustained response: HIV RNA <50 copies/mL at all subsequent visits beyond week 60.
Subsequent HIV RNA >50 copies/mL:
--Virologic failure: confirmed HIV RNA rebound >400 copies/mL or a single HIV RNA rebound
>400 copies/mL followed by discontinuation.
--"Blips": subsequent HIV RNA >50 copies/mL without meeting virologic failure criteria.
Analysis
--Among subjects with HIV RNA <50 copies/mL for weeks 24-60, the association between week 60 HIV RNA value by SCA and subsequent virologic outcomes was assessed by one-way analysis of variance.
RESULTS
Week 60 Results
--As shown previously,3 no difference between treatment groups in week 60 HIV RNA level by SCA was observed, with a mean value of 0.51 log10 copies/mL (p>0.9) in each treatment group.
--However, week 60 HIV RNA value was significantly associated with baseline HIV RNA level (p<0.001 for each group).
--In an analysis based on combined treatment groups, a slow (slope of decline: -0.004 log10 copies/mL/week), but statistically significant (p=0.04) decline in persistent viremia was observed over the period from weeks 60-110.
Virologic Outcomes Beyond Week 60
Median (range) total follow-up was 95 (60-114) weeks for the LPV/r group (n=71) and 95 (60-109) weeks for the NFV group (n=74).
3 subjects in each group had no data available after week 60 and were excluded.
118 subjects (58 LPV/r, 60 NFV) maintained HIV RNA <50 copies/mL at all subsequent visits (median 32 additional weeks, range 9-54).
6 subjects (1 LPV/r, 5 NFV) met criteria for virologic failure (p=0.076 for the difference between groups). In 4/5 NFV-treated subjects, lamivudine and/or PI resistance was observed.
15 subjects (9 LPV/r, 6 NFV) had "blips" >50 copies/mL. Subjects with blips had isolated values between 50-400 copies/mL (7 LPV/r, 3 NFV), multiple values between 50-400 copies/mL (1 NFV), or single values >400 copies/mL followed by resuppression (2 LPV/r, 2 NFV).
Association Between Week 60 HIV RNA Level and Virologic Outcomes
For NFV-treated subjects, those with subsequent detectable HIV RNA >50 copies/mL (n=11) had significantly higher week 60 HIV RNA values compared to those (n=60) with sustained response (0.98 vs. 0.41 log10 copies/mL, p=0.001). The effect remained statistically significant (p=0.01) if a lone outlying value in the detectable HIV RNA group was excluded.
In contrast, LPV/r-treated subjects with subsequent detectable HIV RNA >50 copies/mL (n=10) had similar mean week 60 HIV RNA values compared to those (n=58) with sustained response (0.53 vs. 0.50 log10 copies/mL, p=0.83).
CONCLUSIONS
Among subjects with HIV RNA <50 copies/mL consistently for at least 36 weeks who had samples tested by SCA at week 60, a trend toward higher risk of subsequent virologic failure (confirmed rebound >400 copies/mL) was observed among NFV-treated subjects compared to LPV/r-treated subjects. This suggests that a LPV/r-based regimen continues to show superior long-term virologic efficacy compared to a NFV-based regimen even among patients achieving
undetectable viral load (<50 copies/mL) for an extended duration of time.
Week 60 SCA values were significantly associated with subsequent HIV RNA rebound >50 copies/mL for NFV-treated subjects, but not for LPV/r-treated subjects, suggesting that the clinical significance of very low level viremia may be different for regimens containing different protease inhibitors.
REFERENCES
1. Ruane, P, et al. 1st IAS Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina, July 2001. Abstract 6.
2. Palmer, S, et al. J Clin Microbiol 2003;41(10):4531-36.
3. Palmer, S, et al. 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 2005. Abstract 163.
| |
| |
| |
| |
|
|
|
|
|
