Conslusions
In this retrospective multicentric study of PWH on ART (one-third on
first-line therapy and two-thirds ART-experienced), neither PIs use, nor
the type of ART regimen were associated with differential odds of CVE
after accounting for historical drug resistance genotype. Conversely, an
almost 4-fold higher odds of CVE was found in participants with plasma
RAMs in HIV-1 RT gene. In line with this finding, unadjusted CPE scores
did not associate with CVE, while lower HGRT-adjusted CPE scores
associated with increased risk of escape. All these findings were also
confirmed by sensitivity analyses in participants with plasma
suppression.
In anatomical reservoirs where drugs reach low inhibitory quotients,
partially resistant viruses may replicate and favor the selection of
further RAMs, eventually leading to CVE. PIs penetrate the CNS less
effectively than other ARVs classes17–21. Therefore,
RAMs in the RT gene may have exposed patients to functional monotherapy
leading to loss of virological control in CNS. In our study, CPE values
were similar between participants with and without CVE, suggesting that
unadjusted values alone may not discriminate those at risk. However,
after RAMs were factored into CPE values, median adjusted CPE scores in
CSF were lower in participants with CVE, suggesting that accumulation of
RAMs combined with the reduced penetration of ARVs within CNS may lead
to local ineffective viral control. These results are not in
contradiction with previous larger and longitudinal cohorts reporting
association between PI use and CVE, but may be complimentary to the
previous lack of genotype resistance
assessment12,14,15,29. Indeed, when GRT was available,
CVE has been associated with HIV-1 mutant viruses harboring M184 along
with other major RAMs that conferred resistance to at least one ARV
composing ART at the time of CVE development12.
PIs use was not associated with CVE. Compared to countries where PIs use
has been repeatedly associated with CVE, in Europe PIs have been more
commonly used as third companion drug also in first-line ART regimens,
and therefore larger proportion of ART-naïve patients starting on PIs
and individuals proactively switching to PI-based regimen have been
enrolled in our study population. This could explain why no strong
association between PIs use and CVE has been observed in our sample
compared to setting where PIs were reserved to patients with virological
failure12,14,15. Indeed, in patients treated with
NNRTIs plus non-active companion drugs or with dolutegravir monotherapy,
systemic virological failure has been quickly
reported31, while in patients on PI-based functional
or actual monotherapy, low-level HIV replication in the CSF may occur
despite peripheral viral suppression potentially leading to more
frequent detections of CVE32–35.
To the best of our knowledge, this study describes the largest sample of
data on genotype resistance testing in reverse transcriptase and
protease genes linked to the risk of CVE. It is also the largest dataset
that assessed factors associated with primary CVE in a clinical setting
that adhered to European guidelines for the treatment of HIV infection
during the last two decades. While many ART regimens included in this
study can be considered currently dismissed by several countries, they
are still first-line regimens in many resource-limited countries. Our
data should also be useful as framework to understand CVE risk in newer
ARVs combinations presenting low CNS penetration as well as to evaluate
the efficacy of dual regimens in hard-to-reach compartments. Dual
regimens per se may be safe and effective in controlling CNS HIV
infection36, but require proper combinations
accounting for virus and patients characteristics, that include
historical genotype. Furthermore, while it could be debatable any ART
change in CVE cases with no RAMs, we observed that most CVE cases
occurred in the presence of RAMs affecting at least one of the
antiretrovirals composing the current ART regimen; this finding should
prompt to an intensification or change of the current ART regimen
regardless of concomitant neurological signs or symptoms and of
alterations in CSF analysis or in brain imaging. Based on these
findings, a prompt reassessment of the HGRT and of potentially newly
selected RAMs in both plasma and CSF seems also highly recommended in
any case of symptomatic or asymptomatic CVE. The lack of a longitudinal
design indeed does not allow us to evaluate how many of the asymptomatic
cases can evolve into symptomatic CVE with no change in the ART regimen.
This study has several limitations, including the retrospective design,
the long period of inclusion potentially introducing heterogeneity of
regimens and clinical management, potential selection bias due to 16.7%
of participants undergoing LP for research purposes, and the lack of a
complete GRT assessment in CSF. The lack of data on timing of infection
limited the possibility to confirm this variable as relevant for CVE and
may explain why other time variables such as age or ART duration were
found linked with escape. The lack of an assessment of participants ART
adherence may limit the causality hypothesis; individuals with poor
adherence could experience more episodes of virological failures leading
to RAMs and thereby the association between CVE and RT mutations could
be mediated by the lack of adherence rather than the mutations
themselves. Nevertheless, our findings were confirmed in sensitivity
analyses restricted to participants with plasma suppression, where
adherence should be deemed of substantial degree to reach such plasma
control. Lastly, we could not exclude that some CVE cases were secondary
to rare infections or inflammatory processes that were not routinely
detected. In this regard, tailored studies are warranted to better
identifying other mechanisms underlying the rarer cases of CVE
(<10%) occurring in the absence of RAMs.
In conclusion, CVE was not associated with PIs use nor with any other
type of ART regimen or ARV class. Viruses harboring mutations may favor
CVE and the impact of single drug classes such as PIs may lose
significance when adjusted for the presence and effect of specific RAMs
as most CVE cases were explained by functional dual or mono-therapies
due to the presence of archived RAMs in the RT gene.