Positive and negative drug selection pressures on the N348I connection domain mutation: new insights from in vivo data

By:

Price, H

Contributor(s):

Publication details: 2010ISSN:

13596535

Uniform titles:

Antiviral Therapy

Online resources:

Summary: <h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; background-position: initial initial; background-repeat: initial initial;">BACHGROUND: There is conflicting evidence onspecific reverse transcriptase inhibitors to which the N348I mutation inthe connection domain of HIV type-1 reverse transcriptaseconfers resistance. Here, we examined associations between the emergence of N348I andantiretroviral history in a large clinical database.</h4><h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; float: left; background-position: initial initial; background-repeat: initial initial;">METHODS: We analysed 5,353 resistance tests (that were sequenced beyond codon 348)among 2,266 antiretroviral-experienced patients. Associations between N348I and individual antiretroviral drug exposure were estimated using amatched case-control approach. Cases were defined as the first resistance testwhere N348I was detected; for each case, the 10closest (in calendar time) N348N tests were selected as controls. Odds ratios(ORs) adjusted for effects of all other drugs were estimated by conditionallogistic regression.</h4><h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; background-position: initial initial; background-repeat: initial initial;">RESULTS: N348I was detected in 198 (8.7%)cases. Drugs that were statistically significantly positively associated with N348I were efavirenz (OR 1.55, 95%confidence interval [CI] 1.08-2.23; P=0.017) and nevirapine (OR 2.06, 95% CI1.49-2.85; P<0.001). Tenofovir disoproxil fumarate (TDF) was significantlynegatively associated (OR 0.27, 95% CI 0.15-0.48; P<0.001) with N348I.Similar findings were observed when the analysis was repeated to include onlythose tests within 2 years of the resistance test. Effects for zidovudine andstavudine were evident only in an additional analysis, which consideredexposure to both drugs jointly within 2 years prior to the resistance test:exposure to zidovudine alone (OR 4.61, 95% CI 1.83-11.61; P<0.001) andexposure to stavudine alone (OR 3.39, 95% CI 1.32-8.71; P=0.011).</h4><h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; background-position: initial initial; background-repeat: initial initial;">CONCLUSIONS: This is the first clinical evidence to suggest that efavirenz mightselect for N348I in addition to nevirapine, thatstavudine might select for N348I inaddition to zidovudine and that TDF might protect against the mutation.</h4>

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Item type	Home library	Collection	Class number	Status	Date due	Barcode
Book	Ferriman information and Library Service (North Middlesex) Shelves	Staff publications for NMDX		Available

NMUH Staff Publications

<h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; background-position: initial initial; background-repeat: initial initial;">BACHGROUND: There is conflicting evidence onspecific reverse transcriptase inhibitors to which the&nbsp;N348I&nbsp;mutation&nbsp;inthe&nbsp;connection&nbsp;domain&nbsp;of HIV type-1 reverse transcriptaseconfers resistance. Here, we examined associations between the emergence of&nbsp;N348I&nbsp;andantiretroviral history in a large clinical database.</h4><h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; float: left; background-position: initial initial; background-repeat: initial initial;">METHODS: We analysed 5,353 resistance tests (that were sequenced beyond codon 348)among 2,266 antiretroviral-experienced patients. Associations between&nbsp;N348I&nbsp;and individual antiretroviral&nbsp;drug&nbsp;exposure were estimated using amatched case-control approach. Cases were defined as the first resistance testwhere&nbsp;N348I&nbsp;was detected; for each case, the 10closest (in calendar time) N348N tests were selected as controls. Odds ratios(ORs) adjusted for effects of all other drugs were estimated by conditionallogistic regression.</h4><h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; background-position: initial initial; background-repeat: initial initial;">RESULTS: N348I&nbsp;was detected in 198 (8.7%)cases. Drugs that were statistically significantly positively associated with&nbsp;N348I&nbsp;were efavirenz (OR 1.55, 95%confidence interval [CI] 1.08-2.23; P=0.017) and nevirapine (OR 2.06, 95% CI1.49-2.85; P&lt;0.001). Tenofovir disoproxil fumarate (TDF) was significantlynegatively associated (OR 0.27, 95% CI 0.15-0.48; P&lt;0.001) with&nbsp;N348I.Similar findings were observed when the analysis was repeated to include onlythose tests within 2 years of the resistance test. Effects for zidovudine andstavudine were evident only in an additional analysis, which consideredexposure to both drugs jointly within 2 years prior to the resistance test:exposure to zidovudine alone (OR 4.61, 95% CI 1.83-11.61; P&lt;0.001) andexposure to stavudine alone (OR 3.39, 95% CI 1.32-8.71; P=0.011).</h4><h4 style="margin: 0cm 3pt 0.0001pt 0cm; text-align: justify; line-height: 9.8pt; background-position: initial initial; background-repeat: initial initial;">CONCLUSIONS: This is the first clinical evidence to suggest that efavirenz mightselect for&nbsp;N348I&nbsp;in addition to nevirapine, thatstavudine might select for&nbsp;N348I&nbsp;inaddition to zidovudine and that TDF might protect against the&nbsp;mutation.</h4>&nbsp;

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