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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Geretti AM, editor. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006.

Chapter 1 Resistance to nucleoside reverse transcriptase inhibitors

Authors

Anne-Geneviève Marcelin.

Introduction
Resistance and cross-resistance to nucleoside reverse transcriptase inhibitors (NRTIs) is becoming better understood.
This is a complex phenomenon, which involves mutations that occur under the selective pressure of drugs and
interactions between mutations. Resistance studies have highlighted distinct evolution patterns of mutations and cross-
resistance among the NRTIs, which have the ability to impact on the choice of subsequent salvage treatment. A good
knowledge of NRTI-resistance pathways is a key aspect of HIV-1-treatment strategies as it allows anticipation of the
evolution of the virus.

Mechanisms of NRTI resistance

One mechanism for resistance to NRTIs is discrimination, whereby the reverse transcriptase (RT) enzyme is able to
avoid binding of the NRTI, while retaining the ability to recognise the analogous natural deoxynucleoside triphosphate
(dNTP) substrate. Examples include virus with the point mutations K65R, L74V, Q151M and M184V, which cause
diminished affinity of RT for specific NRTIs with little or no change in affinity for the corresponding dNTP substrate.
The consequence is a diminished incorporation of drugs into the DNA chain.

The other mechanism is the enhanced phosphorolytic removal of the chain-terminating NRTI from the 3′-terminus of
the primer after it has been incorporated into the viral DNA. NRTI-associated mutations may affect the phosphorolytic
activity of RT, in some cases overcoming chain termination in a mechanism called `primer unblocking'. Mutations that
enhance primer unblocking activity include those selected by zidovudine (ZDV) and stavudine (d4T), and are known as
thymidine analogue mutations (TAMs): M41L, D67N, K70R, L210W, T215Y/F and K219Q/E. TAMs are involved in
resistance to all NRTIs, except lamivudine (3TC), but the degree of cross-resistance depends on the NRTI considered
and the number of TAMs on the virus. Some interactions exist between the different mechanisms of resistance. The
M184V/I mutations, selected by 3TC and emtricitabine (FTC), delay the appearance of TAMs and increase the in vitro
susceptibility to ZDV and d4T.

NRTI-associated resistance mutations

Multiresistance-associated mutations
Q151M results from changes in a conserved domain of RT, often reported following therapy with didanosine (ddI) in
combination with ZDV or d4T [1]. In a resistance substudy of the ALBI trial (d4T/ddI versus ZDV/3TC) in 21 patients
in the d4T/ddI arm, Q151M was selected in three of the 21 (14%) patients [2]. This mutation alone has been shown to
confer intermediate resistance (4- to 10-fold increase relative to wild-type) to ZDV, ddI, d4T and abacavir (ABC).
When Q151M is accompanied by mutations at codons 62, 75, 77 and 116, the resulting Q151M complex confers high-
level resistance (>10-fold increase) to the aforementioned NRTIs (ZDV, ddI, d4T and ABC), as well as to 3TC. In
addition, the Q151M complex is associated with decreased susceptibility to tenofovir (TDF) (2- to 5-fold decrease).

Insertions at position 69 are observed in a small proportion of heavily NRTI treatment-experienced patients and have
been linked to combination therapy that includes a thymidine analogue [3]. In combination with TAMs, T69 insertions
confer high-level resistance to ZDV, d4T, ddI, ABC and TDF.

Mutations selected by NRTI monotherapies

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ZDV and d4T

Monotherapy with ZDV or d4T selects TAMs [4]. Loss of ZDV susceptibility occurs incrementally with an ordered
sequence of mutations. A mutation at codon 70 (K70R) is key to ZDV failure, and is followed by T215Y/F, D67N,
M41L and K219Q/E. Prolonged ZDV monotherapy has been shown to result in the accumulation of a large number of
TAMs. These mutations confer cross-resistance to ZDV and d4T, as well as to most NRTIs to varying degrees.

Two distinct pathways of TAMs exist: (1) the first includes M41L, L210W and T215Y; (2) the second includes D67N,
K70R, T215F and K219Q/E [5,6] (Table 1). The second pathway is twice as frequent as the first and is associated with
a high level of resistance to ZDV and most other NRTIs, including ABC and TDF. The second pathway has been
associated with lower levels of resistance to TDF and other NRTIs. Nonetheless, this distinction should not be
considered absolute because several mutations from one group can coexist with those from the other. Indeed, these
pathways may in some cases overlap, especially for viruses with five or six TAMs. However, clinical studies are
warranted to characterise fully the resistance effects of different TAM pathways. Further studies are also required to
define the determinants of these pathways.

Mutation V75T can be also selected by d4T, but this mutation is rarely seen in clinical practice.

ddI

In monotherapy, ddI predominantly selects for the L74V mutation (56% of all ddI-treated patients at 24 weeks) and
more rarely the K65R mutation [7]. In vivo, the presence of isolated L74V mutation only has a real impact on
sensitivity to ddI; however, L74V confers cross-resistance to ABC and TDF when associated with other mutations such
as TAMs [8]. In vitro, it is associated with an increase in susceptibility to ZDV.

3TC and FTC

The M184V/I mutations emerge rapidly in virtually all patients receiving non-suppressive therapy with 3TC or FTC
[9]. The M184V mutation alone confers high-level resistance to 3TC and FTC (>100-fold increase). The mutation also
confers low-level resistance to ABC in vitro, but this does not appear to be clinically significant unless other mutations
(e.g. TAMs, K65R or L74V) are present. The impact of M184V on ddI susceptibility is somewhat conflicting, in vitro
data showing a reduced phenotypic susceptibility and in vivo genotypic data showing no impact or even a greater
virological response to ddI in the presence of M184V. M184V acts antagonistically with ZDV-induced mutations to
partially restore susceptibility to ZDV, and can delay the emergence of TAMs. M184V-related changes in RT increase
fidelity and diminish processivity, thus leading to reduced viral fitness. Previous clinical data indicated that patients on
3TC monotherapy with M184V maintained their plasma HIV-1 RNA load at approximately 0.5 log10 copies/ml lower
than pre-treatment levels [10]. A recent, prospective, randomized study of 50 drug-experienced patients with moderate
virological failure (>1000 copies/ml and CD4 count >500 cells/μl) compared 3TC monotherapy with treatment
interruption over 48 weeks. Compared with patients who discontinued therapy completely, patients receiving 3TC
monotherapy showed relative control of viral load and reduced rate of loss of CD4 cells [11]. These results suggest
some residual anti-HIV-1 activity of the drug, despite high-level phenotypic resistance. Coupled with data showing the
reduced fitness of M184V mutants, this provides an argument for maintaining 3TC in a failing regimen.

ABC

In treatment-naive patients, 12 weeks of ABC monotherapy leads to the selection in 49% (21/43) of cases of one to
three of the following mutations: K65R, L74V, Y115F and M184V [12]. The resistance profile most frequently
observed (11/21 patients) was L74V and M184V. Despite the small sample size, results from Virologic's database [13]
on the resistance effects of the combination of L74V plus M184V show increased susceptibility to ZDV and d4T and
resistance to most other NRTIs, but a preservation of susceptibility to TDF. These results are conflicting with clinically
based genotypic interpretation showing that this resistance profile is associated with a real impact on 3TC and ddI, and
a moderate impact on ABC and TDF susceptibility [8].

TDF
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In vitro, TDF consistently selects the K65R mutation, which reduces susceptibility to TDF by 3-to 4-fold. This
mutation also reduces susceptibility in vitro to ddI, 3TC and ABC, but not to ZDV [14]. Preliminary clinical data show
a great reduction of viral load when ZDV is added to the regimen in patients with K65R-containing viruses. The effect
of K65R on d4T has not been fully characterised as the data show conflicting results. Due to a strong antagonist
interaction between K65R and TAMs, the coexistence of K65R and TAMs is rare, the strongest antagonism being
observed between K65R and T215Y. Thus, for NRTI-experienced patients with viruses harbouring TAMs, there is a
very low risk of K65R selection associated with the use of TDF, if TAMs, especially the T215Y, are present on the
genotype and maintained by selective pressure of drugs such as thymidine analogues. The antagonism is due to K65R-
mediated reduction of the excision process induced by TAMs.

Mutations selected by dual-NRTI therapies

Resistance pathways of combination regimens highlight the importance of interactions between mutations. Mutations
selected by antiretroviral agents used alone do not necessarily predict those that will arise when multiple NRTIs are
combined. For example, like K65R, M184V acts antagonistically with TAMs by diminishing ATP- or pyrophosphate-
mediated primer unblocking. The mutational patterns selected by dual NRTI therapies are shown in Table 2.

ZDV or d4T plus 3TC or FTC

The use of 3TC and presumably FTC in combination with thymidine analogues, such as ZDV or d4T, delays the
appearance of TAMs in treatment-naive patients. With 3TC, the rate of TAM selection is similar with ZDV or d4T (0–
5% at failure) [15]. The systematic use of 3TC or FTC with thymidine analogues has the advantage of a low rate of
resistance mutations at failure and may therefore preserve future options, if long-term viral replication under this
regimen is avoided.

The E44D and V118I mutations have been shown to appear predominantly in genotypes with multiple TAMs and may
contribute broad class resistance in the setting of multiple NRTI mutations.

ZDV/ddI and d4T/ddI

When thymidine analogues are used in combination with ddI, a high rate of TAMs is observed at failure. Unlike ddI
monotherapy, ZDV/ddI in combination does not select L74V, as shown in the AIDS Clinical Trial Group (ACTG) 143
study of combined ZDV/ddI versus the sequential use of ZDV followed by ddI [16]. This in vivo observation, together
with in vitro studies [17], suggests an antagonism between L74V and TAMs. In the ACTG 143 trial, 8.5% of patients
developed the Q151M mutation, which is not observed with the use of ZDV or ddI in monotherapy. In the ALBI trial
(42 drug-naive patients treated with d4T/ddI versus ZDV/3TC), 62% of patients developed T215Y/F in the d4T/ddI
arm versus only 9.5% in the ZDV/3TC arm [2]. Moreover, 14% of patients developed Q151M in the d4T/ddI arm
versus none in the ZDV/3TC arm.

These data indicate that the combination of a thymidine analogue with ddI does not show a favourable resistance
profile because it carries a high risk of cross-resistance in the case of virological failure.

ABC/3TC

The ZODIAC (Ziagen Once Daily In Antiretroviral Therapy) study (CNA 30021) evaluated drug-naive patients
randomly allocated to receive ABC once daily or twice daily in combination with 3TC/efavirenz (EFV) over 48 weeks.
Resistance testing at failure (analysis restricted to the patients with no mutation at baseline) showed one case of L74V
in the once-daily arm (13 genotypes) and two cases of L74V and one case of Y115F in the twice-daily arm (18
genotypes) [18]. No K65R mutations were detected and M184V/I were selected in seven out of 13 and six of 18 cases,
in the once-daily and twice-daily arms, respectively. The CNA 30024 study, which evaluated ABC/3TC/EFV versus
ZDV/3TC/EFV in drug-naive patients, showed similar results in the ABC arm. Among the 13 genotypes analysed at
failure, most viruses were wild-type (n=8), whereas five showed EFV resistance either alone (n=1), with M184V (n=3),
or with L74V plus M184V (n=1).

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These data indicate that combination of ABC/3TC, in case of virological failure, may offer the advantage of preserving
future options because, in the case of M184V mutation alone, susceptibility to most NRTIs is conserved and, in the
case of L74V mutation alone or in combination with M184V, there is a large impact only on ddI susceptibility and a
moderate impact on susceptibility to ABC and TDF.

The lowest rate of mutation selection was observed when ABC/3TC was used with a boosted protease inhibitor
regimen [GSK SOLO study of ABC/3TC in combination with fosamprenavir/ritonavir (FPV/r) or nelfinavir (NFV)]:
among the 32 genotypes analysed in the boosted fosAPV arm, four M184V and no K65R or L74V mutations were
observed in contrast to 30 M184V, two K65R and one L74V in the 54 genotypes of the NFV arm.

TDF/3TC and TDF/FTC

The Gilead Sciences (GS) 903 study was conducted in treatment-naive patients treated with TDF or d4T in
combination with 3TC/EFV. At 48 weeks, 36/299 patients met the definition of treatment failure in the TDF arm [19].
Genotypes showed wild-type viruses (11/36), EFV-related mutations (8/36), EFV-related mutations, M184V and K65R
(5/36), EFV-related mutations plus M184V (6/36), M184V alone (3/36) and EFV-related mutations plus K65R (3/36).
The M184V/K65R profile is associated with a reduced susceptibility to TDF and most other NRTIs, except ZDV and
d4T. However, the effect of K65R on d4T susceptibility has not been fully characterised as the data show conflicting
results. Lower occurrence of K65R was observed in the GS 934 study [TDF/FTC/EFV versus Combivir (ZDV/3TC;
CBV)/EFV]: at week 48 in the TDF/FTC/EFV arm, 12/244 patients had a viral load of > 400 copies/ml
(discontinuation or virological failure) and no K65R was observed among the two patients with virological failure. Due
to the low number of patients with virological failure analysed, it is not possible to make conclusions about the
prevalence of mutation selection with this combination. However, similar results have been found in the Abbott 418
study [TDF/FTC in combination with lopinovir/ritonovir (LPV/r) once daily or twice daily]: among the 22 patients
with detectable viral load at week 48, the 15 genotypes analysed showed no K65R.

Mutations selected by triple-NRTI therapies

ABC/3TC/ZDV

ABC/3TC/ZDV was compared with 3TC/ZDV/EFV and ABC/3TC/ZDV/EFV in a randomised, double-blind study
(ACTG 5095) [20]. Of 382 patients on ABC/3TC/ZDV, 80 (21%) were considered to show virological failure versus
84 of 765 patients (11%) in the other arms combined. Most patients with failure on this treatment had either wild-type
virus (22%) or the M184V mutation alone (34%). Approximately 11% had M184V plus other NRTI mutations, and 2%
had NRTI mutations other than M184V. Thus, this combination has the advantage of a low rate of resistance mutations
at failure and the potential preservation of future options, if one avoids viral replication under treatment.

ABC/3TC/TDF

High rates of virological failures (approximately 50%) have been observed with the use of this particular triple-NRTI
therapy. In a pilot study on 19 patients, five of the 11 failing therapy had the M184V mutation, four had both M184V
and K65R, and the remaining two had wild-type virus [21]. In the larger ESS30009 study (a randomised trial
comparing ABC/3TC/TDF with ABC/3TC/EFV in antiretroviral-naive patients), 23 of the 36 failing patients (64%) at
week 12 had both M184V and K65R, and 13 (36%) had M184V alone [22]. Similar data were found in the TONUS
study (open-label pilot study evaluating a once-daily regimen of ABC/3TC/TDF in 38 antiretroviral-naive patients) in
which the presence of K65R was detected even earlier (at week 4) using a clone-sensitive genotyping method (Table 3)
[23]. The reason for the failure of this regimen is not known, but one proposed explanation is the low genetic barrier to
resistance, associated with the ability of K65R to simultaneously cause resistance to all drugs in the regimen.

Other NRTI combinations

A pilot study of 24 treatment-naive patients treated with 3TC/ddI/TDF once daily was stopped early because of a high
rate of virological failure (91%) after 12 weeks of treatment [24]. Of the 20 genotypes measured, all harboured M184V

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and half of them harboured the K65R mutation.

Very few data are available concerning CBV/TDF. However, this combination has potential interest regarding the
antagonism between K65R and TAMs. A multicentre study (COL40263) evaluated TZV/TDF once daily during 48
weeks in 123 drug-naive patients [25]. After 24 weeks, eight patients showed virological failure. Genotype
measurements showed two patients with wild-type virus and six with at least one TAM with or without M184V. This
high number of TAMs was probably due to the use of ZDV in a once-daily regimen. Thus, this combination is not
recommended. However, if ZDV is given twice daily in combination with TDF once daily as an NRTI backbone, the
antagonistic mechanism of resistance could be of interest regarding the resistance profile in cases of failure, preventing
the emergence of the K65R mutation. This particular NRTI combination should be further explored.

Other NRTI mutations

Mutations at 19 RT residues have been implicated in NRTI resistance, according to the International AIDS Society
(IAS)-USA panel [26]. However, several reports have suggested the potential role of novel RT mutations in NRTI
resistance, beyond those currently known to confer resistance. There is some evidence that resistance does not simply
result from the accumulation of any RT mutations but rather from specific combinations of mutations, suggesting
intricate patterns of mutational clusters. As other mutations, beyond those currently known, may regulate RT
mutational patterns, NRTI resistance appears to be far more complex than currently thought. Some of these mutations
may be neutral polymorphisms; others may contribute to drug resistance or viral fitness. Multiple RT mutations
(positions 20, 39, 43, 203, 208, 218, 221, 223 and 228) have been reported to be associated with NRTI therapy [27].
Moreover, the combination of additional mutations (H208Y, R211K and L214F) in HIV-1 RT may influence
phenotypic susceptibility to ZDV [28]. In the same way, it has been shown that the Q207D and H208Y mutations
contribute to increase ZDV resistance in a viral genetic background containing multiple TAMs [29]. Thus, mutations at
codons G196, Q207, H208, R211 and L214 have been associated with NRTI exposure, but have uncertain clinical
significance. Consequently, studies should evaluate the effect of these other mutations on virological response to drugs
in order to determine whether these mutations should be taken into account to define algorithms able to predict
correctly resistance to NRTIs.

Conclusion
In case of treatment failure, especially in early regimens, clinicians should intervene quickly with a strategy to prevent
viral evolution and the accumulation of resistance mutations. Further studies are needed to elucidate the mutational
pathways associated with various NRTI-containing regimens to determine differences in resistance patterns, and the
implications of these differences for future options and sequencing therapy.

Recommendations for clinical practice

Ongoing viral replication on NRTI-based regimens leads to the progressive accumulation of mutations with
growing cross-resistance and should therefore be avoided.

Systematic use of 3TC or FTC in combination with thymidine analogues should be recommended.

The 215Y TAM pathway is more common and confers higher-level resistance to NRTIs, including ZDV, than
other pathways.

3TC retains partial activity despite the presence of resistance and should be maintained in a failing regimen.

TAMs and the K65R mutation have opposite effects on ZDV susceptibility.

Only ZDV retains activity in the presence of the K65R mutation.

For NRTI-experienced patients with viruses harbouring TAMs, there is a very low risk of K65R selection
associated with the use of TDF, if TAMs, and in particular T215Y, are already present.

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Tables

Table 1 Mutational patterns selected by NRTI monotherapies

NRTI Mutations most frequently selected References

ZDV, d4T TAMs [4–6]
pathway 1: M41L, L210W, T215Y (2/3 of cases)
pathway 2: D67N, K70R, T215F, K219Q/E (1/3 of cases
ddI L74V [7]
3TC, FTC M184V [9]
ABC L74V and M184V [12]
TDF K65R [14]

ABC, abacavir; ddI, didanosine; d4T, stavudine; FTC, emtricitabine; NRTI, nucleoside reverse transcriptase inhibitor; TAMs, thymidine
analogue mutations; TDF, tenofovir; 3TC, lamivudine; ZDV, zidovudine.

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Table 2 Mutational patterns selected by dual-NRTI therapies

NRTI Mutations most frequently selected Study Reference

ZDV or d4T + 3TC or FTC M184V (80%), TAMs (0–5%) ACTG 343 [15]
ZDV/ddI TAMs (80%), Q151M (8.5%) ACTG 143 [16]
d4T/ddI TAMs (62%), Q151M (14%) ALBI [2]
ABC/3TC M184V (7–11% ; +/− L74V) CNA 30021/30024 [18]
TDF/3TC M184V (22% ; +/− K65R) GS 903 [19]

ABC, abacavir; ddI, didanosine; d4T, stavudine; FTC, emtricitabine; NRTI, nucleoside reverse transcriptase inhibitor; 3TC, lamivudine;
TAMs, thymidine analogue mutations; TDF, tenofovir; ZDV, zidovudine.

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Table 3 Mutational patterns selected by triple-NRTI therapies

Regimen Failure with K65R Failure with TAMs Study Reference

Without ZDV
ABC/3TC/TDF 10/21 (48%) 0% ESS30009 [22]
ABC/3TC/TDF 11/12 (92%) NR TONUS [23]
ddI/3TC/TDF 10/20 (50%) NR Jemsek et al. [24]
With ZDV
TZV BID 0/82 (0%) 10/82 (12%) ACTG 5095 [20]
TZV OD/TDF 1/8 (13%) 5/8 (63%) COL40263 [25]

ABC, abacavir; BID, twice daily; ddI, didanosine; NRTI, nucleoside reverse transcriptase inhibitor; NR, not reported; OD, once daily;
TAMs, thymidine analogue mutations; TDF, tenofovir; 3TC, lamivudine; ZDV, zidovudine; TZV, Trizivir (zidovudine/lamivudine/abacavir).

Copyright © 2006, Mediscript.

Bookshelf ID: NBK2241 PMID: 21249766

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