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HIV-1 AMINO ACID SUBSTITUTIONS ASSOCIATED WITH ANTIRETROVIRAL DRUG RESISTANCE AND MORE
FREQUENTLY FOUND in vivo.1
Drugs
Mutations
Nucleoside analogue RT inhibitors
Zidovudine (AZT, Retrovir)
M41L, D67N, K70R, V118I, L210W, T215F/Y, K219E/Q
Zalcitabine (ddC, Hivid)
K65R, T69D, L74V, M184V
Didanosine (ddI, Videx)
K65R, L74V, M184V
Lamivudine (3TC, Epivir)
(E44D, V118I) 2, (K65R, Q151M) 3, M184I/V
Stavudine (d4T, Zerit) 4
M41L, D67N, K70R, V118I, L210W, T215F/Y, K219E/Q
Abacavir (1592U89, Ziagen)
K65R, L74V, Y115F, M184V, (M41L, D67N, K70R, L210W, T215F/Y, K219E/Q)
Emtricitabine (FTC, Emtriva)
(K65R, Q151M) 3, M184V
Tenofovir (Viread)
K65R
5
Combinations of mutations that confer resistance to various nucleoside analogues
M41L, D67N, K70R, L210W, T215F/Y, K219E/Q 5
A62V, V75I, F77L, F116Y, Q151M
An insertion between codons 69-70 (i.e. T69SSS or T69SSG or T69SSA), M41L, A62V, K70R, L210W,
T215F/Y
Nonnucleoside RT inhibitors
Nevirapine (Viramune)
L100I, K101P, K103N/S, V106A/M, V108I, Y181C/I, Y188C/L/H, G190A/C/E/Q/S/T
Delavirdine (Rescriptor)
K103H/N/T, V106M, Y181C, Y188L, G190E, P236L
Efavirenz (Sustiva)
L100I, K101P, K103H/N, V106M, V108I, Y188L, G190A/S/T, P225H, M230L
Etravirine (Intelence)
V90I, A98G, L100I, K101E/H/P/Q, V106I, E138A/G/K/Q/R/S, V179D/F/I/L, Y181C/I/V, G190A/S,
F227C, M230L, T386A, E399D
Rilpivirine (Edurant) 7
V90I, K101E/P, E138A/G/K/Q/R, V179F/I/L, Y181C/I/V, M184I/V, Y188L, V189I, H221Y, F227C,
M230I/L
Combinations of mutations that confer resistance to nevirapine, delavirdine and efavirenz
K103N alone
V106M alone
Y188L alone
2 or more of L100I, V106A, Y181C/I, G190A/S, M230L and Y318F
Protease inhibitors 8
Saquinavir (Invirase, Fortovase) L10I/R/V, G48V, I54L/V, A71T/V, G73S, V77I, V82A, I84V, L90M, and A431V [in p7(NC)/p1)]
Ritonavir (Norvir)
L10I/R/V, K20M/R, V32I, L33F, M36I, M46I/L, I54L/V, A71T/V, V77I, V82A/F/S/T, I84V, L90M,
and A431V [in p7(NC)/p1)]
Indinavir (Crixivan)
L10I/R/V, K20M/R, L24I, V32I, M36I, M46I/L, I54V, A71T/V, G73A/S, V77I, V82A/F/S/T, I84V,
L90M, and Gag cleavage sites: A431V [in p7(NC)/p1)] and L449F [in p1/p6]
Nelfinavir (Viracept)
L10F/I, D30N, M36I, M46I/L, A71T/V, V77I, V82A/F/S/T, I84V, N88D/S, L90M, and Gag cleavage
sites L449F and P453L [in p1/p6]
Amprenavir (Agenerase)
L10F/I/R/V, V32I, M46I/L, I47V, I50V, I54V/M, I84V, L90M, and Gag cleavage sites L449F and
P453L [in p1/p6]
Lopinavir/r (Kaletra) 9
L10F/I/R/V, G16E, K20I/M/R, L24I, V32I, L33F, E34Q, K43T, M36I/L, M46I/L, I47A/V, G48M/V,
I50V, I54L/V/A/M/S/T, Q58E, I62V, L63T, A71T, G73T, T74S, L76V, V82A/F/S/T, I84V, L89I/M,
L90M and A431V [in p7(NC)/p1)]
Atazanavir (Reyataz) 10
L10F/I/V, K20I/M/R, L24I, L33F/I/V, M36I/L/V, M46I/L, G48V, I50L, I54L/V, L63P, A71I/T/V,
G73A/C/S/T, V82A/F/S/T, I84V, N88S, L90M
Tipranavir (Aptivus) 11
L10I/S/V, I13V, K20M/R, L33F/I/V, E35G, M36I/L/V, K43T, M46L, I47V, I54A/M/V, Q58E, H69K,
T74P, V82L/T, N83D, I84V, L89I/M/V, L90M
Darunavir (Prezista)
V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, V82F, I84V, L89V, and Gag cleavage sites A431V
[in p7(NC)/p1)] and S451T and R452S [in p1/p6]
Combinations that confer resistance to multiple protease inhibitors
L10F/I/R/V, M46I/L, I54L/M/V, V82A/F/T/S, I84V, L90M 12
Fusion inhibitors
Enfuvirtide (Fuzeon)
G36D/E/S, I37T/N/V, V38A/E/M, Q40H, N42T, N43D/K/S (all in gp41)
Raltegravir (Isentress)
G140S, Y143C/R, Q148H/K/R, N155H
Elvitegravir
T66A/I/K, L74M, E92Q/V, Q148H/K/R, V151L, N155H
Dolutegravir
F121Y, E138A/K, G140A/S, Q148H, R263K
Integrase inhibitors
Entry inhibitors (CCR5 antagonists)
Maraviroc (Selzentry, Celsentri) Resistance usually develops through the selection of viruses that use the CXCR4 (X4) coreceptor. In
addition, maraviroc resistance mutations appear mainly in the V3 loop of gp120 (see Chapters 6 and 12
for details and discussion).
1
Additional information in in Wensing et al. Top Antivir Med 2015; 23: 132-141; http://www.iasusa.org.
Conflicting data exist regarding the significance of E44D and V118I. It has been reported that both
mutations confer increased phenotypic resistance to lamivudine in the absence of M184V (Hertogs et al.
Antimicrob Agents Chemother 2000; 44: 568-573), but their clinical impact is limited.
2
Isolates containing this combination of mutations showed significant or high-level resistance to the
inhibitor in phenotypic assays (Ross et al. 13th Conference on Retroviruses and Opportunistic Infections
2006, Denver, USA. Abstract 602).
3
The amino acid substitutions at position 75 were rarely observed in vivo. Cross-resistance between
stavudine and zidovudine has been found in the presence of T215Y and the other indicated mutations
related to zidovudine resistance.
4
Resistance profiles obtained in vitro with tenofovir alafenamide and drug susceptibilities of a panel of
HIV-1 isolates were very similar to those obtained with classical formulations of tenofovir (Margot et al.
Antimicrob Agents Chemother 2015; 59: 5917-5924).
5
Three or more secondary resistance mutations of this group may confer resistance to all nucleoside
analogues except lamivudine (see also Table 4.29). In the case of AZT, resistance mediated by M41L,
K70R, T215F/Y, etc… can be suppressed by antagonist mutations such as K65R, L74V, V75I, W88G,
E89K, L92I, S117T, S156A, Q161L, M164I, Y181C or M184V (see Table 4.1). Suppression of AZT
resistance by the mutation M184V depends on the sequence context (for example, dual resistance to AZT
and 3TC is observed in the presence of the substitution G333D/E, and perhaps in the presence of T386I).
6
Information on mutations associated with rilpivirine resistance are based on data obtained in vitro (see
Table 4.17), and results of Phase III trials [Rimsky et al. Antivir Ther 2011; 16 (suppl. 1): A17]. The
contribution to rilpivirine resistance of amino acid substitutions shown between parentheses is still unclear
(e.g. K103N in combination with L100I decreases inhibitor susceptibility by 5- to 20-fold; see Table 4.17).
7
Although the primary/secondary mutation distinction is debatable, we have indicated in bold the most
relevant amino acid changes involved in protease inhibitor resistance.
8
All protease inhibitors are prescribed in combination with ritonavir (low-dose) to enhance drug exposure
(reviewed in Hull & Montaner. Ann Med 2011; 43: 375-388). The accumulation of 6 or more of these
mutations has been associated with diminished response to lopinavir/ritonavir (see also Table 4.25).
Protease mutation L63P is common in viruses that have never been exposed to protease inhibitors (Kozal
et al. Nat Med 1996; 2: 753-759) and may be more prevalent in viruses from patients in whom a protease
inhibitor-containing regimen has failed. It does not cause any appreciable increase in the IC50 for any
protease inhibitor. L63P is listed for lopinavir/ritonavir (and not any other protease inhibitor) because the
prescribing information approved by the FDA lists it as one of the several mutations that when together with
other mutations predict a lack of viral load response to lopinavir/ritonavir-containing regimens.
9
The accumulation of 5 or more of these substitutions was predictive of significant phenotypic resistance
to atazanavir (>3.0-fold increase in the IC50 for the inhibitor) (Colonno et al. Antimicrob Agents Chemother
2003; 47: 1324-1333).
10
The identification of mutations involved in tipranavir resistance is still incomplete, although L10V,
L33F, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, L74P, V82L/T, N83D and I84V appear to be the largest
contributors to drug resistance (Schapiro et al. Antivir Ther 2010; 15: 1011-1019).
11
Multiple protease inhibitor resistance can be achieved through the accumulation of 4 or 5 mutations, of
those indicated in the list.
12