HIV Medicine 2005 | Drug Resistance
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HIV Drug Resistance 2005
by Eva Wolf
5.1. Introduction
5.2. Assays for resistance testing
5.3. Background
5.4. Interpretation of genotypic resistance profiles
5.5. Summary
5.6. References
Table 1. Mutations leading to RTI resistance
Table 2. Mutations leading to NNRTI resistance
Table 3. Mutations leading to PI resistance
Table 4. Mutations leading to PI resistance
The development of resistant viral strains is one of the main reasons for failure of antiretroviral therapy. If there is resistance to several drug classes, the number of alternative treatment regimens is limited and the virological success of subsequent therapies, or so-called salvage regimens, may be only short-lived.
The rapid development of resistant variants is due to the high turnover of HIV - approximately 10 million new viral particles are produced every day (Perelson 1996) - and the exceptionally high error rate of HIV reverse transcriptase. This leads to a high mutation rate and constant production of new viral strains, even in the absence of treatment. In the presence of antiretroviral drugs, resistant strains are selected for as the dominant species (Drake 1993).
Assays for resistance testing
There are two established assays for measuring resistance or sensitivity of HIV to specific antiretroviral drugs - the genotypic and the phenotypic resistance tests (Wilson 2003). Both assays are commercially available (examples of genotypic resistance tests are: HIV-1 TrueGene?, Bayer Healthcare Diagnostics; ViroSeq?, Celera Diagnostics/Abbott Laboratories; virco ® Type HIV-1, Virco ; GenoSure (Plus)?, LabCorp; and GeneSeq?, Virologic . Phenotypic resistance tests include: Antivirogram ® , Virco ; PhenoSense?, ViroLogic; and Phenoscript?, Viralliance ).
The cost of genotyping ranges from 350 to 500 Euro, depending on the assay and laboratory used. It is approximately twice as high for phenotyping.
The drawback with both methods is that a minimum amount of virus is necessary in order to perform the test. A viral load below 500-1000 copies/ml often does not allow any detection of resistance.
Phenotyping
Phenotypic resistance tests involve direct quantification of drug sensitivity. Viral replication is measured in cell cultures under the selective pressure of increasing concentrations of antiretroviral drugs and is compared to viral replication of wild-type virus.
Drug concentrations are expressed as IC 50 values (50% inhibitory concentration). The IC 50 is the concentration of drug required to inhibit viral replication by 50%. The sensitivity of the virus is expressed as the IC 50 compared to the so-called cut-off value. The cut-off value indicates by which factor the IC 50 of an HIV isolate can be increased in comparison to that of the wild-type, whilst still being classified as sensitive. The determination of the cut-off is crucial for the interpretation of the results!
Three different cut-offs are currently being used. The technical cut-off is a measure of the methodological variability of the assay and is approximately 2.5 fold more than the IC 50 . The biological cut-off , for example the comparative value on an antivirogram, involves the inter-individual variability of virus isolates from ART-naive HIV patients and is slightly higher than the technical cut-off. The biological cut-off does not, however, allow prediction of the clinical response to a drug. The clinical cut-off indicates up to which levels of IC 50 virological success can still be expected.
For protease inhibitors (PIs), one has to take into account whether or not the respective clinical cut-off values are derived from clinical studies using unboosted or boosted PIs. Through boosting with ritonavir, drug levels may overcome certain levels of resistance.
Disadvantages of phenotypic testing include the lengthy procedure and high expense of the assay.
Genotyping
Genotypic assays are based on the analysis of mutations associated with resistance. These are determined by the direct sequencing of the amplified HIV genome or by specific hybridization techniques with wild-type or mutant oligonucleotides. Genotype tests only detect viral mutants comprising at least 20 to 30% of the total population and provide an indirect measurement of drug resistance. Mutations that are associated with reduced sensitivity have been well-described for most HIV drugs, but the high number of different resistance patterns, which may also contain compensatory mutations, make the determination of the degree of resistance to particular drugs difficult.
The analysis of genotypic resistance patterns is based on the correlation between the geno- and the phenotype. There is data available from in vitro studies, clinical observations and duplicate testing, in which genotypically localized mutations were investigated for phenotypic resistance.
One approach to predict phenotype from genotype is the so-called "virtual" phenotype (e.g. VirtualPhenotype?): a genotypic mutation pattern is interpreted with the aid of a large database of samples of paired genotypic and phenotypic data. Genotypes matching the patient's virus are identified through a database search. The IC 50 's of these matching viruses are averaged, thus producing the likely phenotype of the patient's virus.
Rule-based interpretation systems are commonly available to aid the interpretation of genotypic mutation patterns. Expert panels (e.g. the French ANRS (National Agency for AIDS Research) AC11 Resistance group) have developed algorithms based on literature and clinical outcomes.
In addition, machine learning approaches such as decision trees and support vector machines (as implemented by the geno2pheno system) can be applied to predict phenotypic drug resistance (Beerenwinkel 2003).
Some of the most important databases for resistance profiles and interpretational systems are available free of charge on the following websites:
Stanford-Database: http://hiv.net/link.php?id=24
Los Alamos-Database: http://hiv.net/link.php?id=25
geno2pheno: http://hiv.net/link.php?id=26
HIV Genotypic Drug Resistance Interpretation - ANRS AC11:
http://hiv.net/link.php?id=138
Commercial suppliers of resistance tests also provide interpretation guidelines for their systems (e.g. VirtualPhenotype? and virco®Type HIV-1, Virco ; TruGene?, Bayer Healthcare Diagnostics ; Retrogram?, Virology Networks ).
The discussion about genotypic resistance in this chapter focuses on the sequencing of the reverse transcriptase, the protease and the env (gp41) gene and on the respective resistance patterns that emerge with treatment.
Most data are derived from patients with subtype B viruses (representing only 12% of the worldwide HIV-infected population). However, by now, non-subtype B viruses have also been investigated for the development of resistance (van de Vijver 2004). Resistance pathways and patterns may differ in the various subtypes.
Background
Within the nucleotide sequences of the HIV genome, a group of three nucleotides, called a codon, defines a particular amino acid in the protein sequence. Resistance mutations are described using a number, which shows the position of the relevant codon, and two letters: the letter preceding the number corresponds to the amino acid specified by the codon at this position in the wild-type virus; the letter after the number describes the amino acid that is produced from the mutated codon.
Mechanisms of resistance
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) are prodrugs that only become effective after being converted to triphosphates. Nucleotide analogs require only two instead of three phosphorylation steps. Phosphorylated NRTIs compete with naturally occurring dNTPs (deoxynucleotide triphosphates). The incorporation of a phosphorylated NRTI into the proviral DNA blocks further elongation of the proviral DNA and leads to interruption of the chain.
There are two main biochemical mechanisms that lead to NRTI resistance (De Mendoza 2002). Sterical inhibition is caused by mutations enabling the reverse transcriptase to recognize structural differences between NRTIs and dNTPs. Incorporation of NRTIs is then prevented in favor of dNTPs (e.g. in the presence of the mutations M184V, Q151M, L74V, or K65R; Naeger 2001, Clavel 2004). Phosphorylysis via ATP (adenosine triphosphate) or pyrophosphate leads to the removal of the NRTIs already incorporated in the growing DNA chain. This is the case with the following mutations: M41L, D67N, K70R, L210W, T215Y and K219Q (Meyer 2000). Phosphorylysis leads to cross-resistance between NRTIs, the degree of which may differ between substances (AZT, d4T > ABC > ddC, ddI > 3TC).
Non-nucleoside RT inhibitors (NNRTIs) also inhibit the viral enzyme reverse transcriptase (RT). NNRTIs are small molecules that bind to the hydrophobic pocket close to the catalytic domain of the RT. Mutations at the binding site reduce the affinity of the NNRTI to the RT and thus lead to treatment failure.
Protease inhibitors (PIs) hinder the cleavage of viral precursor gal-pol-polyprotein by the enzyme protease, thereby producing immature, non-infectious viral particles. PI resistance usually develops slowly, as several mutations must first accumulate. This is also referred to as the genetic barrier. For PIs, a distinction is made between major (or primary) and minor (or secondary) mutations . Major mutations are those, which are selected for early in the process of resistance to one drug and which are located within the active site of the target enzyme, the HIV protease. They reduce the ability of the protease inhibitor to bind to the enzyme. Major or primary mutations may also lead to reduced activity of the protease . Minor or secondary mutations are located outside the active site and usually occur after primary mutations. They compensate for the reduction in viral fitness caused by primary mutations (Johnson 2004). However, the differentiation of primary and secondary mutations can only provide an approximate estimation of the degree of resistance.
Fusion inhibitors differ from NRTIs, NNRTIs and PIs, which block the replication of HIV in the infected cell. Instead, fusion inhibitors prevent HIV from entering its target cells. The first step in cell entry occurs when the HIV envelope glycoprotein, gp120, binds to the CD4-receptor and the chemokine co-receptors, CCR5 or CXCR4, of the target cell. Once gp120 binds to the CD4/chemokine complex, a conformational change in the transmembrane glycoprotein subunit, gp41, enables fusion of the viral and cellular membranes and thereby the entry of HIV into the host cell.
The fusion inhibitor T-20 (enfuvirtide) is a synthetic peptide that inhibits the conformational change of gp41 necessary for fusion of virions to host cells. A single amino acid substitution in gp41 can reduce the efficacy of T-20.
Transmission of resistant HIV strains
The prevalence of mutations already present in treatment-naïve patients differs among demographic regions. In a European multi-centric study with more than 1,600 newly diagnosed HIV-infected patients, the prevalence of primary resistance mutations in 1996 - 2002 was about 10%. Resistance was primarily observed in recent infections with subtype B (Wensing 2003). Out of 371 isolates of treatment- naïve patients in 40 cities in the U. S., 14% had at least one resistance mutation (Ross 2004). In San Francisco and in a Spanish study, the prevalence of resistance among patients with acute or recent infection was even higher, at 26% and 19% respectively (Grant 2003, de Mendoza 2003).
The clinical relevance of primary resistance mutations at the initiation of treatment is apparent. Transmitted resistance mutations can limit further treatment options. However, primary treatment outcomes in ART-naïve patients are not necessarily affected by pre-existing mutations (Hicks 2003, Little 2002, Hanna 2001, Balotta 1999). Under careful consideration of any pre-existing resistance, primary treatment success is often possible. A retrospective study with 202 patients showed that, when initiating treatment without the knowledge of resistance, patients with pre-existing mutations had a slower treatment response and a higher risk of treatment failure (Little 2002).
Clinical studies
The clinical importance of performing resistance testing before making changes to the therapy, has been demonstrated in several prospective, controlled studies, both for genotypic (Durant 1999, Baxter 1999, Tural 2001) and phenotypic resistance testing (Cohen 2000). Patients whose physicians had access to information about any existing mutations before the therapy was changed, usually had more significant decreases in the viral load than patients in whom treatment was changed without knowledge of the resistance profile.
Interpretation of genotypic resistance profiles
NRTIs
For several NRTIs, such as lamivudine, and for NNRTIs, a high degree of resistance can develop following only a single mutation (Havlir 1996, Schuurman 1995). For this reason, such drugs should only be used in highly effective regimens. However, the lamivudine-specific mutation, M184V, also reduces viral replication capacity (often referred to as reduced viral fitness) by 40 - 60% (Sharma 1999, Miller 2003). After 52 weeks with lamivudine monotherapy, the viral load remained 0.5 log below the initial levels despite early development of the M184V mutation (Eron 1995). When compared to treatment interruptions, continuous monotherapy with 3TC delays virological and immunological deterioration (Castagna 2004).
FTC (emtricitabine), an NRTI approved in 2003, has the same resistance pattern as 3TC. Treatment failure is associated with the M184V mutation (van der Horst 2003).
Thymidine analog mutations, mostly referred to as "TAMs", include the mutations M41L, D67N, K70R, L210W, T215Y and K219Q, which were initially observed with zidovudine therapy (Larder 1989). It is now known that these mutations can also be selected for by stavudine (Loveday 1999). Three or more TAMs are associated with a relevant reduction in the sensitivity to stavudine (Shulman 2001, Calvez 2002, Lafeuillade 2003). The term "NAMs" (nucleoside analog mutations) is also used instead of TAMs, as these mutations are associated with cross-resistance to all other nucleoside analogs, with the exception of lamivudine and emtricitabine.
Viral mutants, isolated from patients in whom treatment on zidovudine, lamivudine or abacavir has failed, usually have a measurable phenotypic resistance. Two TAMs result in a 5.5-fold, three TAMs in a 29-fold and four TAMs or more in a >100-fold reduced sensitivity to zidovudine. The use of abacavir in cases where there is a more than 7-fold reduction in sensitivity no longer promises success. This usually requires at least 3 TAMs in addition to the M184V mutation (Harrigan 2000).
The development of a measurable phenotypic resistance to stavudine or didanosine has been observed less frequently, and has been more moderate in character (Larder 2001). The clinical cut-off for stavudine lies below the technical cut-off of 1.8. Presumably, this is also the case for didanosine (Shulman 2004). Since most interpretation systems still use biological cut-offs, phenotypic resistance might be underestimated.
Clinical data indicates that tenofovir is effective even in the presence of NAMs such as D67, K70R, T215Y/F or K219Q/E. However, if three or more NAMs include M41L or L210W, a reduced virological response can be expected (Antinou 2003). The lamivudine-associated mutation, M184V, as well as the L74V mutation, observed on didanosine treatment, and the NNRTI-specific mutations, L100I and Y181C, may have an antagonistic effect on the development of resistance (Vandamme 1999).
M184V induces resensitization to zidovudine and stavudine, providing that there are no more than three other zidovudine- or stavudine-associated mutations present (Shafer 1995, Naeger 2001). In one genotypic and phenotypic resistance study consisting of 9000 samples, a combination of M41L, L210W and T215Y decreased the susceptibility to zidovudine by more than 10-fold in 79% of cases. If the M184V mutation was also present, only 52% had a more than 10-fold decreased susceptibility to zidovudine (Larder 1999a). The M184V mutation also increases the sensitivity to tenofovir (Miller 2001). In contrast, the presence of M184V plus multiple NAMs or mutations at positions 65, 74 or 115 increased the resistance to didanosine, zalcitabine and abacavir (Harrigan 2000, Lanier 2001).
So-called multidrug resistance (MDR) to all nucleoside analogs - except lamivudine - is established if one of the following combinations occurs: T69SSX, i.e. the T69S mutation plus an insertion of 2 amino acids (SS, SG or SA) between positions 69 and 70, plus a zidovudine-associated mutation or Q151M, plus a further MDR mutation (V75I, F77L or F116; Masquelier 2001).
The MDR mutation, Q151M, alone leads to intermediate resistance to zidovudine, stavudine, didanosine, zalcitabine and abacavir (Shafer 2002a). It is relatively uncommon, with a prevalence of less than 5%. In contrast, Q151M does not lead to the loss of activity of tenofovir. Instead, the T69S insertion induces an approximately 20-fold increase in the resistance to tenofovir (Miller 2001).
The insertion T69SSX together with the mutation M184V, as well as the mutation Q151M together with M184V, leads to a 70% reduction in the viral replication capacity (Miller 2003).
The L74V mutation emerges on didanosine or abacavir and leads to a 2-5 fold increase in the resistance to didanosine or zalcitabine (Winters 1997). The loss of efficacy by a factor of around 2-3 for abacavir is not considered clinically relevant and requires further mutations (Tisdale 1997).
The K65R mutation can emerge while on tenofovir, abacavir, didanosine or zalcitabine and leads to an intermediate resistance to tenofovir, abacavir, didanosine, zalcitabine, lamivudine, emtricitabine, and possibly stavudine (Shafer 2002a, Garcia-Lerma 2003). There is no cross-resistance with zidovudine (Miller 2004). Compared to other mutations, K65R has been observed very rarely. In large clinical trials using tenofovir (TDF) within divergent (PI- or NNRTI-containing) treatment regimens, less than 5% developed the K65R mutation. However, virological failure of triple-NRTI-combinations such as TDF+3TC+ABC or TDF+3TC+DDI was often associated with the development of K65R (Farthing 2003, Gallant 2003, Landman 2003, Jemsek 2004). The main reason for the high failure rate seems to be the low genetic barrier of these regimens: the emergence of K65R induces a loss of sensitivity to all three drugs.
With combinations containing zidovudine, the incidence of K65R is lower. K65R and TAMs represent two antagonistic resistance pathways. K65R increases the sensitivity to zidovudine and induces a resensitization to zidovudine in the presence of TAMs. Vice versa, TAMs reduce the K65R-associated resistance to TDF, ABC, DDI and DDC (Parikh 2004).
As with M184V, the mutation K65R leads to a 40 - 50% reduction in the viral replication capacity. If both mutations, K65R and M184V, are present, replication capacity is reduced by 70% (Miller 2003).
The V75T mutation, which is associated with an approximately 5-fold increase in the resistance to stavudine, didanosine and zalcitabine, is only rarely observed (Lacey 1994).
In large patient cohorts, quantitative measurements of sensitivity have shown that up to 29% of NRTI-experienced patients have a hypersusceptibility to NNRTIs (i.e. a reduction in the inhibitory concentration by a factor of 0.3 - 0.6). A reduction in the zidovudine or lamivudine sensitivity correlated with an increased NNRTI susceptibility (Whitcomb 2000). However, these results have not influenced treatment strategies so far.
NNRTIs
A single mutation can confer a high degree of resistance to one or more NNRTIs. The relatively frequent K103N mutation leads to a 20 to 30-fold increase in resistance to all available NNRTIs (Petropolus 2000). Further use of NNRTIs in the presence of this mutation is therefore not recommended.
V106A leads to a 30-fold increase in nevirapine resistance and intermediate efavirenz resistance. In contrast to subtype B viruses, the mutation V106M is more frequent in subtype C viruses. V106M is associated with high-level resistance not only to nevirapine but also to efavirenz (Grossman 2004).
A98G (which occurs more frequently in subtype C viruses), K101E and V108 lead to low-grade resistance to all available NNRTIs. Intermediate resistance to efavirenz and delavirdine and low-grade resistance to nevirapine result from the L101I mutation. Y181C/I causes a 30-fold increase in nevirapine resistance, and response to efavirenz is only temporary. G190A is associated with a high degree of nevirapine resistance and an intermediate resistance to efavirenz and delavirdine. G190S and Y188C/L/H are mutations resulting in a high degree of nevirapine and efavirenz resistance (Shafer 2002b, De Mendoza 2002).
PIs
The spectrum of PI mutations is very large. Although there is a high degree of cross-resistance between saquinavir, nelfinavir, indinavir and ritonavir, the primary mutations are relatively specific for the individual drugs. If treatment is changed early on to another PI combination, i.e. before the accumulation of several mutations, the subsequent regimen may still be successful.
Polymorphisms at positions 10, 20, 36, 63, 71, 77 and 93 do not lead to resistance per se, but compensate for the reduced protease activity caused by primary mutations (Nijhuis 1999).
The typical nelfinavir-specific resistance profile, with the D30N primary mutation and further secondary mutations, results in only a low degree of cross-resistance to other PIs (Larder 1999a). Virological failure on nelfinavir can also be associated with the emergence of L90M (Craig 1999). In subtype B viruses, treatment with nelfinavir generally leads to the emergence of D30N or M46I plus N88S. In subtype C, G and AE viruses, however, the mutations L90M and I84V occur more frequently. A reason for these different resistance pathways is the prevalence of natural polymorphisms: whereas the polymorphism M36I is present in only 30% of subtype B viruses, M36I is present in 70 - 100% of non-B subtypes (Gomes 2002, Grossman 2004, Sugiura 2002, Hackett 2003).
A comparison between the replicative capacities of a virus with a single protease mutation (D30N or L90M) and that of the wild-type virus, demonstrated a significant loss of viral fitness in the presence of the D30N mutation selected by nelfinavir. In contrast, the L90M mutation only leads to a moderate reduction in the replicative capacity, which can be compensated by the frequently occurring L63P polymorphism. Conversely, the L63P mutation hardly influences the reduced replicative capacity of D30N mutants (Martines 1999).
G48V mainly emerges on saquinavir and leads to a 10-fold decrease in the susceptibility to saquinavir - in combination with L90M it results in a high degree (over 100-fold) decreased susceptibility to saquinavir (Jakobson 1995). Yet generally, any 4 mutations out of L10I/R/V, G48V, I54V/L, A71V/T, V77A, V82A, I84V and L90M, are required to reduce the efficacy of RTV-boosted saquinavir (Valer 2002).
V82A(/T/F/S) occurs mainly with indinavir and/or ritonavir - and, in combination with other mutations, leads to cross-resistance to other PIs (Shafer 2002c).
Mutants that frequently develop with indinavir, harboring M46I/L63P/V82T/I84V or L10R/M46I/L63P/V82T/I84V, are just as fit as the wild-type virus.
The resistance pattern of amprenavir and fosamprenavir is different to that of other PIs. In the course of failing treatment with unboosted amprenavir or fosamprenavir, the following mutations have been selected: I54L/M, I50V or V32I plus I47V - often together with the mutation M46I. In a small study, the corresponding virus isolates showed full susceptibility to saquinavir and lopinavir (Chapman 2004, Ross 2003).
In studies with boosted fosamprenavir as part of a first-line regimen, no specific PI-mutations have been selected to date (DeJesus 2004).
A loss of sensitivity to (fos-) amprenavir and all other approved PIs can be anticipated if the mutation I84V (together with other mutations) is present (Snowden 2000, Schmidt 2000, Kempf 2001, Maguire 2002, MacManus 2003). Researchers on a small study, with 49 PI-experienced patients who were switched to boosted amprenavir, developed an algorithm that also included resistance mutations at positions 35, 41, 63 and 82 (Marcelin 2003).
No specific mutations have been described for lopinavir to date. However, the response to lopinavir in PI-experienced patients correlates with the number of any of the following mutations: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M (Kempf 2000, Kempf 2001). Five mutations or less result in an increase in the IC 50 by a median factor of 2.7, with 6-7 mutations this factor is 13.5, and with at least 8 mutations it is 44. The good efficacy, even with several mutations, is due to the high plasma levels of boosted lopinavir, which - for the wild-type virus - are >30-fold above the EC 50 -concentration during the entire dose interval (Prado 2002).
In studies where boosted lopinavir is part of a first-line regimen, no primary PI-mutations have been observed to date. Very few case reports of primary lopinavir resistance have been published. In one patient, virological failure was associated with the occurrence of V82A followed by the mutations V32I, M46M/I and I47A. Phenotyping resulted in high-grade lopinavir resistance. Susceptibility to other PIs, especially saquinavir, was not affected (Parkin 2004). In a second case, with some pre-existing polymorphisms (M36I, L63P and I93L), the mutations 54V and V82A, followed by L33F, were selected (Conradie 2004).
A more recent algorithm to predict lopinavir resistance also includes mutations at novel amino acid positions. Viruses with any 7 mutations out of L10F/I, K20I/M, M46I/L, G48V, I50V, I54A/M/S/T/V, L63T, V82A/F/S, G16E, V32I, L33F, E34Q, K43T, I47V, G48M/V, Q58E, G73T, T74S, L89I/M display approximately a 10-fold increase in IC 50 . Mutations at positions 50, 54 and 82 particularly affect the phenotypic resistance (Parkin 2003).
A German team recently reported that even with 5 - 10 PI-mutations, which normally confer broad PI-cross-resistance, resensitization is possible. The mutation, L76V, which is primarily selected for by lopinavir and rarely by amprenavir, is associated with high-grade resistance to lopinavir and (fos-) amprenavir, but can lead to resensitization to atazanavir and saquinavir (Müller 2004).
The resistance profile of atazanavir, an aza-peptidomimetic PI, partly differs to that of other PIs. In patients, in whom first-line treatment with atazanavir failed, the mutation I50L - often combined with A71V - was primarily observed. On the one hand, I50L leads to a loss of sensitivity to atazanavir; on the other hand, I50L leads to an increased susceptibility to all other currently approved PIs. In PI-experienced patients, the I50L mutation was selected for in only one third of patients failing atazanavir (Colonno 2002, Colonno 2003, Colonno 2004).
In PI-experienced patients, at least partial cross-resistance to atazanavir is probable (Snell 2003). The accumulation of PI-mutations such as L10I/V/F, K20R/M/I, L24I, L33I/F/V, M36I/L/V, M46I/L, M48V, I54V/L, L63P, A71V/T/I, G73C/S/T/A, V82A/F/S/T, L90M, and, in particular, I84V, leads to a loss of sensitivity to atazanavir.
For unboosted atazanavir, the threshold for resistance is generally met if 3-4 PI-mutations are present; for boosted atazanavir, resistance is likely with 6 or more mutations (Colonno 2004, Johnson 2004).
Fusion inhibitors
This section focuses on T20-resistance. A loss of efficacy is generally accompanied by the appearance of mutations at positions 36 to 45 in the HR1 (heptad repeat 1) region of gp41, and most frequently with substitutions at positions 36, 38, 40, 42, 43 and 45 (e.g. G36D/E/S, 38A/M/E, Q40H/K/P/R/T, N42T/D/S, N43D/K, or L45M/L). Further mutations in the gp41 genome, which consists of 351 codons, were found at positions 72, 90 and 113 (Sista 2004, Monachetti 2004, Loutfy 2004). In a small study, 6 of 17 patients with virological failure additionally developed the mutation S138A in the HR2 region of gp41 - mostly combined with a mutation at position 43 in the HR1-region and a range of HR2 sequence changes at polymorphic sites (Xu 2004).
The replication capacity (RC) in the presence of HR1-mutations is markedly reduced when compared to wild type virus with a relative order of RC wild type > N42T > V38A > N42T, N43K » N42T, N43S > V38A, N42D » V38A, N42T (Lu 2004).
New drugs
The following chapter describes the resistance profiles of several newly developed antiretroviral drugs.
TMC125 , a second generation NNRTI is effective against both wild-type viruses and viruses with NNRTI-mutations such as L100I, K103N, Y188L and/or G190A/S. In 12 of 16 patients who had failed on previous efavirenz- or nevirapine-based regimens, viral load was reduced by more than 0.5 log after 7 days on TMC125 (Gazzard 2002).
In vitro attempts showed that drug resistance to TMC125 emerges significantly slower than to nevirapine or efavirenz. High-level resistance to TMC125 emerged after 5 in vitro passages. The dominant virus population contained the RT-mutations V179F (a new variant at this position) and Y181C. Further mutations were E138K, Y188H and M230L (Brillant 2004).
AG1549 (capravirine) , a second generation NNRTI, shows activity even in the presence of the classical NNRTI-mutations such as Y181C, which is associated with loss of sensitivity to nevirapine and delavirdine, or K103N, which confers resistance to all currently available NNRTIs (Dezube 1999, Potts 1999).
Tipranavir (TPV) , the first non-peptidic protease inhibitor, shows good efficacy against viruses with multiple PI-mutations. In phenotypic resistance testing, 90% of isolates with a high degree of resistance to ritonavir, saquinavir, indinavir and nelfinavir were still sensitive to tipranavir (Larder 2000). In a study of 41 patients, pre-treated with at least two PIs, TPV/RTV-treatment remained effective after 48 weeks in 35 patients. A more than 10-fold increase in tipranavir resistance occurred in only one patient. The number and type of PI mutations before initiation of TPV/RTV were not associated with virological response. In four out of six isolates with reduced susceptibility, the point mutations, V82T and L33 (I, F, or V), were observed (Schwartz 2002).
Although tipranavir has shown activity against viruses with up to 20-25 PI-mutations, a reduced sensitivity can be anticipated if three or more PRAMs (protease inhibitor-resistance associated mutations) - also referred to as UPAMs (universal PI-associated mutations) - are present (Cooper 2003). PRAMs include the following mutations: L33I/V/F, V82A/F/L/T, I84V and L90M. On the other hand, a sufficient short term viral load reduction of 1.2 log was seen after two weeks on treatment with boosted tipranavir plus an optimized backbone in patients with at least three PRAMs, compared to only 0.2 - 0.4 log with boosted amprenavir, saquinavir or lopinavir plus an optimized backbone (Mayers 2004). Fourteen percent of patients received T-20 in addition. In a pooled analysis of 291 patients in three phase II-trials, the mutations, V82T, V82F and V82L, but not L90M nor V82A, were associated with tripranavir-resistance. The mutations, D30N, I50V and N88D, were associated with an increased susceptibility for tipranavir (Kohlbrenner 2004).
Summary
With the aid of HIV resistance tests, antiretroviral treatment strategies can be improved. Pharmaco-economic studies have shown that these tests are also cost-effective (Corzillius 2004).
For several years, national and international HIV treatment guidelines have recommended the use of resistance testing (Arastéh 2004, Hirsch 2003, US Department of Health and Human Services 2004, EuroGuidelines Group for HIV Resistance 2001). With some delay, resistance tests are now covered by public health insurance in several countries.
Currently, both genotypic and phenotypic tests show good intra- and inter-assay reliability. However, the interpretation of genotypic resistance profiles has become very complex and requires constant updating of the guidelines. The determination of the thresholds associated with clinically relevant phenotypic drug resistance is crucial for the effective use of phenotypic testing.
Even if treatment failure requires the consideration of other causal factors, such as compliance of the patient, metabolism of drugs and drug levels, resistance testing is of great importance in antiretroviral therapy.
Finally, it needs to be emphasized that - even with the benefit of well-interpreted resistance tests - only experienced HIV practitioners should start, stop or change antiretroviral therapy with respect to the clinical situation and the psycho-social context of the patient.
References
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