INTRODUCTION — Managing patients with HIV drug resistance has become less common. Advances in drug development have allowed for more potent antiretroviral therapy (ART) regimens that are easier to take, resulting in fewer patients who develop drug-resistant strains of HIV . However, there remains a subset of patients infected with drug-resistant variants, which can challenge an HIV clinician.
While resistance mutation patterns can be complex, there are basic principles that underlie effective utilization of resistance data. This topic will review the resistance patterns found in association with different antiretroviral agents and describe how that knowledge can impact selection of an appropriate treatment regimen in patients with virologic failure . The details in this topic refer mainly to resistance patterns seen with HIV subtype B, which is the most prevalent clade in the United States, Europe, Japan, Thailand, and Australia.
Topic reviews that discuss the different types of resistance tests and provide detailed guidance on selecting an ART regimen are found elsewhere. (See "Overview of HIV drug resistance testing assays" and "Evaluation of the treatment-experienced patient failing HIV therapy" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy" and "Treatment of HIV-2 infection".)
FACTORS CONTRIBUTING TO RESISTANCE — Multiple factors influence the development of HIV drug resistance, including the biology of HIV, genetic barriers to resistance, regimen potency, pharmacokinetics of antiretroviral drugs, and medication adherence. Drug-resistant mutations can predate the initiation of a specific drug regimen  or can develop when viral replication continues in the face of ongoing drug pressure.
●HIV biology – HIV infection is characterized by high rates of replication, with more than 109 virions produced daily . In addition, HIV reverse transcriptase, which is responsible for replicating the viral genome, is error-prone. The combination of the high rate of replication and the frequent introduction of mutations during each round of replication leads to the occurrence of randomly generated mutations, some of which confer drug resistance . The resulting population of genetically related, but distinct, HIV variants in a patient is referred to as a "quasispecies."
Viruses with spontaneous mutations are often defective and incapable of replication. However, some mutations can persist in proviral HIV DNA in resting memory cells if the mutant virus has a selective growth advantage over wild-type virus . If viral replication is not fully suppressed by an antiretroviral regimen, these mutants can reemerge. Depending on their level of drug resistance, these mutants can either cause overt virologic failure or become more drug resistant by the gradual accumulation of additional resistance mutations.
●Genetic barriers to resistance – HIV can develop high-level resistance to some drugs with only a single mutation, while other drugs require multiple mutations. Drugs in the former situation are referred to as having a "low genetic barrier" to resistance. (See "Overview of antiretroviral agents used to treat HIV".)
Several antiretroviral agents have a low genetic barrier to resistance. These include the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (and the closely related agent emtricitabine), the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and rilpivirine, and the integrase strand transfer inhibitors (INSTIs) raltegravir and elvitegravir.
By contrast, a high resistance barrier is seen in the protease inhibitor (PI) class and with the INSTIs dolutegravir and bictegravir. Resistance to these agents usually requires the accumulation of multiple mutations.
●Regimen potency – The potency of an antiretroviral regimen is a crucial determinant of viral load suppression. If the viral load is not fully suppressed, continued virus replication in the presence of drug can lead to the accumulation of mutations. This can lead to the development of viral resistance, even to drugs with a high genetic barrier to resistance. As an example, unboosted PIs, which are no longer recommended, had a high genetic barrier to resistance but achieved low serum trough concentrations; thus, virus could continue to replicate and accumulate mutations that led to high levels of resistance. This problem can be offset by the use of pharmacokinetic "boosting" with ritonavir or cobicistat. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)
This principle was illustrated in a trial in which 653 treatment-naïve patients were randomly assigned to receive stavudine and lamivudine in combination with a PI, either lopinavir-ritonavir or nelfinavir (a less potent PI) . After 48 weeks of follow-up, the emergence of resistance and virologic failure was more common in patients in the nelfinavir arm compared with the lopinavir arm.
●Pharmacokinetic factors – There are several ways that pharmacokinetic factors can lead to drug resistance.
•Low serum concentrations – Low serum concentrations of an antiretroviral agent can be seen as a result of drug interactions, poor absorption, or secondary to the pharmacokinetics of a specific agent (eg, unboosted PIs). Continued virus replication in the presence of drug can lead to the accumulation of mutations.
•Varying half-lives – Resistance can result when individual components of an HIV antiretroviral regimen have varying plasma half-lives. In this case, discontinuation of the regimen can lead to functional monotherapy. As an example, when the combination of efavirenz-emtricitabine-tenofovir disoproxil fumarate is discontinued, the half-life of efavirenz is longer than the half-lives of emtricitabine or tenofovir disoproxil fumarate, and the patient may be at risk of developing efavirenz resistance.
•Genetic factors – Pharmacokinetic profiles can vary significantly in different patient populations. This pharmacokinetic variability was well illustrated in a study of 152 patients who were receiving efavirenz, which is metabolized primarily by cytochrome p450 2B6 isoenzymes . A G-to-T polymorphism at position 516 of CYP2B6 was associated with higher plasma efavirenz concentrations and slower clearance .
Therapeutic drug monitoring (TDM) is of theoretical utility to ensure that there is adequate drug exposure . However, the role of TDM in clinical practice remains controversial because of the lack of prospective studies demonstrating that TDM improves clinical outcome in patients with drug-resistant HIV. In addition, plasma NRTI concentrations are not thought to be as important clinically due to the intracellular location of their active forms.
●Medication adherence – Nonadherence to antiretroviral therapy is closely associated with incomplete viral suppression and the development of drug-resistant HIV variants . The relationship between adherence and drug resistance is complex and influenced by drug potency, pill burden, and pharmacokinetics [11,12]. (See "Evaluation of the treatment-experienced patient failing HIV therapy", section on 'Nonadherence'.)
BASIC TERMINOLOGY — This section defines the terms that are used when describing drug resistance.
Wild-type virus — "Wild-type" virus refers to the original parent virus that was predominant prior to the use of antiretroviral medications. A patient may become infected by either a wild-type or a resistant strain. As there are many HIV viral variants that are considered "wild type," all are compared to a reference strain in laboratories that perform drug resistance testing.
Viral fitness — Viral fitness generally refers to the ability of one virus to out-compete a second virus in a defined environment [6,13]. In general, wild-type virus replicates more efficiently (ie, is more "fit") in cell culture than resistant virus and overgrows mutant variants in the absence of drug selection pressure.
In the setting of drug therapy, drug-resistant virus is selected, despite that it is less fit in the absence of drug . Viral variants with reduced fitness may be less pathogenic, although studies examining the correlation of HIV replication fitness with clinical outcome have not given consistent results .
Replication capacity — Replication capacity refers to the ability of the virus to replicate in comparison to another reference virus. Replication capacity can either decrease or increase in the presence of certain mutations.
In the early era of potent antiretroviral therapy, some patients demonstrated transient immunologic benefit despite ongoing viremia [15,16]. This may have been related to the selection of a "less fit" drug-resistant virus population. Viral fitness is inferred through measurement of replication capacity, which can be obtained from one phenotypic assay, PhenoSense HIV (Monogram Biosciences, Clinical Reference Laboratory). (See "Overview of HIV drug resistance testing assays".)
However, the primary goal is always complete viral suppression, which is associated with durable immunologic benefit. Viral suppression is usually achievable with currently available antiretroviral medications, even among patients with multi-class drug resistance [3,17]. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Mutational patterns — By convention, mutations are indicated by a codon number preceded by a letter indicating the consensus amino acid in wild-type (drug-susceptible) virus and followed by a letter indicating the amino acid substitution in the mutant virus. For example, "M184V" indicates that valine has been substituted for methionine at amino acid codon 184 in the reverse transcriptase enzyme. The notation "M184M/V" indicates the presence of a mixture of wild-type (M) and mutant (V) virus.
Signature mutation — A "signature mutation" is a mutation that is typically associated with resistance to a particular drug. As an example, the K103N mutation is the signature mutation for efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI). Other signature mutations are described below. (See 'Interpretation of resistance mutations' below.)
Cross-resistance — The term "cross-resistance" refers to resistance to drugs other than the drug that selected the mutation(s). As examples, the M184V mutation associated with lamivudine confers cross-resistance to the related drug emtricitabine, and the K103N mutation selected by the NNRTIs efavirenz and nevirapine confer cross-resistance to each other. However, a specific mutation may not cause cross-resistance to all agents within a class. Although virus expressing the K103N is resistant to nevirapine and efavirenz, other NNRTIs, such as etravirine and rilpivirine, maintain activity if there are no other additional NNRTI mutations. Similarly, a mutation at position Y143 can confer resistance to raltegravir but has little effect on dolutegravir susceptibility. (See 'Non-nucleoside reverse transcriptase inhibitors' below and 'Integrase strand transfer inhibitors' below.)
Hypersusceptibility — On occasion, resistance to one drug can lead to increased susceptibility, or hypersusceptibility, to another drug. For example, the M184V mutation that confers lamivudine resistance causes hypersusceptibility to zidovudine and tenofovir compared with wild-type virus . Another example is the TAM T215Y, which is associated with efavirenz hypersusceptibility when present .
Accessory mutations — When HIV continues to replicate, additional minor mutations may accumulate over time. These accessory or secondary mutations further increase drug resistance or can compensate for the loss of viral fitness induced by the primary mutations. Thus, it is important to switch antiretroviral therapy rather than expose a patient with ongoing viremia to the same drugs in order to avoid the accumulation of additional mutations . (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Management of patients with incomplete viral suppression'.)
Polymorphisms — In a given sample, some amino acid changes within a viral gene may be identified that differ from the consensus amino acid sequence in wild-type virus. These amino acid substitutions are often termed "polymorphisms" and do not on their own confer phenotypic or in vitro resistance to a particular antiretroviral agent . Resistance interpretations should indicate drug susceptibility when these polymorphisms are identified.
INTERPRETATION OF RESISTANCE MUTATIONS — Because our understanding of how best to interpret resistance testing continues to evolve, a specialist experienced in the management of HIV infection and interpretation of drug resistance testing should be consulted. Patterns of mutations can be complex, and interpretations can change over time as more information is obtained regarding the relationship between drug resistance mutations and response to therapy.
Resistance testing — Resistance testing is important to help guide treatment decisions in both treatment-naïve and treatment-experienced patients [20-22]. Drug-resistant mutations may be related to transmission of a drug-resistant virus at the time of initial infection or may arise due to continued virus replication in the presence of drug (eg, patients who do not take their regimen as prescribed). A discussion of HIV drug resistance assays is presented elsewhere. (See "Overview of HIV drug resistance testing assays".)
In treatment-experienced patients with virologic failure, it is preferable to obtain resistance testing while the patient is taking antiretroviral therapy (ART) or is within weeks of discontinuing treatment; however this might not be possible in patients who are nonadherent to their regimen. In the absence of drug pressure, the wild-type HIV strain may become dominant. Although some mutations may persist off ART , the results can be misleading if drug resistance testing is performed when patients are not receiving ART. Similarly, resistance testing is less reliable at detecting resistance to classes of drugs no longer being taken. These limitations emphasize the importance of taking a complete medication history. (See "Evaluation of the treatment-experienced patient failing HIV therapy".)
Nucleoside reverse transcriptase inhibitors — Any nucleoside reverse transcriptase inhibitor (NRTI) can select for resistance mutations when used in a nonsuppressive regimen. The specific mutation pattern may be associated with varying degrees of NRTI cross-resistance. In general, a single mutation can lead to resistance to lamivudine, emtricitabine, tenofovir, or abacavir, whereas resistance to zidovudine and stavudine usually requires multiple mutations. A summary of NRTI resistance mutations can be found on the International Antiviral Society - USA and the Stanford HIV Drug Resistance Database websites, which are updated regularly [24-27].
Zidovudine and stavudine — Zidovudine and stavudine are thymidine analogs, which share common resistance patterns. Although these agents are no longer recommended as first-line therapy because of their toxicity [28-30], it is important to understand their effect on drug resistance in patients who were previously exposed to these agents.
Common resistance mutations include M41L, L210W, T215Y, D67N, K70R, and K219Q/E/N . These substitutions are referred to as "thymidine analog mutations" (TAMs) because they are selected by the two thymidine analogs (zidovudine and stavudine). Regimens containing a thymidine analog can select for TAMs and additional mutations, including 44D/A, 118I, 207D/E, 208Y.
TAMs typically emerge via one of two "pathways":
●Pattern 1 includes the M41L, L210W, and T215Y mutations.
●Pattern 2 involves the D67N, K70R, and K219Q/E/N mutations [32,33].
However, there can be mixtures of both patterns present in some patients [32,33]. TAMs continue to accumulate when patients continue failing ART regimens.
The first TAM pathway listed above confers cross-resistance to all NRTIs and the nucleotide analog, tenofovir [24,34,35]. The second pathway confers resistance primarily to zidovudine and stavudine but causes less cross-resistance to abacavir, didanosine, and tenofovir. Since zidovudine and stavudine are both thymidine analogs, resistance to zidovudine results in cross-resistance to stavudine, and vice versa.
TAMs are uncommon with early failure of a thymidine analog-containing regimen. At least three TAMs are usually required before virologic activity of zidovudine or stavudine is completely lost. However, continuation of a thymidine analog-containing regimen in the presence of ongoing viremia will result in accumulation of additional TAMs, leading to greater resistance and NRTI cross-resistance [36-38]. (See 'Accessory mutations' above and 'Multinucleoside resistance mutations' below.)
In the case of multiple TAMs, phenotypic testing may be helpful for determining whether any NRTIs are likely to have partial activity . However, the use of fully active agents is preferred whenever feasible; extensive NRTI resistance may require the use of an ART regimen that includes a combination of agents from other drug classes. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Lamivudine and emtricitabine — Lamivudine and emtricitabine are NRTIs with a low genetic barrier to resistance. Lamivudine and emtricitabine both select for the M184V mutation. This is the most prevalent NRTI-associated mutation seen in treated patients, in part because of its widespread use. It is often the first mutation to appear .
M184V (as well as the less common M184I mutation) causes high-level in vitro resistance to both lamivudine and emtricitabine. It also causes a modest decrease in susceptibility to abacavir  and didanosine . However, M184V confers hypersusceptibility to tenofovir, zidovudine, and stavudine and, therefore, partially reverses TAM-mediated resistance to these drugs . (See 'Hypersusceptibility' above and 'Zidovudine and stavudine' above.)
The M184V mutation also leads to decreased replication capacity of HIV . Thus, a viral isolate with this mutation is "less fit" than wild-type virus . Continuation of either lamivudine or emtricitabine, with maintenance of the M184V mutation, leads to a persistent mean 0.5 log decrease in viral load from baseline. (See 'Replication capacity' above.)
Some clinicians maintain lamivudine or emtricitabine in a regimen despite the presence of the M184V mutation because of the safety, tolerability, and residual partial virologic activity of these drugs, as well as the beneficial effect on susceptibility to zidovudine, stavudine, and tenofovir . This is probably most important in regimens containing NRTIs, especially tenofovir. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Tenofovir — Tenofovir is available as one of two tenofovir prodrugs: tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Resistance considerations are generally the same for both agents, although the higher intracellular tenofovir concentrations achieved with TAF may give it greater activity against some NRTI-resistant viruses. A more detailed review of these agents is found elsewhere. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)
K65R is the signature mutation associated with tenofovir resistance . The overall prevalence of the K65R mutation is low. However, when it occurs, it confers significant cross-resistance to abacavir, lamivudine, and didanosine . By contrast, the K65R mutation induces hypersusceptibility to zidovudine , similar to that seen with the M184V mutation. (See 'Lamivudine and emtricitabine' above.)
First-line tenofovir failure has also been associated with other less common mutations at positions K70E and Y115F [48,49]. In addition, tenofovir resistance can be mediated by the presence of multiple TAMs. TAMs are selected by the two thymidine analogs (zidovudine and stavudine) and are discussed above. (See 'Zidovudine and stavudine' above.)
Abacavir — The common mutation for abacavir is L74V [50,51]. Less commonly, abacavir selects for other mutations, including K65R, Y115F, and M184V. When L74V is present in combination with M184V, there is further loss of susceptibility to abacavir. However, the presence of both mutations increases susceptibility to zidovudine and tenofovir . In addition, L74V mutant isolates are less fit than wild-type virus . (See 'Viral fitness' above.)
This same resistance pattern is seen with didanosine, an NRTI that is no longer used because of its toxicity. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors".)
Multinucleoside resistance mutations — While the most common cause of broad NRTI cross-resistance is the combination of multiple TAMs with M184V , two other resistance patterns can also lead to significant NRTI cross-resistance:
●The Q151M complex is associated with resistance to all NRTIs, with the least effect on tenofovir.
●The T69 insertion mutation causes resistance to all NRTIs, including tenofovir, when this mutation is accompanied by one or more TAMs at codons 41, 210, or 215.
These mutations are usually selected by older NRTI combinations that included didanosine plus either zidovudine or stavudine. When these mutations are present, the use of an NRTI-sparing regimen may be considered. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Non-nucleoside reverse transcriptase inhibitors — The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz, nevirapine, and rilpivirine have a low genetic barrier to resistance compared with protease inhibitors (PIs) and the integrase strand transfer inhibitors (INSTI) dolutegravir and bictegravir. Doravirine is a newer NNRTI approved for use in antiretroviral-naïve HIV-1-infected persons [53,54]. Etravirine, which is used in salvage regimens for patients with drug-resistant virus, has a higher resistance barrier and may be active against some efavirenz- and nevirapine-resistant viruses . (See "Overview of antiretroviral agents used to treat HIV", section on 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)' and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'NNRTI-containing regimens'.)
Efavirenz and nevirapine — Initial NNRTI resistance mutations tend to emerge quickly in patients with detectable viremia during NNRTI-based therapy. The most common mutations seen in association with efavirenz or nevirapine are K103N and Y181C . There is significant cross-resistance between those two agents . As a result, selection of one of these single point mutations (eg, Y181C or K103N) confers loss of activity to both drugs .
K103N is selected by efavirenz more frequently than by nevirapine; Y181C is selected more commonly by nevirapine when zidovudine is not coadministered. Although efavirenz may appear phenotypically active in the presence of Y181C , the use of efavirenz after the emergence of the Y181C mutation on nevirapine leads to the rapid development of resistance and virologic failure .
Efavirenz and nevirapine may also select Y188L, which confers high-level resistance to some NNRTIs when present as a single mutation. Other common mutations selected by these NNRTIs include: L100I, V106A, G190S/A, and M230L. Accumulation of two or more of these common mutations is associated with broad NNRTI class resistance. Thus, first-generation NNRTIs should be discontinued in patients experiencing virologic failure and documented resistance. Maintaining NNRTI therapy in viremic patients on either efavirenz or nevirapine risks accumulation of further NNRTI resistance mutations, which may reduce the utility of etravirine. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Management of patients with incomplete viral suppression'.)
Rilpivirine — In clinical trials that have evaluated the efficacy of rilpivirine in treatment-naïve patients, virologic failure was associated with the emergence of the following resistance-associated mutations: K101E, V189I, Y181C, V90I, H221Y, and E138K [59,60]. E138K, the most frequently observed mutation, is a mutation that by itself causes high-level rilpivirine resistance, as well as potential low-level resistance to other NNRTIs [24,61,62].
In studies in which rilpivirine was given with emtricitabine or lamivudine, the E138K mutation was most often seen in association with the NRTI mutation M184I or, less commonly, with M184V [59,60,63]. Although M184I/V mutations are associated with a decline in replication capacity, the coexistence of the E138K mutation appears to restore viral fitness , particularly when found in combination with M184I . (See 'Viral fitness' above.)
Doravirine — Doravirine was approved by the US Food and Drug Administration (FDA) in 2018 . In clinical trials, the most frequent patterns of mutations conferring high-level resistance involved changes at codon V106 in combination with other known NNRTI resistance substitutions (eg, V106A/M with changes at F227C, Y188L, and Y318F) [24,53,54]. In addition, other NNRTI mutations (eg, G190E/Q and M230L) can confer high-level resistance to the drug [24,54,65]. In an analysis of NNRTI cross-resistance, clinical isolates demonstrated resistance to doravirine when Y188L was identified, alone or in combination with K103N or V106I. Also, the NNRTI mutation combination of G190A and F227L, or E138K in combination with Y181C and M230L, showed greater than 100-fold reduced susceptibility to doravirine [24,54,65]. A better understanding of the most common clinically emergent doravirine resistance profiles will likely be forthcoming once the drug has been used more extensively.
Etravirine — Etravirine is an NNRTI with activity against a large proportion of NNRTI-resistant viruses isolated from patients with virologic failure on efavirenz or nevirapine . The K103N mutation, which is the most common mutation associated with efavirenz failure, does not cause cross-resistance to etravirine. However, the presence of other NNRTI-associated mutations may affect etravirine potency, as noted above . There are no clinical data on the use of etravirine after virologic failure on rilpivirine.
The likelihood that etravirine will be active against a particular virus can be determined by the presence of specific mutations. A summary of NNRTI resistance mutations can be found on the International Antiviral Society - USA and the Stanford HIV Drug Resistance Database websites [24,25].
A retrospective analysis from the DUET trials identified a number of mutations that may diminish response to etravirine, including V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V/Y, and G190S/A . An increased number of mutations was correlated with a declining treatment response. In addition, although no single mutation led to high-level resistance to etravirine, some mutations (eg, those at codon 181) led to "intermediate" level resistance and appeared to have a significant negative impact on etravirine susceptibility and activity.
Phenotypic drug resistance testing is helpful in determining the residual activity of etravirine when multiple mutations are found on genotypic testing. (See "Overview of HIV drug resistance testing assays", section on 'Phenotypic resistance assays'.)
Protease inhibitors — Protease inhibitors (PIs) are almost always given in combination with cobicistat or low-dose ritonavir. These boosting agents are used to increase serum trough concentrations of the parent drug. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)
Pharmacologically boosted PIs achieve high serum concentrations and have a high genetic barrier to resistance; therefore, decreased drug susceptibility generally requires the accumulation of multiple mutations. When boosted PIs are used by patients without preexisting PI resistance, treatment failure is rarely associated with PI resistance. (See "Evaluation of the treatment-experienced patient failing HIV therapy".)
When PI-associated mutations do occur, they are classified as either primary (major) or secondary (minor) mutations. The mutations that emerge depend upon which medication is being administered. However, it should be emphasized that most data on mutations associated with failure of PI-based regimens come from studies of unboosted PIs, which are rarely used today.
Atazanavir — The signature mutation associated with use of unboosted atazanavir is I50L, which does not decrease susceptibility to other PIs and, in some cases, may increase PI susceptibility. Other potential mutations include I84V and N88S.
Darunavir — Pharmacologically boosted darunavir is an important agent for use in treatment-experienced patients since darunavir maintains virologic activity despite multiple PI mutations . Mutations that alter the virologic response to darunavir include: 11I, L10F, V32I, L33F, I47V/A, I50V, I54L/M, G73S, T74P, L76V, V82F, I84A/C/V, L89V [24,69]. The dosing of darunavir (once versus twice daily) and the choice of boosting agent depend upon the number of PI mutations. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Protease inhibitors' and "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)
Interpreting complex genotypes can be challenging in patients with multiple PI resistance mutations. Thus, in some cases, phenotypic resistance testing may offer an advantage over genotypic testing, as it measures resistance more directly and can assess relative susceptibility and interactions among mutations. When using phenotypic assays, an optimal response to darunavir is associated with a phenotypic fold change ≤10 . (See "Overview of HIV drug resistance testing assays", section on 'Phenotypic resistance assays'.)
In a pooled subset analysis of clinical trials comparing darunavir with optimized ART in highly treatment-experienced patients, the effect of baseline susceptibility on treatment efficacy was examined . Forty-seven percent of patients who had multiple mutations at baseline attained viral suppression when treated with darunavir. In addition, a prevalence study that evaluated more than 90,000 viral isolates from treatment-experienced patients found that the coexistence of three or more darunavir resistance mutations was seen at the pretreatment baseline in only 7 percent of patients .
Lopinavir — Lopinavir is only available in a coformulation with ritonavir. Several PI mutations are required before its efficacy is significantly compromised . Key mutations include L76V, V32I, I47V/A, I54L/M, V82A/F/T/S, and I84A/C/V. The primary lopinavir resistance mutation, L76V, can sensitize viral strains to tipranavir .
Tipranavir — Tipranavir is only used in heavily treatment-experienced patients and has a unique resistance profile [74,75]. As an example, the mutations I50V, I54L, and L76V, which confer significant resistance to darunavir, are associated with hypersusceptibility to tipranavir in vitro [2,24,25]. The use of either phenotypic resistance testing or a tipranavir mutation score  can be helpful in determining the use of this agent.
Older, less used protease inhibitors
●Fosamprenavir – Common mutations associated with fosamprenavir, an amprenavir prodrug, include I50V and I84V. These mutations are also associated with cross-resistance to other PIs, most notably darunavir.
●Nelfinavir – The signature mutation associated with nelfinavir resistance is D30N, which does not affect susceptibility to other PIs. Another less common mutation associated with nelfinavir use is L90M, which causes cross-resistance to other PIs. Nelfinavir is rarely used because of its gastrointestinal side effects (eg, diarrhea), lower efficacy, and inability to be pharmacologically boosted. (See 'Cross-resistance' above and "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)
●Saquinavir – Common mutations associated with emergence of saquinavir resistance include the unique G48V mutation, as well as the L90M mutation, which is associated with PI cross-resistance. Saquinavir is no longer a recommended drug for the treatment of HIV infection [28,29].
●Indinavir – Common mutations associated with indinavir resistance include M46/I/L, V82A/F/T, and I84V. The latter two mutations are also selected by other PIs and have a significant impact on most other PIs. This drug is no longer recommended for the treatment of HIV infection.
Integrase strand transfer inhibitors — There are four integrase strand transfer inhibitors (INSTIs) approved for use: raltegravir, elvitegravir, dolutegravir, and bictegravir (BIC). All of the INSTIs can be used in treatment-naïve and treatment-experienced patients, although bictegravir is only approved by the US FDA for use in combination with TAF/emtricitabine (FTC) as initial therapy or for use in persons with HIV who do not harbor resistance to BIC/TAF/FTC .
HIV-1 integrase is essential for viral replication; integrase inserts viral DNA into the cellular genome through two catalytic reactions. Loss of integrase activity disrupts the viral life cycle. Due to a different mechanism of action, there is no cross-resistance of these agents with drugs from other classes.
Raltegravir and elvitegravir — Raltegravir and elvitegravir are INSTIs with potent in vitro activity against both wild-type and HIV isolates that are resistant to other drug classes. Both phenotypic and genotypic integrase resistance tests are commercially available. (See "Overview of HIV drug resistance testing assays".)
If resistance develops, there is virtually complete cross-resistance between raltegravir and elvitegravir. Signature mutations in the integrase gene associated with resistance to raltegravir include Q148H/K/R, Y143C, and N155H, which develop along three key resistance pathways. The primary mutations for elvitegravir are Q148R, E92Q, and T66l. An additional mutation at G140a/s can significantly contribute to both raltegravir and elvitegravir resistance. Additional mutations occur at codons 92, 138, and 147 .
Mutations at codon 148 are associated with the highest level of integrase resistance and become more prevalent with ongoing failure. As an example, in a longitudinal analysis of a phase II study, there was a trend for the N155H mutation to be replaced by the Q148H mutation, which became predominant over time . These data suggest that viruses with the Q148H mutation, in combination with other secondary mutations, have greater replicative fitness in vitro than virus with the N155H mutation [80,81]. (See 'Replication capacity' above.)
Dolutegravir — Dolutegravir has a higher barrier to resistance than raltegravir or elvitegravir. In addition, dolutegravir is active against raltegravir- and elvitegravir-resistant virus with Y143C- or N155H-mediated resistance. However, susceptibility is reduced in the presence of codon 148 mutations when other mutations are present.
Twice-daily dosing is recommended in patients who are INSTI-experienced if a viral isolate is found to have resistance to raltegravir and elvitegravir but remains susceptible to dolutegravir, or if INSTI resistance is clinically suspected. When dosed twice daily, dolutegravir appears to have partial activity against virus with the 148 mutation .
Bictegravir — Bictegravir (BIC) was approved by the US FDA for use in a combination pill with TAF/FTC as an initial treatment for HIV or to replace an ART regimen in patients with suppressed viremia and no known resistance to BIC/TAF/FTC [77,83-85]. Like dolutegravir, bictegravir has a high barrier to resistance, and emergent resistance patterns have not been seen in clinical trials evaluating these patient groups [83-87].
In vitro, mutations at positions M50I and 263K confer reduced susceptibility to bictegravir . In addition, in vitro cross-resistance studies have suggested that mutations at G140A/C/S and Q148H/RK will confer reduced susceptibility to bictegravir, especially when additional INSTI mutations are present [77,83]. As bictegravir is used more broadly, a better understanding of resistance patterns should emerge.
CCR5 antagonists — CCR5 antagonists, such as maraviroc, are entry inhibitors. To see if maraviroc will be active, a pretreatment screening test must be utilized to assess viral tropism. (See "Overview of HIV drug resistance testing assays", section on 'Tropism assays'.)
To enter the CD4 cell, HIV requires binding to coreceptor molecules, CCR5 (by R5 viruses) or CXCR4 (by X4 viruses), in addition to attaching to the CD4 receptor. However, CCR5 antagonists are not active against viruses that enter the cell by binding to the CXCR4 receptor or viruses that enter by using both the CCR5 and CXCR4 receptor (dual or mixed tropic virus). (See "Overview of antiretroviral agents used to treat HIV", section on 'CCR5 antagonists'.)
In clinical trials, virologic failure of maraviroc has been attributed to the emergence of X4 viruses. The primary mechanism for this phenomenon was selection of preexisting minority populations that were not detected at baseline due to the extreme diversity of viral subpopulations in treatment-experienced patients . This may be a less important problem given the improved sensitivity of available tropism assays for detecting X4 or dual/mixed tropic virus. However, even the contemporary assays can miss low frequency variants that can emerge under nonsuppressive treatment .
Treatment failure can also occur as a result of emergence of maraviroc resistance mutations in R5 tropic virus, but this process has not been well characterized, and resistance testing is not yet commercially available. A summary of mutations in the envelope gene associated with resistance to entry inhibitors can be found at the IAS-USA and Stanford HIV Drug Resistance Database websites, which are updated regularly [24,25].
Phenotypically, resistance to CCR5 receptor antagonists manifests not as a rightward shift of the IC50 curve, but as a plateau in the maximum achievable suppression of viral replication . This plateau correlates with the ability of HIV to adapt to the inhibitor-bound form of CCR5 for entry .
Fusion inhibitors — Fusion inhibitors bind to the envelope glycoprotein 41 (gp41) of HIV to prevent viral membrane fusion to the CD4 T cell membrane. The only approved fusion inhibitor is enfuvirtide (sometimes referred to as T-20). (See "Overview of antiretroviral agents used to treat HIV", section on 'Fusion inhibitors'.)
Enfuvirtide has a low barrier to resistance. Resistance to enfuvirtide is a result of mutations occurring in a critical sequence of 10 amino acids (aa 36 to 45) within the helical region (HR-1) of gp41 envelope (env) gene and, to a lesser extent, in other areas of the envelope gene  (figure 1). The substitutions most frequently associated with resistance to enfuvirtide include: G36D/S/V/E, V38A/E/M, Q40H, N42T, and N43D .
Genotypic assays for enfuvirtide resistance are commercially available. However, there are few data to guide practitioners as to whether enfuvirtide has residual activity based on these resistance mutation patterns [13,92]. Thus, it is practical to expect maximal activity with enfuvirtide when it is used for the first time; by contrast, there is likely to be minimal antiviral activity if this drug was previously utilized in a nonsuppressive regimen.
Ibaluzimab — Ibaluzimab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV-1 into cells by noncompetitive binding to CD4 [93,94]. Ibaluzimab was approved by the US FDA in 2018 for use in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who are failing their current antiretroviral regimen . Decreased susceptibility to ibaluzimab has been described in some patients experiencing virologic failure and may be associated with genotypic changes in the HIV-1 envelope. The clinical significance of decreased susceptibility to ibaluzimab has not been fully elucidated. There is no commercial assay available to evaluate for virologic resistance to this agent in the event of virologic breakthrough on treatment.
ADDITIONAL RESOURCES — Complex mutational patterns can be difficult to interpret. Multiple websites are available that contain comprehensive summaries of HIV-1 drug resistance mutations that are helpful to clinicians. Two of the websites are listed below :
●The International Antiviral Society-USA (IAS-USA) drug resistance mutation site is maintained by a group of experts that updates its summary biannually (www.iasusa.org/resources/hiv-drug-resistance-mutations/).
●The Drug Resistance Summary section of the Stanford University HIV Drug Resistance Database contains diagrammatic summaries of mutations by drug class, and provides interpretation of specific genotypes that are input by the user (hivdb.stanford.edu).
SUMMARY AND RECOMMENDATIONS
●With improvements in the efficacy, safety, tolerability, and convenience of antiretroviral therapy (ART), there are fewer patients with detectable viremia and resistance. Nevertheless, clinicians caring for HIV-infected patients need to understand the resistance patterns associated with specific antiretroviral medications so that they may appropriately select treatment regimens that will maximize the likelihood of viral suppression. (See 'Introduction' above.)
●Multiple factors influence the development of HIV drug resistance, including the biology of HIV, genetic barriers to resistance, regimen potency, pharmacokinetics of antiretroviral drugs, and medication adherence. Drug-resistant mutations can predate the initiation of a specific drug regimen or can develop when viral replication continues in the face of ongoing drug pressure. (See 'Factors contributing to resistance' above.)
●"Wild-type" virus refers to the original parent virus that was predominant prior to the use of antiretroviral medications. In general, wild-type virus replicates more efficiently (ie, is more "fit") in cell culture than resistant virus and may overgrow mutant variants in the absence of drug selection pressure. (See 'Basic terminology' above.)
●Resistance testing is important to help guide treatment decisions in both treatment-naïve and treatment-experienced patients. In treatment-experienced patients with virologic failure, it is preferable to obtain resistance testing while the patient is taking antiretroviral therapy, or within weeks of discontinuing treatment, to fully assess for evidence of resistance. However, this might not be possible, as many patients with viremia are nonadherent to their regimens. (See 'Resistance testing' above.)
●Any nucleoside reverse transcriptase inhibitor (NRTI) can select for resistance mutations when used in a nonsuppressive regimen. In general, a single mutation can lead to resistance to lamivudine, emtricitabine, tenofovir, or abacavir, whereas resistance to zidovudine and stavudine usually requires multiple thymidine analogue mutations. (See 'Nucleoside reverse transcriptase inhibitors' above.)
●The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz, nevirapine, and rilpivirine have a low genetic barrier to resistance, and single mutations can eliminate antiviral activity of these drugs. Doravirine is a newer NNRTI, and in clinical studies, a combination of mutations (eg, at codon V106 with other known NNRTI resistance substitutions) conferred high-level resistance to the drug. Etravirine has a somewhat higher barrier to resistance and may be active against some efavirenz- and nevirapine-resistant isolates. (See 'Non-nucleoside reverse transcriptase inhibitors' above.)
●Pharmacologically boosted protease inhibitors (PIs) achieve high serum concentrations and have a high genetic barrier to resistance; therefore, decreased drug susceptibility generally requires the accumulation of multiple mutations. When boosted PIs are used by patients without preexisting PI resistance, treatment failure is rarely associated with PI resistance. (See 'Protease inhibitors' above.)
●There are four integrase strand transfer inhibitors (INSTIs) available, raltegravir, elvitegravir, dolutegravir, and bictegravir. If integrase resistance develops, there is virtually complete cross-resistance between raltegravir and elvitegravir. Dolutegravir and bictegravir have higher barriers to resistance than raltegravir or elvitegravir. Dolutegravir can be used in treatment-experienced patients if the drug maintains activity against raltegravir- and elvitegravir-resistant virus with Y143C- or N155H-mediated resistance. However, susceptibility is reduced in the presence of codon 148 mutations when other mutations are present. (See 'Integrase strand transfer inhibitors' above.)
●CCR5 antagonists, such as maraviroc, are entry inhibitors. These agents are not active against viruses that enter the CD4 cell by binding to the CXCR4 receptor or those that enter by using both the CCR5 and the CXCR4 receptor (dual or mixed tropic virus). (See 'Entry inhibitors' above.)
●Ibaluzimab is a humanized monoclonal antibody that blocks the cell entry of HIV-1 by noncompetitive binding to CD4. There is no commercially available resistance assay that can be used to evaluate the activity of ibaluzimab if virologic failure occurs while a patient is on this agent.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Calvin J Cohen, MD, MSc, and Joel Gallant, MD, who contributed to an earlier version of this topic review.
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