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Geretti AM, editor. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006.
Andrea De Luca.
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].
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.
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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.
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].
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Compensatory mutations
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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.
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].
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,
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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.
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.
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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.
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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Figures
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 [6,7].
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Tables
ddI, didanosine; IAS-USA, International AIDS Society-USA; NRTI, nucleoside reverse transcriptase inhibitor; TAM, thymidine analogue
mutation; WT, wild-type; ZDV, zidovudine; >>, much greater than.
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Fitness
NNRTI- compared
resistance with wild- Fitness compared with Presence
mutations type other mutants Type of evidence and technique of drugs Reference
L100I > WT In vitro, growth competition No [66]
K103N 100% In vitro, growth competition; in vivo, No [16,23,67,
treatment interruption (persistence) 68]
V106A WT> (approx K103N, Y181C, G190A In vitro, growth competition and No [68–71]
15%) and Y188C>; =G190A (in single-replication cycle assay
other example)
Y181C WT = or > > G190A, Y188C; V106A; In vitro, growth competition; in vivo, Both [23,68,
K103N> worse CD4 recovery; persistence after 71,72]
treatment interruption
Y181I = WT In vitro, single-replication cycle assay; No [23,70]
persistence after treatment
interruption
Y188L/H = WT In vitro, single-replication cycle assay No [70]
Y188C WT = or > K103N, Y181C, G190A, In vitro, growth competition and No [68,70]
V106A/Y181C> single replication cycle assay
G190A 83% K103N, Y181C> and In vitro, growth competition; in vivo: No [23,68,71,
>Y188C persistence after treatment 73]
interruption
G190S 21% In vitro, growth competition No [73]
P225H 100% In vitro, single-replication cycle assay No [70]
M230L WT> In vitro, single-replication cycle assay No [70]
P236L 35% K103N> Ex vivo, growth competition; single- No [70,74]
replication cycle assay
IAS-USA, International AIDS Society-USA; NNRTI, non-nucleoside reverse transcriptase inhibitor; WT, wild-type; >>, much greater than.
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Table 3 Influence of drug resistance-associated mutations in the protease and gp41 coding regions
(IAS-USA 2005 list) on viral fitness measures
Fitness
compared Fitness compared with other
with wild- mutants: compensatory effect of Presence
type other mutations Type of evidence and technique of drugs Reference
Mutations in protease
I84V WT> or ~90% L10I partially compensates In vitro, growth competition and No [66,75,76]
replication kinetics; in vivo,
treatment interruption
V82A WT>; 79% L10I partially compensates In vitro, processivity; in vivo, No [75,76]
treatment interruption
V82F = WT = L63P, A71V, I84V In vitro, replication kinetics No [77]
V82T WT>> M46I, L63P>> In vitro, growth competition No [17,31]
L90M WT>> L10I and 63P compensatory In vitro and ex vivo, replication No [13,75]
kinetics; ex vivo single-replication
cycle assay
I50V WT>> In vitro, single-replication cycle No [19,78]
assay
N88S WT> L63P and V77I partially In vitro, growth competition No [9]
compensatory
N88D ~90% In vivo, treatment interruption No [76]
D30N 88% or WT>> L90M>> In vivo, treatment interruption; in No [13,76]
vitro replication kinetics
V32I = WT I84V/A further reduced fitness In vitro, growth competition, No [79]
protease catalytic activity
M46I 79% In vivo, treatment interruption No [76]
or L
I54V ~90% In vivo, treatment interruption No [76]
G73S ~90% In vivo, treatment interruption No [76]
L10F WT> In vitro, growth competition or No [19,80]
replication kinetics
G48V WT>> > L90M In vitro, protease activity No [81]
Mutations in the gp41 env
G36D WT > With V38M In vitro, growth competition No [82]
or S
V38M WT > In vitro, growth competition No [82]
N42T WT > In vitro, growth competition No [82]
IAS-USA, International AIDS Society-USA; WT, wild-type; >>, much greater than.
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