The impact of HIV-1 reverse transcriptase polymorphisms on responses to first-line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1-infected adults Nicola E. Mackiea, David T. Dunnb, David Dollingb, Lucy Garveya, Linda Harrisonb, Esther Fearnhillb, Peter Tilstonc, Caroline Sabind, Anna M. Gerettie, on behalf of UK HIV Drug Resistance Database, UK CHIC study Objective: HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90–108, 135–138, 179–190, 225–348) on virologic responses to first-line NNRTI-based ART. Methods: Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks. Results: Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n ¼ 597) or more than two (n ¼ 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07–1.92; P ¼ 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15–2.73; P ¼ 0.009), 1.55 (1.16–2.08; P ¼ 0.003), and 1.75 (1.00–3.05: P ¼ 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P ¼ 0.001) but not virologic failure. Conclusion: The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation. ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2013, 27:2245–2253 Keywords: HIV, nonnucleoside reverse transcriptase inhibitor, polymorphism, reverse transcriptase
a Department of HIV/GUM, Imperial College Healthcare NHS Trust, bMRC Clinical Trials Unit, London, cDepartment of Clinical Virology, Manchester Royal Infirmary, Manchester, dResearch Department of Infection and Population Health, UCL Medical School, London, and eInstitute of Infection & Global Health, University of Liverpool, Liverpool, UK. Correspondence to Dr Nicola E. Mackie, Clinical Trials Centre, Winston Churchill Wing, St Mary’s Hospital, London W2 1NY, UK. Tel: +44 776 969 4340; fax: +44 207 886 6645; e-mail: [email protected] Received: 15 February 2013; revised: 14 May 2013; accepted: 16 May 2013.
DOI:10.1097/QAD.0b013e3283636179
ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
2245
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2246
AIDS
2013, Vol 27 No 14
Introduction In antiretroviral therapy (ART)-naive HIV-1-infected patients, amino-acid variations from subtype B wild-type consensus sequence are seen to occur naturally in reverse transcriptase in the absence of selective drug pressure. The prevalence of such polymorphisms in ARTnaive individuals appears to be partly associated with the infecting HIV-1 subtype [1,2]. Several polymorphisms have been demonstrated within reverse transcriptase regions 90–108, 135–138, 179–190, and 225–348, which also harbor major mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) [3,4]. Some polymorphisms in these regions confer low-level phenotypic NNRTI resistance in vitro [4]; however, their impact upon virologic response to efavirenz (EFV) or nevirapine (NVP) in vivo remains unclear. Current treatment guidelines recommend the use of a NNRTI, typically EFV, in combination with two nucleos(t)ide analogue reverse transcriptase inhibitors (NRTIs) as one of the preferred options for first-line ART based on its demonstrated efficacy [5,6]. Patients typically undergo reverse transcriptase sequencing at diagnosis or prior to starting ART to detect transmitted drug resistance. In clinical practice, it is often uncertain whether the reporting of reverse transcriptase polymorphisms in a baseline genotypic resistance test should be taken as indication to avoid NNRTI-based therapy as an initial regimen due to concerns over suboptimal efficacy. Avoidance of the standard of care in this scenario carries implications for pill-burden, cost, tolerability, and potentially adherence. The aims of this study, therefore, were to determine the prevalence of polymorphisms with possible effects on EFV and NVP susceptibility in ARTnaive patients and assess the impact of such polymorphisms upon virologic responses to first-line NNRTIbased therapy.
Methods Study population Eligible individuals underwent baseline genotypic resistance testing while ART-naive and commenced a regimen containing EFVor NVP with at least two NRTIs between 1997 and 2010. Reverse transcriptase and protease sequences obtained prior to patients commencing ART were retrieved from the UK HIV Drug Resistance Database [7], which collects results of resistance testing performed in routine care, and linked to anonymized clinical information from the UK Collaborative HIV Cohort (UK CHIC) Study [8]. The first resistance test performed after HIV diagnosis was included as well as any additional resistance test done prior to commencing ART for each individual. The study only included individuals with week 4 (2 weeks) viral load measurements. Exclusion criteria included a pre-ART
viral load less than 50 copies/ml as a possible indicator of unrecorded treatment, and the detection of major NNRTI, NRTI, or protease inhibitor resistance mutations (as defined by the International AIDS Society (IAS)–USA 2011 list [9]) in any of the pre-ART resistance tests; major protease inhibitor mutations were taken into account as they could indicate the presence of major reverse transcriptase mutations at subdetectable levels. Polymorphisms were defined as any change from the Stanford HIV Drug Resistance Database consensus subtype B reference sequence, other than major recognized NNRTI resistance mutations, occurring at the following reverse transcriptase codons: 90, 98, 100, 101, 103, 106, 108, 135, 138, 179, 181, 188, 190, 225, 227, 230, 234, 236, 238, 318, and 348. Virologic failure was defined as follows [10]: two consecutive viral load measurements more than 200 copies/ml after previous suppression to less than 200 copies/ml; one viral load measurement more than 200 copies/ml after previous suppression to less than 200 copies/ml followed by a treatment change; or one viral load more than 200 copies/ml after 6 months of treatment without previous suppression. In a separate analysis, virologic failure was defined as two consecutive viral load measurements more than 50 copies/ml after at least 6 months of ART. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool version 2.0 [11].
Analysis The frequency of single and multiple-occurring NNRTI polymorphisms was established. Variables associated with the occurrence of any polymorphism were assessed in a logistic regression model. From the original list of screened codons, polymorphisms present in at least 10 patients were selected for further analysis. Overall virologic responses were compared between patients with wild-type sequences and those with sequences containing one or at least one polymorphism(s). The effect of each polymorphism was analyzed by comparing responses in patients with and without the polymorphism at each codon. The analyses were initially analyzed using an intent-to-treat (ITT) approach, in which any changes to the initial NNRTI-based regimen were ignored. A second, on-NNRTI treatment analysis was performed censoring patients at the date of their last viral load measurement prior to discontinuing either EFV or NVP. Early virologic responses were measured as a change in viral load from baseline to week 4 (2 weeks) and investigated using interval regression analyses to account for left-censoring due to the lower limit of quantification of viral load assays [12]. Time to virologic failure was examined using Kaplan–Meier plots and multivariable Cox regression analysis. All analyses were adjusted for baseline viral load and CD4þ cell count, HIV-1 subtype (categorized as B, C, and non-B/non-C), the specific NRTIs and NNRTI used, year of ART initiation, age at baseline resistance testing, risk group, and ethnicity. Eight percent of individuals had at least one prognostic
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Significance of NNRTI polymorphisms Mackie et al.
factor missing. Because missing values were likely to be missing at random, and to avoid a loss in efficiency, missing values for baseline CD4þ, possible exposure source, and ethnicity were imputed using multiple imputation by chained equations [13]. Ten imputed datasets were created by replacing missing values with simulated values from a set of imputation models constructed from potential prognostic factors and, when applicable, time to virologic failure outcome variables. Separate analyses of specific amino acid polymorphisms were conducted when significant codon level effects were detected. Formal adjustments to P values were not made for multiple statistical tests being performed; this is less important when results for all codons are presented [14]. All analyses were conducted in Stata/IC 12.1 software (StataCorp LP, College Station, Texas, USA).
Results Study population Between 1997 and 2010 [median September 2006; interquartile range (IQR) December 1999 to June 2009], a total of 5512 individuals commenced a first-line regimen with EFV or NVP in combination with at least two NRTIs following baseline (pre-ART) genotypic resistance testing; of these, 4528 were eligible for the study. The majority of these individuals (n ¼ 3592) had a
2247
single pre-ART genotypic resistance test performed and 936 of 4528 (21%) had more than one genotypic resistance test. Of the 984 patients who were excluded, 299 had major NNRTI/NRTI/protease inhibitor mutations at baseline, 79 had an undetectable viral load at treatment initiation, 561 had insufficient viral load data to perform further analyses, and 45 had resistance test results that only reported on major drug resistance mutations. Resistance tests were conducted a median (IQR) of 62 (24–321) days prior to commencing firstline ART. The characteristics of the study population are summarized in Table 1. Of the eligible patients, most were white (2819, 62%), men who have sex with men (2837, 63%), infected with HIV-1 subtype B (3010, 67%). Baseline viral load and CD4þ cell counts were 4.90 (IQR 4.36– 5.35) log10 copies/ml and 210 (IQR 130–280) cells/ml, respectively. Most patients (3793, 84%) commenced an EFV-based regimen with a variety of NRTI backbones reflective of routine clinical practice.
Prevalence and patterns of reverse transcriptase polymorphisms Overall, 2598 (57%) individuals had at least one polymorphism identified in their baseline reverse transcriptase sequence within the regions analyzed. Most patients (1929, 42.6%) had a single polymorphism; 669 (15%) had multiple polymorphisms, most commonly two (n ¼ 597).
Table 1. Demographic and clinical characteristics of the study population. Transmission group n (%)
Ethnicity n (%) HIV-1 subtype n (%)
Age (years) CD4þ cell count (cells/ml) Viral load (log10 copies/ml) Treatment
Total
Men who have sex with men Male heterosexual Female heterosexual Other Unknown White Black Other Unknown A B C D G CRF01 AE CRF02 AG Other Unknown Median (IQR) Median (IQR) Median (IQR) NVP þ TDF þ 3/FTC NVP þ ZDV þ 3/FTC NVP þ ABC þ 3/FTC NVP þ other NRTIs EFV þ TDF þ 3/FTC EFV þ ZDV þ 3/FTC EFV þ ABC þ 3/FTC EFV þ other NRTIs n
2837 509 640 243 299 2819 1170 407 132 172 3010 647 47 83 67 178 44 280 36.4 210 4.90 205 276 133 121 2143 598 692 360 4528
(62.7) (11.2) (14.1) (5.4) (6.6) (62.2) (25.8) (9.0) (2.9) (3.7) (66.5) (14.3) (1.0) (1.8) (1.5) (3.9) (1.0) (6.2) 31.2–42.4 130–280 4.36–5.35 (4.5) (6.1) (2.9) (2.7) (47.3) (13.2) (15.3) (8.0)
3/FTC, lamivudine or emtricitabine; ABC, abacavir; EFV, efavirenz; IQR, interquartile range; NRTIs, nucleos(t)ide reverse transcriptase inhibitors; NVP, nevirapine; TDF, tenofovir; ZDV, zidovudine.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
V I A S,G K R,Q,N K R, Q, S, E V I I T, V, R, M, L, K, A, C E A, G, K, D V I, D, E, T, A, S, C K R, Q, N
90
4386 142 4159 369 4456 72 4448 80 4434 94 2652 1876 4363 165 4081 447 4450 78
(96.9) (3.1) (91.9) (8.1) (98.4) (1.6) (98.2) (1.8) (97.9) (2.1) (58.6) (41.4) (96.4) (3.6) (90.1) (9.9) (98.3) (1.7)
No. (%) – 0.07 (0.20 – 0.01 (0.09 – 0.00 (0.18 – 0.10 (0.27 – 0.10 (0.07 – 0.01 (0.06 – 0.06 (0.18 – 0.13 (0.21 – 0.07 (0.12 to 0.26)
to 0.05)
to 0.06)
to 0.04)
to 0.26)
to 0.07)
to 0.19)
to 0.07)
to 0.06)
Adjusted difference (95% CI)
0.455
0.001
0.341
0.689
0.250
0.237
0.955
0.766
0.286
P value 445 22 414 53 457 10 454 13 460 7 276 191 450 17 419 48 460 7
(10.1) (15.5) (10.0) (14.4) (10.3) (13.9) (10.2) (16.3) (10.4) (7.5) (10.4) (10.2) (10.3) (10.3) (10.3) (10.7) (10.3) (9.0)
No. (%) failures
0.96 (0.45–2.08)
1.00 (0.73–1.36)
0.83 (0.51–1.36)
1.07 (0.89–1.30)
0.58 (0.27–1.23)
1.75 (1.00–3.05)
1.45 (0.78–2.73)
1.55 (1.16–2.08)
1.78 (1.15–2.73)
HR (95% CI)
0.927
0.977
0.464
0.460
0.156
0.049
0.244
0.003
0.009
P value
376 21 352 45 388 9 386 11 391 6 228 169 382 15 360 37 394 3
(8.6) (14.9) (8.5) (12.2) (8.7) (12.5) (8.7) (13.8) (8.8) (6.4) (8.6) (9.0) (8.8) (9.2) (8.8) (8.3) (8.9) (3.7)
No. (%) failures
0.42 (0.13–1.32)
0.92 (0.64–1.32)
0.87 (0.51–1.47)
1.13 (0.92–1.39)
0.64 (0.29–1.45)
1.76 (0.96–3.23)
1.64 (0.84–3.18)
1.52 (1.10–2.09)
2.10 (1.33–3.30)
HR (95% CI)
On NNRTI analysis
0.138
0.636
0.604
0.244
0.287
0.067
0.148
0.012
0.001
P value
CI, confidence interval; HR, hazard ratio; NNRTI, nonnucleoside reverse transcriptase inhibitor. a Polymorphic codons observed in at least 10 patients were included. Results of the intention-to-treat (ITT) and on-treatment analyses are shown. b A negative value indicates that individuals with a specific polymorphism did not have as large a decrease in viral load ((in log10 copies/ml) as those with a wild-type amino acid at that codon.
238
179
138
135
106
103
101
98
AA
Codon
ITT analysis
Time to virology failure
AIDS
Reduction in viral load at week 4b
Table 2. Multivariate analysis of early (week 4) virologic response and time to virologic failure by codona.
2248 2013, Vol 27 No 14
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2249
CI, confidence interval; HR, hazard ratio; NNRTI, nonnucleoside reverse transcriptase inhibitor. a Results of the intention-to-treat (ITT) and on-treatment analyses are shown. b A negative value indicates that individuals with polymorphisms did not have as large a decrease in viral load (in log10 copies/ml) as those without polymorphisms. c Most patients (n ¼ 597) showed two polymorphisms.
– 0.220 0.016 – 1.15 (0.92–1.44) 1.43 (1.07–1.92) 155 (8.0) 171 (8.9) 71 (10.6) – 0.164 0.022 – 1.16 (0.94–1.42) 1.37 (1.05–1.79) 185 (9.6) 200 (10.4) 82 (12.3) – 0.105 0.080 – 0.04 (0.09 to 0.01) 0.06 (0.13 to 0.01) 1930 (42.6) 1929 (42.6) 669 (14.8)
P value HR (95% CI)
ITT analysis
No. (%) failures P value Adjusted difference (95% CI) No. (%) No. polymorphisms
0 1 2c
HR (95% CI) No. (%) failures
On NNRTI analysis Time to virologic failure Reduction in viral load at week 4b
Early virologic response Week 4 viral load responses after starting EFV-based or NVP-based first-line ARTare shown in Table 2, in which a negative value indicates that individuals with a specific polymorphism did not have as large a decrease in viral load as those with a wild-type amino acid at that codon, and in Table 3, in which a negative value indicates that individuals with polymorphisms did not have as large a decrease in viral load as those without polymorphisms. The individual polymorphisms occurring at the nine codons listed in Table 2 were analyzed for their impact on week 4 viral load decrease. By week 4 of ART, interval regression estimated the overall average viral load decrease to be 2.40 (95% CI 2.37–2.42) log10 copies/ml. A statistically significant (P
AIDS 2013, 27:2245–2253 Keywords: HIV, nonnucleoside reverse transcriptase inhibitor, polymorphism, reverse transcriptase
a Department of HIV/GUM, Imperial College Healthcare NHS Trust, bMRC Clinical Trials Unit, London, cDepartment of Clinical Virology, Manchester Royal Infirmary, Manchester, dResearch Department of Infection and Population Health, UCL Medical School, London, and eInstitute of Infection & Global Health, University of Liverpool, Liverpool, UK. Correspondence to Dr Nicola E. Mackie, Clinical Trials Centre, Winston Churchill Wing, St Mary’s Hospital, London W2 1NY, UK. Tel: +44 776 969 4340; fax: +44 207 886 6645; e-mail: [email protected] Received: 15 February 2013; revised: 14 May 2013; accepted: 16 May 2013.
DOI:10.1097/QAD.0b013e3283636179
ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
2245
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2246
AIDS
2013, Vol 27 No 14
Introduction In antiretroviral therapy (ART)-naive HIV-1-infected patients, amino-acid variations from subtype B wild-type consensus sequence are seen to occur naturally in reverse transcriptase in the absence of selective drug pressure. The prevalence of such polymorphisms in ARTnaive individuals appears to be partly associated with the infecting HIV-1 subtype [1,2]. Several polymorphisms have been demonstrated within reverse transcriptase regions 90–108, 135–138, 179–190, and 225–348, which also harbor major mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) [3,4]. Some polymorphisms in these regions confer low-level phenotypic NNRTI resistance in vitro [4]; however, their impact upon virologic response to efavirenz (EFV) or nevirapine (NVP) in vivo remains unclear. Current treatment guidelines recommend the use of a NNRTI, typically EFV, in combination with two nucleos(t)ide analogue reverse transcriptase inhibitors (NRTIs) as one of the preferred options for first-line ART based on its demonstrated efficacy [5,6]. Patients typically undergo reverse transcriptase sequencing at diagnosis or prior to starting ART to detect transmitted drug resistance. In clinical practice, it is often uncertain whether the reporting of reverse transcriptase polymorphisms in a baseline genotypic resistance test should be taken as indication to avoid NNRTI-based therapy as an initial regimen due to concerns over suboptimal efficacy. Avoidance of the standard of care in this scenario carries implications for pill-burden, cost, tolerability, and potentially adherence. The aims of this study, therefore, were to determine the prevalence of polymorphisms with possible effects on EFV and NVP susceptibility in ARTnaive patients and assess the impact of such polymorphisms upon virologic responses to first-line NNRTIbased therapy.
Methods Study population Eligible individuals underwent baseline genotypic resistance testing while ART-naive and commenced a regimen containing EFVor NVP with at least two NRTIs between 1997 and 2010. Reverse transcriptase and protease sequences obtained prior to patients commencing ART were retrieved from the UK HIV Drug Resistance Database [7], which collects results of resistance testing performed in routine care, and linked to anonymized clinical information from the UK Collaborative HIV Cohort (UK CHIC) Study [8]. The first resistance test performed after HIV diagnosis was included as well as any additional resistance test done prior to commencing ART for each individual. The study only included individuals with week 4 (2 weeks) viral load measurements. Exclusion criteria included a pre-ART
viral load less than 50 copies/ml as a possible indicator of unrecorded treatment, and the detection of major NNRTI, NRTI, or protease inhibitor resistance mutations (as defined by the International AIDS Society (IAS)–USA 2011 list [9]) in any of the pre-ART resistance tests; major protease inhibitor mutations were taken into account as they could indicate the presence of major reverse transcriptase mutations at subdetectable levels. Polymorphisms were defined as any change from the Stanford HIV Drug Resistance Database consensus subtype B reference sequence, other than major recognized NNRTI resistance mutations, occurring at the following reverse transcriptase codons: 90, 98, 100, 101, 103, 106, 108, 135, 138, 179, 181, 188, 190, 225, 227, 230, 234, 236, 238, 318, and 348. Virologic failure was defined as follows [10]: two consecutive viral load measurements more than 200 copies/ml after previous suppression to less than 200 copies/ml; one viral load measurement more than 200 copies/ml after previous suppression to less than 200 copies/ml followed by a treatment change; or one viral load more than 200 copies/ml after 6 months of treatment without previous suppression. In a separate analysis, virologic failure was defined as two consecutive viral load measurements more than 50 copies/ml after at least 6 months of ART. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool version 2.0 [11].
Analysis The frequency of single and multiple-occurring NNRTI polymorphisms was established. Variables associated with the occurrence of any polymorphism were assessed in a logistic regression model. From the original list of screened codons, polymorphisms present in at least 10 patients were selected for further analysis. Overall virologic responses were compared between patients with wild-type sequences and those with sequences containing one or at least one polymorphism(s). The effect of each polymorphism was analyzed by comparing responses in patients with and without the polymorphism at each codon. The analyses were initially analyzed using an intent-to-treat (ITT) approach, in which any changes to the initial NNRTI-based regimen were ignored. A second, on-NNRTI treatment analysis was performed censoring patients at the date of their last viral load measurement prior to discontinuing either EFV or NVP. Early virologic responses were measured as a change in viral load from baseline to week 4 (2 weeks) and investigated using interval regression analyses to account for left-censoring due to the lower limit of quantification of viral load assays [12]. Time to virologic failure was examined using Kaplan–Meier plots and multivariable Cox regression analysis. All analyses were adjusted for baseline viral load and CD4þ cell count, HIV-1 subtype (categorized as B, C, and non-B/non-C), the specific NRTIs and NNRTI used, year of ART initiation, age at baseline resistance testing, risk group, and ethnicity. Eight percent of individuals had at least one prognostic
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Significance of NNRTI polymorphisms Mackie et al.
factor missing. Because missing values were likely to be missing at random, and to avoid a loss in efficiency, missing values for baseline CD4þ, possible exposure source, and ethnicity were imputed using multiple imputation by chained equations [13]. Ten imputed datasets were created by replacing missing values with simulated values from a set of imputation models constructed from potential prognostic factors and, when applicable, time to virologic failure outcome variables. Separate analyses of specific amino acid polymorphisms were conducted when significant codon level effects were detected. Formal adjustments to P values were not made for multiple statistical tests being performed; this is less important when results for all codons are presented [14]. All analyses were conducted in Stata/IC 12.1 software (StataCorp LP, College Station, Texas, USA).
Results Study population Between 1997 and 2010 [median September 2006; interquartile range (IQR) December 1999 to June 2009], a total of 5512 individuals commenced a first-line regimen with EFV or NVP in combination with at least two NRTIs following baseline (pre-ART) genotypic resistance testing; of these, 4528 were eligible for the study. The majority of these individuals (n ¼ 3592) had a
2247
single pre-ART genotypic resistance test performed and 936 of 4528 (21%) had more than one genotypic resistance test. Of the 984 patients who were excluded, 299 had major NNRTI/NRTI/protease inhibitor mutations at baseline, 79 had an undetectable viral load at treatment initiation, 561 had insufficient viral load data to perform further analyses, and 45 had resistance test results that only reported on major drug resistance mutations. Resistance tests were conducted a median (IQR) of 62 (24–321) days prior to commencing firstline ART. The characteristics of the study population are summarized in Table 1. Of the eligible patients, most were white (2819, 62%), men who have sex with men (2837, 63%), infected with HIV-1 subtype B (3010, 67%). Baseline viral load and CD4þ cell counts were 4.90 (IQR 4.36– 5.35) log10 copies/ml and 210 (IQR 130–280) cells/ml, respectively. Most patients (3793, 84%) commenced an EFV-based regimen with a variety of NRTI backbones reflective of routine clinical practice.
Prevalence and patterns of reverse transcriptase polymorphisms Overall, 2598 (57%) individuals had at least one polymorphism identified in their baseline reverse transcriptase sequence within the regions analyzed. Most patients (1929, 42.6%) had a single polymorphism; 669 (15%) had multiple polymorphisms, most commonly two (n ¼ 597).
Table 1. Demographic and clinical characteristics of the study population. Transmission group n (%)
Ethnicity n (%) HIV-1 subtype n (%)
Age (years) CD4þ cell count (cells/ml) Viral load (log10 copies/ml) Treatment
Total
Men who have sex with men Male heterosexual Female heterosexual Other Unknown White Black Other Unknown A B C D G CRF01 AE CRF02 AG Other Unknown Median (IQR) Median (IQR) Median (IQR) NVP þ TDF þ 3/FTC NVP þ ZDV þ 3/FTC NVP þ ABC þ 3/FTC NVP þ other NRTIs EFV þ TDF þ 3/FTC EFV þ ZDV þ 3/FTC EFV þ ABC þ 3/FTC EFV þ other NRTIs n
2837 509 640 243 299 2819 1170 407 132 172 3010 647 47 83 67 178 44 280 36.4 210 4.90 205 276 133 121 2143 598 692 360 4528
(62.7) (11.2) (14.1) (5.4) (6.6) (62.2) (25.8) (9.0) (2.9) (3.7) (66.5) (14.3) (1.0) (1.8) (1.5) (3.9) (1.0) (6.2) 31.2–42.4 130–280 4.36–5.35 (4.5) (6.1) (2.9) (2.7) (47.3) (13.2) (15.3) (8.0)
3/FTC, lamivudine or emtricitabine; ABC, abacavir; EFV, efavirenz; IQR, interquartile range; NRTIs, nucleos(t)ide reverse transcriptase inhibitors; NVP, nevirapine; TDF, tenofovir; ZDV, zidovudine.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
V I A S,G K R,Q,N K R, Q, S, E V I I T, V, R, M, L, K, A, C E A, G, K, D V I, D, E, T, A, S, C K R, Q, N
90
4386 142 4159 369 4456 72 4448 80 4434 94 2652 1876 4363 165 4081 447 4450 78
(96.9) (3.1) (91.9) (8.1) (98.4) (1.6) (98.2) (1.8) (97.9) (2.1) (58.6) (41.4) (96.4) (3.6) (90.1) (9.9) (98.3) (1.7)
No. (%) – 0.07 (0.20 – 0.01 (0.09 – 0.00 (0.18 – 0.10 (0.27 – 0.10 (0.07 – 0.01 (0.06 – 0.06 (0.18 – 0.13 (0.21 – 0.07 (0.12 to 0.26)
to 0.05)
to 0.06)
to 0.04)
to 0.26)
to 0.07)
to 0.19)
to 0.07)
to 0.06)
Adjusted difference (95% CI)
0.455
0.001
0.341
0.689
0.250
0.237
0.955
0.766
0.286
P value 445 22 414 53 457 10 454 13 460 7 276 191 450 17 419 48 460 7
(10.1) (15.5) (10.0) (14.4) (10.3) (13.9) (10.2) (16.3) (10.4) (7.5) (10.4) (10.2) (10.3) (10.3) (10.3) (10.7) (10.3) (9.0)
No. (%) failures
0.96 (0.45–2.08)
1.00 (0.73–1.36)
0.83 (0.51–1.36)
1.07 (0.89–1.30)
0.58 (0.27–1.23)
1.75 (1.00–3.05)
1.45 (0.78–2.73)
1.55 (1.16–2.08)
1.78 (1.15–2.73)
HR (95% CI)
0.927
0.977
0.464
0.460
0.156
0.049
0.244
0.003
0.009
P value
376 21 352 45 388 9 386 11 391 6 228 169 382 15 360 37 394 3
(8.6) (14.9) (8.5) (12.2) (8.7) (12.5) (8.7) (13.8) (8.8) (6.4) (8.6) (9.0) (8.8) (9.2) (8.8) (8.3) (8.9) (3.7)
No. (%) failures
0.42 (0.13–1.32)
0.92 (0.64–1.32)
0.87 (0.51–1.47)
1.13 (0.92–1.39)
0.64 (0.29–1.45)
1.76 (0.96–3.23)
1.64 (0.84–3.18)
1.52 (1.10–2.09)
2.10 (1.33–3.30)
HR (95% CI)
On NNRTI analysis
0.138
0.636
0.604
0.244
0.287
0.067
0.148
0.012
0.001
P value
CI, confidence interval; HR, hazard ratio; NNRTI, nonnucleoside reverse transcriptase inhibitor. a Polymorphic codons observed in at least 10 patients were included. Results of the intention-to-treat (ITT) and on-treatment analyses are shown. b A negative value indicates that individuals with a specific polymorphism did not have as large a decrease in viral load ((in log10 copies/ml) as those with a wild-type amino acid at that codon.
238
179
138
135
106
103
101
98
AA
Codon
ITT analysis
Time to virology failure
AIDS
Reduction in viral load at week 4b
Table 2. Multivariate analysis of early (week 4) virologic response and time to virologic failure by codona.
2248 2013, Vol 27 No 14
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2249
CI, confidence interval; HR, hazard ratio; NNRTI, nonnucleoside reverse transcriptase inhibitor. a Results of the intention-to-treat (ITT) and on-treatment analyses are shown. b A negative value indicates that individuals with polymorphisms did not have as large a decrease in viral load (in log10 copies/ml) as those without polymorphisms. c Most patients (n ¼ 597) showed two polymorphisms.
– 0.220 0.016 – 1.15 (0.92–1.44) 1.43 (1.07–1.92) 155 (8.0) 171 (8.9) 71 (10.6) – 0.164 0.022 – 1.16 (0.94–1.42) 1.37 (1.05–1.79) 185 (9.6) 200 (10.4) 82 (12.3) – 0.105 0.080 – 0.04 (0.09 to 0.01) 0.06 (0.13 to 0.01) 1930 (42.6) 1929 (42.6) 669 (14.8)
P value HR (95% CI)
ITT analysis
No. (%) failures P value Adjusted difference (95% CI) No. (%) No. polymorphisms
0 1 2c
HR (95% CI) No. (%) failures
On NNRTI analysis Time to virologic failure Reduction in viral load at week 4b
Early virologic response Week 4 viral load responses after starting EFV-based or NVP-based first-line ARTare shown in Table 2, in which a negative value indicates that individuals with a specific polymorphism did not have as large a decrease in viral load as those with a wild-type amino acid at that codon, and in Table 3, in which a negative value indicates that individuals with polymorphisms did not have as large a decrease in viral load as those without polymorphisms. The individual polymorphisms occurring at the nine codons listed in Table 2 were analyzed for their impact on week 4 viral load decrease. By week 4 of ART, interval regression estimated the overall average viral load decrease to be 2.40 (95% CI 2.37–2.42) log10 copies/ml. A statistically significant (P
