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NNRTI's -- New Insights- "THE NNRTI TAIL": drug resistance; prevention of mother-to-child HIV transmission; HAART interruption
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Written for NATAP By Ronald Reisler MD MPH, Institutes of Human Virology University of Maryland Medical School
11th Annual Retrovirus Conference, Feb 8-11, 2004, San Francisco
Note from Jules Levin: at the conference several presentations discussed NNRTI resistance: nevirapine (Viramune) resistance due to single dose use in preventing mother-to-child HIV transmission, and potential for efavirenz (Sustiva) resistance (which could apply to nevirapine as well) developing if a patient stops taking all the drugs in a NNRTI-based regimen at once because NNRTI have a long half-life. The long half life means the drugs can stay in blood for longer periods of time at decreasing levels. The following article reports these study findings to you, which were presented at the conference. And an easy to understand summary of the findings and a discussion of implications by Dr Reisler are at the end of the report.
Perhaps the most important findings presented at the 11th CROI were Oral Abstracts: [38, 39, 41LB, 131- 133] and Poster Abstracts [604, 891, and 892]. THESE FINDINGS COULD POTENTIALLY HAVE MAJOR IMPACT UPON both NEVIRAPINE AND EFAVIRENZ based regimen implementation in Sub-Saharan Africa and Mother To Child Transmission (MTCT) prevention programs using nevirapine and the ability to subsequently treat mothers with NNRTI based regimens.The reported half-life of Efavirenz is 40 to 55 hours and the reported half-life of nevirapine is 45 hours (single dose) and 25 - 30 hours (multiple doses). However, these values were obtained from select subjects from Western Europe and the US and may not reflect the wide variations in drug metabolism that are now emerging.
With regard to efavirenz, Taylor et al. (Abstract 131) report that "After Discontinuation of Efavirenz, Plasma Concentrations May Persist for 2 Weeks or Longer". It seems that for some individuals, efavirenz can take a very long time to be cleared. In his small pharmacokinetic study of 10 individuals, who stopped efavirenz for various reasons, 5/10 had an efavirenz half-life in excess of 100 hours. Of these, 4 were black African women. Of the 4, 3/4 had therapeutic efavirenz levels {>1000ng/ml} 2 weeks after stopping. If viral rebound occurs while efavirenz levels are sub-therapeutic, efavirenz resistance may emerge. The authors recommend to consider stopping efavirenz at least 7 - 14 days prior to stopping NRTIs to avoid the emergence of NNRTI resistance by "covering the NNRTI tail." (Editorial note from Jules Levin: there are several ways that have been suggested for stopping an NNRTI regimen & the NNRTI component in a regimen). Hitti et. al reported in Abstract 604 that women had significantly lower efavirenz AUC compared with men, even after adjustment for weight (p <0.05). There were no significant sex differences in the AUC of indinavir, nelfinavir, or M8. Increased weight was significantly associated with lower efavirenz and indinavir AUC (p <0.05). These data suggest differences in the absorption or elimination of efavirenz between men and women. The presence or absence of co-administered antiretroviral medications did not modify these observed associations.
With regard to efavirenz and race Ribaudo et al. (Abstract 132) report in A5097s (a sub study of ACTG A5095) that - Efavirenz clearance is strongly associated with race. Both clearance and volume of distribution were associated with weight. Increasing efavirenz drug levels were associated with an increased rate of efavirenz discontinuation. However, there was no association with efavirenz pharmacokinetics and the incidence of CNS toxicities or viral load response. Dr. Ribaudo said that "it is unclear whether racial differences will impact long-term virology". Haas et al (Abstract 133) reported on NWCS 214 - a genetics sub-study of patients in A5097s that looked at relevant liver metabolism profiles for CYP2B6, 3A4, 3A5, and MDR1. Haas et al. found that the CYP2B6 allelic variant (CYP2B6 G516T TT homozygous) occurs more commonly in blacks (20%) than whites (3%) and is associated with approximately 3-fold higher plasma Efavirenz levels. The CYP2B6 G516 TT, genotype was associated with CNS adverse events (p= 0.04).
In Abstract 891, Muro et al demonstrated that in healthy non-pregnant HIV negative Dutch women, nevirapine plasma concentrations were still detectable after more than 2 weeks in the majority of women receiving single-dose nevirapine 200 mg. The median half-life was 57 hours with a range of a range of 26 to 164 hours. The time to the first undetectable NVP plasma concentration was 11 days in 4 subjects, 15 days in 12, 18 days in 12, and 21 days in 9 subjects. In the remaining 7 subjects NVP was still detectable on day 22, the last day of sampling. Time to an undetectable NVP plasma concentration was not influenced by age, height, body weight, body surface area, alcohol use or smoking.
Abstracts 38 (Martinson et al), 41LB(Jourdain et al), and 892 (Lyons et al) emphasize the need to reassess the impact of nevirapine MTCT programs upon the emergence of NNRTI resistance in the mothers. Rates of resistance range from as high as 44% (abstract 38) (almost all HIV clade C) 18% (abstract 41LB) and 16% (abstract 892).
Jourdain et al. in abstract 41LB, report that at 3 months, 80% of the 66 women with at least one mutation, 87% of the 112 SD-NVP exposed women with no mutation and 88% of the 41 non exposed women had a viral load <400 copies/mL (viral load <50: 45%, 46%, and 54%). At 6 months, 68% of the 50 women with at least one mutation, 80% of the 92 exposed women without mutation and 85% of the 27 non exposed women had a viral load <400 (p for trend = 0.057) (viral load <50: 38%, 50%, 74%; p for trend = 0.0034). Of SD-NVP-exposed women without and with mutations who started therapy more than 6 months after delivery, 91% and 77%, had a viral load <400, vs. 69% and 58% of those who started earlier (p = 0.006) (viral load <50: p = NS).
Conclusions: Mothers exposed to SD-NVP for PMTCT experienced a lower virological success rate of subsequent NNRTI-based therapy compared to non-exposed mothers. However, a clinically meaningful proportion of women still achieved virological success at 6 months even in the presence of mutations. Importantly, later initiation of therapy after NVP exposure was associated with an improved virological response. These results suggest that drug-resistance mutations that arise following SD-NVP exposure have an effect on the efficacy of subsequent NNRTI-based therapies. They also provide insight and demonstrate the necessity for further development of synergistic strategies which will maximize benefit of subsequent antiretroviral therapy for the mother while preserving the remarkable achievements of potent antiretroviral therapy for PMTCT. (Reviewer's note: What this means, is that we could potentially observe up to an additional 16 to 44% failure rate in excess of a typical 30 - 35 % 48 week failure rate for nevirapine based ART regimens in mothers treated previously with nevirapine. On one hand, it is somewhat reassuring to know that women who initiated therapy 6 months after delivery had a better virologic outcome in the short term. On the other hand, questions about long term durability remain. One would expect that the frequency of NNRTI resistant variants to peak in plasma 2 -- 4 weeks after single dose nevirapine so measuring frequency of NNRTI resistance at 3 months probably underestimates the frequency. In addition, we now know that these resistant variants are archived. The 48 week viral load data will be critical in assessing the durability of this approach in patients who develop minor NNRTI resistant variants.)
If we couple this information with the data presented in abstract 39 that prior NNRTI exposure can select minor NNRTI-resistant variants that are missed by standard genotyping. Standard genotype did not identify NNRTI mutations in baseline samples from 48 (22%) NNRTI-experienced patients who actually harbored NNRTI resistance. Mellors et al. conclude that these minor variants contribute to failure of EFV-based regimens. (Reviewer's note: clearly, the same would hold true for nevirapine based regimens.)
NNRTI Conclusions:
- There are significant populations of patients with HIV that exhibit prolonged clearance of NNRTI's - efavirenz and nevirapine (that is, it takes longer for NNRTIs to leave the blood than other HAART drugs).
- If either ongoing viral replication occurs (in the case of one dose MTCT prevention) or if viral rebound occurs while NNRTI levels are sub-therapeutic (when HAART is stopped), NNRTI resistance may emerge.
- Taylor et al suggest that NNRTIs should be stopped 7 - 14 days prior to stopping NRTIs to avoid the emergence of NNRTI resistance. (UK BHIVA July 2003 guidelines recommend 7 days)
- MTCT Prevention studies need to study the impact upon future virologic success in subsequent treatment of mothers. New strategies need to be adopted to improve therapeutic outcome in mothers who receive NNRTIs as part of MTCT and are subsequently treated with NNRTI based ART.
- Women had significantly lower efavirenz AUC then men
- Efavirenz clearance is strongly associated with race. Both clearance and volume of distribution were associated with weight. Increasing efavirenz drug levels were associated with an increased rate of Efavirenz discontinuation.
- CYP2B6 allelic variant (CYP2B6 G516T TT homozygous)occurs more commonly in blacks (20%) than whites (3%) and is associated with approximately 3-fold higher plasma Efavirenz levels. The CYP2B6 G516 TT, genotype was associated with CNS adverse events (p= 0.04).
- Minor variants not detected in standard genotypic assays contribute to failure of Efavirenz-based regimens
(Editorial note from Jules Levin: the differences in NNRTI clearance or AUC (drug blood levels) reported for men vs women or according to race are new data from studies. Importantly, it is premature to presume clinical implications, so caution is advised in translating these study results into treatment decision making without consultation with your physician. More information related to treatment decision making is needed to interpret these findings and to better understand the application in treatment outcomes. For Robert Schooley, MD, from the University of Colorado Health Sciences Center in Denver, speaking of this study as well as another study presenting further data on the pharmacokinetics of EFV, the principle of this type of research has far-reaching implications down the road. Researchers should not get lost in some of the small discontinuation rates seen in these data, he pointed out. "The most important thing is that we can use genetic markers for research, which has the potential to impact the development of therapy globally," Dr. Schooley said.
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