Editorial :
In 90 s
the introduction of antiretroviral therapy for HIV treatment changed gradually
HIV infection in a chronic disease. The consolidated use of highly active antiretroviral
treatment (HAART)substantially affect HIV RNA plasma viremia levels, leading
circulating virus below the current analytical cut off limits, and, in the major
part of cases, to CD4+ T cells recovery. However, it is not ableto eliminate
HIV- 1, which persists as a latent infection in anatomical and functional
reservoirs, such as resting memory CD4+ T cells [1]. Moreover, HAART is unable
to reduce or clock the persistent immune dysfunction, inflammation and
coagulation abnormalities, which are commonly observed in HAART-treated
patients and that are strongly predictors of risk for non-AIDS morbidity and
mortality [2, 3]. In the last years the cases such as the “Berlin
patient” [4,5] and the “Mississipi Baby” [6] revived hopes for a cure against
HIV both in researchers and patients, opening novel challenges both for the
identification new interventions for virus eradication as well as the
epistemological approach for designing and evaluating the efficacy of such
interventions. These cases, although not conclusive, have revived the interest
of researchers and scientific word to rethink the fight against HIV with a new
point of view: a cure may be possible. In the
absence of an effective vaccine or other preventive therapy, the research against
HIV/AIDS is moving now to looking for therapeutic interventions capable to generate
a cure for
HIV both eliminating the chronic symptoms and co-morbidities in infection
without eliminate the virus (functional
cure), and both eradicating virus from host
with or without effective HAART (structural or sterilizing cure) [7]. In the
current guidelines for clinical development of new HIV antiviral drugs, early studies,
including short period of functional mono therapy followed by optimization of
the treatment in treatment naïve subjects and confirmatory head-to-head studies (by “add-on”
or “substitution” design) aimed at comparing the investigational product to the
standard cART with direct antiviral properties [GUIDELINE ON THE CLINICAL
DEVELOPMENT OF MEDICINAL PRODUCTS FORTHE TREATMENT OF HIV INFECTION Doc. Ref.
EMEA/CPMP/ EWP/633/02Revision 2, 2009] are foreseen. New drug efficacy is
evaluated using generally accepted surrogate markers such as HIV RNA viral load
and CD4+ T-cell counts [GUIDELINE ON THE CLINICAL DEVELOPMENT OF MEDICINAL PRODUCTS
FORTHE TREATMENT OF HIV INFECTION Doc. Ref. EMEA/ CPMP/EWP/633/02Revision 2,
2009]. The comparison with the standard antiviral therapy is performed
measuring the capability of reducing HIV plasma viremia up to levels the limit
of quantification of the validated RT PCR test and containing the immunological
deplation measured by CD4+ T lymphocytes decay. Although relevant parameters
for the monitoring of cART efficacy, the use of these outcomes in studies aimed
at individuating benefits of treatment optimization and/or eradication with concomitant
cART appears quite limited. In the
development of new therapeutics for functional or sterilizing cure of HIV, the
identification and validation of novel efficacy biomarkers represent a major scientific
and regulatory need. In the absence of robust surrogate markers, clinical studies
of novel therapeutic agents having as objective HIV eradication (therapeutic immunizations
or drugs) should directly demonstrate their effects on the persistence of virus
not only in its circulating form in infected cells. The lonely detection of HIV
RNA plasma viremia, which in effective cART quickly goes to levels below the
limit of detection of assays currently in use, may not provide information on
the persistence of viral reservoir and the interruption of antiretroviral
therapy backbone, is not advisable at the current state of knowledge [8- 10].
In addition, the same cART backbone could be also essential, acting in synergy
with the novel tested treatment. Is the scientific word really ready for this
new challenge? Which parameters may directly or not detect the persistence of
HIV or HIV-unrelated morbidities? Detection of HIV gene/protein expression or
ultra-sensitive HIV RNA plasma viremiais unable to reveal latent virus as well
as immunological responses may persist years after virus exposition. Evaluation
of blood HIV proviral DNA may represent a good solution, because of its role as
a prognostic factor for therapy efficacy is known [11] and since it is already methodologically
accepted as parameter for diagnosis of HIV in infants, where common assays for
HIV (ELISA and a confirmatory WB, if appropriate) cannot be used due to the
presence of persisting maternal HIV antibody against HIV proteins in the child
up to 15- 18 months of age [12]. A
consensus for the evaluation of the efficacy of a functional cure may be also
generated on the basis of available data on the major non-AIDS co-morbidities
(such as cardio-vascular diseases, malignancies, or accelerated aging) observed
also in successfully HAART-treated patients [2,13]. Epidemiological data of the
same pathologies in HIV-uninfected subjects and the common use in medical
practice of prognostic risk factors may be of help to both meliorate the
management of HIV patient and to evaluate potential new interventions affecting
these co-morbidities [14]. A not trivial question is demanded to HIV
researchers, but “guttacavatlapidem” (Lucrezio)…. 1. Deeks
SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS
related morbidity (2009) BMJ 338: a3172. Pathology, Antiretroviral therapy, HIV Transmission, CD4 countReady for New HIV Challenges in Post-ART Era?
Full-Text
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