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

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Antiretroviral Resistance in Clinical Practice.

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Chapter 12The impact of resistance on viral fitness and its clinical implications

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Introduction

The primary goal of antiretroviral treatment is to durably suppress viral replication in order to promote immune reconstitution and reduce AIDS-related morbidity and mortality. In HIV-1-infected patients with a history of treatment failure, the selection of drug-resistant and multidrug-resistant virus may not allow complete suppression of viral replication. In these patients, immunological stability is often observed despite ongoing viral replication, when drug-resistant virus with lower fitness is selected by antiretroviral drug pressure [1]. In fact, when HIV-1 develops resistance to antiretroviral drugs through the acquisition of mutations in the pol gene, it often pays a price in terms of reduced replication capacity and reduced pathogenicity [2,3]. The deleterious effects on viral fitness associated with the acquisition of drug resistance presumably result from mutation-induced structural changes in the binding of the natural substrate and in the catalytic activity of the reverse transcriptase (RT) and protease [4,5]. However, the degree of impairment of viral replication appears to vary widely among viral strains that are resistant to antiretroviral agents (see Figure 1) [6,7]. Additional data suggest also that viral fitness varies among clinical isolates from drug-naive individuals, reflecting natural genetic polymorphisms present in each viral strain [8].

Figure 1. : Distribution of replication capacity of 139 HIV-1 isolates from baseline plasma samples of patients failing highly active antiretroviral therapy enrolled in the Argenta trial [6].

Figure 1

: Distribution of replication capacity of 139 HIV-1 isolates from baseline plasma samples of patients failing highly active antiretroviral therapy enrolled in the Argenta trial [6].

Evidence to date clearly indicates that several drug-resistance mutations are associated with reduced ability of HIV-1 to replicate. More recent data also suggest that, whereas drug susceptibility remains the most important determinant of treatment response, reduced viral fitness can be exploited to derive a clinical benefit, especially in settings in which patients have limited therapeutic alternatives.

Definition of HIV-1 fitness

Fitness refers to the ability of an organism to adapt and reproduce in a defined environment. Alterations in any of the viral genes that play a key role in the replication cycle, as well as in the evasion of HIV-1 from the immune response or from antiretroviral drug pressure, can affect viral fitness.

Methods to determine HIV-1 fitness

A number of methods have been developed to measure viral fitness in vitro, ex vivo or in vivo. These can be categorised as follows:

Growth competition assays

These consist of competitive culture assays in which two viral variants are mixed and, after serial passage, the proportions of the competing viruses are carefully measured over time using a variety of genotypic or phenotypic techniques (e.g. recombinant marker virus assay and heteroduplex tracking assay) [911]. For example, a wild-type and a drug-resistant mutant are cultured together at a defined wild-type:mutant ratio in the MT-2 cell line or in stimulated peripheral blood mononuclear cells (PBMCs), and the relative amount of the drug-resistance mutation is measured after several passages [12,13]. Competition experiments are currently the `gold standard' to measure viral fitness because they estimate the replicative abilities of two viral strains under identical conditions. However, these assays are labour intensive and take weeks to perform.

Assays of replication kinetics

These assays quantify the level of HIV-1 replication in parallel cultures [9,14]. Following infection of either cell lines (e.g. MT-2 and MT-4) or PBMCs, the total replication capacity of each virus is determined by quantifying the production of p24 antigen or the RT activity in cell culture supernatants at several time points [13,15,16]. The method is relatively simple but suffers from lack of sensitivity in determining subtle differences in replication kinetics between viruses.

Single-cycle replication assays

A fixed amount of recombinant virus is used to infect indicator cell lines that release an indicator enzyme upon infection. To measure the infectious titre, the enzymatic activity in the supernatant is quantified after a single viral replication cycle using an adequate substrate in a colorimetric assay. The ratio of mutant to wild-type infectivity obtained from parallel assays is then calculated to obtain a fitness-related value in the absence or in the presence of drugs at different concentrations [17]. This assay can be used both for measuring phenotypic drug susceptibility (Phenoscript, Viralliance, France) and for measuring viral fitness in the absence of drugs.

Another single-cycle replication assay uses luciferase as the reporter gene and is a modification of an assay for the determination of antiretroviral phenotypic susceptibility (PhenoSense; Monogram Biosciences, San Francisco, CA, USA) [2,18]. The replication capacity is expressed as a percentage of a reference wild-type recombinant virus. The assay can measure replication capacity in the absence or the presence of varying concentrations of drugs [19]. This `replication capacity' assay does not measure viral fitness directly, but rather measures a component of viral fitness. Because the assay is run using a recombinant vector containing a portion of the patient's virus, including the 3′ end of gag, all of protease and most of RT, not all of the possible determinants of viral fitness are captured [20,21].

Indirect methods to estimate viral fitness

In addition to the aforementioned in vitro systems, viral fitness can be indirectly estimated in vivo by the relative outgrowth of specific viral populations using calculations derived from standard population genetics theory [22]. For example, Frost and colleagues calculated the relative fitness of M184V and M184I in vivo by using the relative rates of outgrowth of these lamivudine (3TC)-resistant mutants during monotherapy with 3TC derived from the observed frequency of resistant mutants over time and a mathematical model. The same can be done by calculating the time needed for specific mutants to disappear after antiretroviral treatment interruption [23,24]. Under conditions that allow ongoing replication of virus in the presence of drug pressure, wild-type virus acquired at the time of infection is replaced as the dominant quasispecies by resistant variants of lower relative fitness. The dominance of the resistant variant persists for as long as drug pressure continues because, in the presence of drugs, the resistant variant is the fitter virus. However, once drug pressure is removed, the fitter wild-type virus re-emerges and eventually outgrows the resistant variant. The time required for the wild-type variant to re-establish dominance is a function of a number of variables, including the fitness difference between the two viruses and the size of the archived reservoir of wild-type virus. For example, M184V, which is associated with 3TC resistance and has a signficant impact on viral fitness, rapidly disappears from the dominant quasispecies after specific drug pressure is removed [24].

Genotypic drug resistance and viral fitness

Assessments of viral fitness using different techniques indicate an association between the accumulation of resistance mutations and diminished fitness. In vitro kinetic and competition studies, as well as in vivo data, have established a role for several resistance-associated mutations in reducing viral fitness. Table 1 shows the fitness effects associated with the individual drug-resistance mutations cited by the International AIDS Society (IAS)-USA 2005 panel [25]. The fitness effect of a combination of mutations was deliberately omitted from Table 1 in order to give preference to findings on the fitness impact of individual mutations. One should consider several limitations when interpreting the fitness data. Fitness values for a given mutation may vary depending on the presence of other drug-resistance mutations or viral charactersistics, as well as on experimental conditions. In addition to defects in RT and in protease, other elements influencing the fitness of a viral clone include the cell system used for the assay and the type of assay employed (see above).

Table 1. Influence of nucleoside reverse transcriptase inhibitor resistance-associated mutations (IAS-USA 2005 list) on viral fitness measures.

Table 1

Influence of nucleoside reverse transcriptase inhibitor resistance-associated mutations (IAS-USA 2005 list) on viral fitness measures.

Nucleoside reverse transcriptase inhibitor-resistant mutations

Several nucleoside reverse transcriptase inhibitor (NRTI)-resistant mutations are associated with reduced viral fitness (Table 1). The 3TC/emtricitabine resistance-associated mutations at codon 184 are clearly associated with reduced fitness. Other mutations linked to reduced fitness are the thymidine analogue mutations (TAMs), especially the TAM pattern 1 mutations (M41L, L210W and T215Y), the K65R and L74V mutations that emerge with the newer non-thymidine NRTI regimens, and the multi-nucleoside resistance pattern associated with insertions at codon 69. However, the TAM pattern 2 mutations (particularly D67N, K70R and K219Q/E, as T215F is less well characterised), which usually confer less cross-resistance to NRTIs than the TAM pattern 1 mutations, do not differ significantly in fitness from wild-type. In addition, the 215 `revertant' mutations T215D/S do not appear to reduce viral fitness and show a better fitness than T215Y in the absence of drug pressure. Finally, the Q151M multi-NRTI resistance pattern does not seem to affect viral fitness significantly.

Non-nucleoside reverse transcriptase inhibitor-resistant mutations

Resistance mutations selected by available non-nucleoside reverse transcriptase inhibitors (NNRTIs) generally have a modest impact on viral fitness (Table 2). These in vitro data are confirmed by the in vivo finding of a slow disappearance of these mutations from the dominant quasispecies after interruption of NNRTI-based therapy. However, differences between mutations can be observed within this class. The two most common resistant mutants, K103N and Y181C, show a fitness that is very close to that of wild-type virus. Less-frequent mutations, such as V106A, Y188C and G190S, are associated with lower viral fitness (for more details, see Table 2 and references therein).

Table 2. Influence of non-nucleoside reverse transcriptase inhibitor resistance-associated mutations (IAS-USA 2005 list) on viral fitness measures.

Table 2

Influence of non-nucleoside reverse transcriptase inhibitor resistance-associated mutations (IAS-USA 2005 list) on viral fitness measures.

Protease inhibitor-resistant mutations

The impact on fitness of individual resistance-associated mutations in the protease region is difficult to explore because viral mutants often contain multiple changes at both major and minor resistance sites. For example, growth competition experiments have shown that strains with the mutation D30N, which is associated with resistance to nelfinavir, are outcompeted by wild-type strains, whereas mutants with L90M, usually selected by saquinavir, are less fit than wild -type but usually outgrow D30N mutants [13]. Combinations of drug-selected mutations in protease have variable effects on viral fitness [9,19]. Table 3 shows results from studies to investigate the impact of single mutations. Substantial reductions in viral fitness have been observed in clinical isolates and/or molecular clones containing the mutations D30N, G48V, I50V and V82A/T. In addition, M46I/L, I54V, I84V, N88D/S and L90M are also associated with significant reductions in fitness.

Table 3. Influence of drug resistance-associated mutations in the protease and gp41 coding regions (IAS-USA 2005 list) on viral fitness measures.

Table 3

Influence of drug resistance-associated mutations in the protease and gp41 coding regions (IAS-USA 2005 list) on viral fitness measures.

Glycoprotein gp41 resistance mutations

Preliminary observations have shown that enfuvirtide-resistance mutations in the first heptad repeat (HR-1) coding region of the gp41 gene are associated with reduced viral fitness (see Table 3). In vitro data are confirmed by the in vivo observation of prompt disappearance of the mutant virus from the dominant quasispecies after drug discontinuation. The mechanism thought to be responsible for the reduced fitness is a reduction in viral infectivity as a result of delayed and reduced efficiency in the fusion process [26].

Other mutations associated with reduced viral fitness

A number of other mutations in RT are associated with reduced fitness. These include rare resistance mutations not included in the IAS-USA list (such as the deletion at codon 67 or V179D), including amino acid substitutions not conferring drug resistance, which occurs at codons involved in drug resistance (such as Q151L/K and K70E) and mutations at sites not known to be associated with resistance (E89K, L92I, E138X and S156A). In the protease, insertions at codons 17, 35 and 95 have been found to confer reduced viral fitness [27]. Polymorphisms at codons 14 and 43, and the R41N mutation have been associated with low replication capacity using the Phenosense assay [28].

Compensatory mutations

A number of mutations have been found to restore viral fitness of drug-resistant mutants. In the RT, S68G [29] and M230I [30] have both been associated with recovery of viral fitness in the presence of other mutations that impair fitness. Most studies, however, have focused on the mechanisms leading to increased fitness during therapy with protease inhibitors. It has been found that several mutations in the protease gene, including substitutions at codons 10I, 63P, 71V and 77I [15,31], compensate for the fitness loss associated with major protease-resistant mutations.

Other determinants of viral fitness

Viral replication capacity is also influenced by polymorphisms located outside the therapy target-coding regions. The envelope (env) gene, which is linked to multiple viral characteristics such as entry into the host cell, transmission, co-receptor usage and tropism, plays a major role in fitness of wild-type HIV-1 [32,33]. In particular, Marozsan and coauthors have reported a higher avidity to the cell receptors CD4 and CCR5 mediated by the gp120 coding region of the env gene in isolates with increased fitness. This was associated with an increased binding/fusion, as well as decreased sensitivity to entry inhibitors. By producing chimeric env viruses with common HIV-1 genetic backbones, Marozsan et al. have confirmed that the gp120 region of the HIV-1 env gene alone was sufficient to explain the fitness of the entire primary HIV-1 strain from which it was derived. This finding implies that, in wild-type isolates, viral entry, rather than other replication steps, is the major determinant of viral fitness. How much the variability of env will determine the fitness of drug-resistant HIV-1 strains remains to be established.

Changes in gag also play a role in restoring viral fitness. Mutations at cleavage sites in gag (between p7 and p1) increase the processing of the gag polyprotein [34,35], whereas mutations in other regions of gag render the cleavage sites more accessible to the viral protease [36,37] and mutations of the frameshift signal lead to increased protease synthesis [38]. Additional changes associated with increased fitness occur at the polypeptide region adjacent to the protease coding region [39] and in the primer-binding-site loop of the 5′-end of the non-coding region [40].

Viral fitness and therapeutic response: potential clinical applications

Viral fitness as a predictor of clinical outcomes

The potential benefit of measuring HIV-1 fitness for predicting clinical outcome is under investigation both in drug-naive and in drug-experienced patients failing therapy.

The Hemophilia Growth and Development Study [41] enrolled 207 HIV-1-infected haemophilia patients between 6 and 19 years of age in 1989 and 1990. Among these, 128 were assessed every 6 months during 1997 using the Phenosense replication capacity assay. The baseline replication capacity correlated with the baseline plasma HIV-1 RNA load (r=0.189; P =0.03), was inversely related to the CD4 count (r = −0.197; P =0.03), and independently predicted the rate of decline in CD4 count and progression to AIDS.

Barbour et al. [42] studied 191 drug-naive subjects who had recently been diagnosed with HIV-1 infection and found that the viral replication capacity, measured using the Phenosense assay, was associated with CD4 count at study entry and over time, both before and after treatment initiation. The significant association between replication capacity and CD4 count persisted after adjustment for drug resistance.

In a study of patients with low-level virological failure (viral load, <5000 copies/ml) on protease inhibitor-based therapy, a significantly greater replication capacity (Phenosense) was found among patients with declining CD4 counts (mean replication capacity, 22%) than among patients with stable or increasing CD4 counts (mean replication capacity, 12%; P =0.04) [43]. Despite the limited size of the study, the data were consistent with prior observations suggesting an inverse relationship between replication capacity and CD4 count [2].

In an analysis [44] of 207 patients from the CCTG 575 trial [45], the baseline replication capacity (Phenosense) was the strongest predictor of an increase in CD4 count from pre-study nadir to study baseline in multivariate models (P =0.0004). A similar association with replication capacity was noted for the change in CD4 count from nadir to months 6 and 12 of the study (P <0.002). A decrease in replication capacity of 1 log10 unit at baseline led to an average rise in CD4 count from nadir of 82 cells/μl. Furthermore, among 97 patients with virological failure at month 6 of the study, the median change in viral load from baseline to month 6 was −0.54 log10 copies/ml in patients with a replication capacity below 35% (n =49) as compared with +0.08 log10 copies/ml in patients with baseline replication capacity values greater than 35% (n =48; P=0.0003) [44].

In a longitudinal observational study of patients maintained on failing protease inhibitor-based regimens for a median period of 26 months, gradual increases in plasma viral load and phenotypic resistance to protease inhibitors were observed, whereas the replication capacity (Phenosense) remained stable and the CD4 count increased gradually [21]. Emergence of compensatory mutations occurred relatively slowly over time and did not lead to a recovery of replication capacity to the levels observed with wild-type virus.

De Luca et al. analysed 139 patients from the Argenta trial with an extended follow-up of 36 months. Patients had experienced a median of two previous highly active antiretroviral therapy (HAART) regimens and received a median of 18 months of HAART [7]. The median baseline replication capacity, as measured by the Phenosense assay, was 59% (see Figure 1) and correlated positively with the number of phenotypically active drugs (r =0.32; P <0.001). Overall, replication capacity did not predict treatment outcome. However, in a subset of 85 patients who remained viraemic (viral load >500 copies/ml at each time point), a higher replication capacity predicted less-profound changes in viral load at 3 months. In 25 patients with a phenotypic susceptibility score (PSS) of 3 for the first salvage regimen (i.e. a first salvage regimen containing three drugs to which the patients' virus was shown to be fully susceptible), a higher replication capacity predicted less pronounced viral load responses at 3 months. In persistently viraemic patients, after adjusting for PSS, a higher baseline replication capacity was an independent predictor of lower gains in CD4 count at months 3, 9, 12 and 24. The conclusion of this work was that, in patients in whom viral suppression cannot be achieved, replication capacity can be a useful tool, after resistance testing, to guide treatment decisions.

Viral fitness and treatment interruption studies

Several studies have exploited the strategy of partial treatment interruptions in patients with virological failure to identify the residual antiviral activity of different components of a regimen. In one study [46], patients interrupting treatment with protease inhibitors and continuing NRTI therapy showed a stable viral load. The pre-existing protease-resistance mutations decreased and replication capacity, as well as viral load, increased only after long-term observation. This means that, in the presence of NRTI drugs, significant antiviral activity persisted that kept viral replication partially under control, selecting for a viral isolate with reduced fitness for a significant period of time. The HIV-1 RNA levels also remained stable in subjects interrupting NNRTI treatment, indicating lack of residual antiviral activity of available NNRTIs after the emergence of resistance, consistent with the lack of a significant impact on viral fitness of common NNRTI-associated resistance mutations. In contrast, all subjects who interrupted NRTI treatment exhibited immediate increases in viral load with loss of NRTI-resistance mutations. Therefore, NRTIs often exert continued antiviral activity in the setting of drug-resistance mutations, and both NRTIs and protease inhibitors can select for drug-resistance mutations that reduce viral fitness [46]. In another study [47], patients with the M184V mutation were randomly assigned to discontinue therapy or continue monotherapy with 3TC (the drug that selects for M184V). At 48 weeks, patients assigned to 3TC continued to carry M184V and had a less pronounced viral load increase and CD4 cell loss compared with those interrupting therapy, who had a concurrent rapid loss of M184V and steeper decrease in CD4 count. Patients in the 3TC arm also maintained other drug-resistance mutations as well as significantly reduced viral fitness as compared to the control arm. This implies that, despite high-level resistance, 3TC continues to exert clinically significant antiviral activity in the presence of virus of lower fitness with M184V and other resistance mutations selected by previous drug treatments.

Although data regarding the clinical utility of fitness measurements are still preliminary, certain consistent findings have emerged from the studies reported to date. In patients failing antiretroviral therapy, as well as in untreated, acutely or chronically infected patients, detection of virus with lower fitness is associated with higher CD4 counts. Lower fitness is also associated with lower viral load during treatment failure. In addition, in patients with virological failure, low viral fitness is associated with stable or increasing CD4 counts, despite increasing viral load. Low viral fitness and stable CD4 counts appear to be maintained over several years of follow-up.

Conclusions

The fitness, or replication capacity, of HIV-1 is an intrinsic viral characteristic that has multiple viral determinants and several virological and clinical correlates. Although reduced viral fitness is typically associated with the emergence of resistance mutations in the targets of antiretroviral therapy, wild-type strains of HIV-1 can also demonstrate reduced fitness. Despite numerous studies, the genotypic correlates of viral fitness remain to be fully characterised. The fitness cost associated with the development of antiretroviral resistance is probably responsible for the sustained immunological benefit that is often observed in patients with failure of HAART and virological breakthrough. Further studies are required to define strategies to exploit optimally these fitness effects of drug resistance in order to at least partially prolong the effect of treatment.

Recommendations for clinical practice

  • Virological suppression remains the primary goal of treatment. This goal should be pursued in all cases, where clinically feasible, by selecting active drugs for salvage therapy using a resistance assay.
  • In multidrug-experienced patients with limited or no drug options available, one management option might be to continue the failing therapy if the virus has low replication capacity/fitness.
  • Patients failing therapy with a virus of high replication capacity/fitness may benefit from treatment change, even if there are few available options, in order to attempt to select for a virus with lower fitness.
  • The Phenosense replication capacity assay is the only assay currently available for clinical practice. Nevertheless, no study has been carried out to show whether using this assay confers more benefit than using surrogate markers of fitness, such as viral load and/or CD4 count, to guide therapy management in clinical practice. Notwithstanding, the fact that the replication capacity assay is able to predict the subsequent viral load and CD4 count, implies that it is an early marker that could be used to anticipate and more favourably drive treatment outcome.
  • In the absence of a viral fitness assay in a patient with a low CD4 count who has failed multidrug treatment, it seems reasonable to select the treatment that, with acceptable tolerability, will contain the highest possible number of active drugs, together with drugs that tend to select for mutations associated with reduced viral fitness.

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