Opportunistic
parasite infections (OPIs) are an important cause of morbidity and mortality in persons infected with HIV. In industrialised countries, the use of
Highly Active AntiRetroviral Therapy (
HAART) results to be effective in suppressing the HIV viral load, with a quantitative and qualitative improvement in the CD4+ T-cell count followed by a strong reduction of
opportunistic infections including those caused by parasites. These successes have been mainly attributed to the reconstitution of the cell immunity, which play the most important role in controlling OPIs. However, there are many clinical reports and several laboratory results, which suggest that the control of OPIs in HIV-positive persons under
HAART is also induced by the anti-
HIV protease inhibitors (PIs), which inhibit the
aspartyl proteases of the parasites. The non-conventional use of HIV-PIs seems to be an alternative way for the treatment of
parasitic infections, which should be deeply investigated. Of five longitudinal studies carried out before and after the introduction of
HAART, four studies showed a strong reduction of toxoplasmic
encephalitis (TE) in HIV-positive persons under
HAART, whereas in another study, no difference was observed in the incidence rate of TE before and after the introduction of
HAART. The influence of
HAART in reducing TE has been also confirmed in a randomised, controlled clinical trial, which showed that there is no increase in the risk of developing TE after beginning
HAART, even though HIV-infected persons with TE had a discontinuing prophylaxis for Toxoplasma gondii. Four
HIV protease inhibitors were tested against the T. gondii virulent RH strain in vitro, alone or in association with
pyrimethamine or
sulfadiazine.
Ritonavir and
nelfinavir were highly inhibitory for the parasite growth. Furthermore, none of the
antiviral drugs negatively affected the anti-Toxoplasma activity of
pyrimethamine or
sulfadiazine. In HIV-Leishmania
co-infections, a changing pattern has been observed in the
HAART era, characterised by a high rate of relapses, which could be explained by the increased survival rate resulting from the effective antiretroviral
therapy. A 64.8% decrease of the
visceral leishmaniasis incidence was detected after
HAART began to be used extensively in Spain. In a large cohort study carried out in ten European countries and in Australia, the relative risk to contract
cryptosporidiosis as the
first AIDS defining disease was reduced by 96% in the
HAART era. In Italy, the relative risk of death for
cryptosporidiosis reduced of 74% in the period 1997-98, when HIV-positive persons received
HAART. In a large study carried out in Italy,
isosporiasis was included in the group of
opportunistic infections, of which the relative hazards showed a reduction of 95% in the
HAART era. Since 1997, there was the evidence that the use of
HAART in persons with advanced
HIV infection can improve chronic diarrhoea and lead to disappearance of Enterocytozoon bieneusi from the stools. Although the reconstitution of the cellular immunity seems to be the main factor influencing the reduction of OPIs in persons with
AIDS who undergo
HAART, there are clinical and microbiological evidences, as well as in vitro and in vivo results, which indicate direct effects of HIV-PIs on the
proteases of opportunistic parasites. These findings stress the existence of non-conventional unexpected benefits of PIs in
HAART against protozoa. In addition, this benefit of PIs has been demonstrated also for Candida albicans
secreted aspartyl proteases and for P. carinii
acid proteases. In spite of these important results, HIV PIs are still very toxic for humans, specially in cases of very long treatment, and no clinical trial has been carried out for persons at risk, such as children and pregnant women, because the priority was to reduce the severity of HIV and not the evaluation of possible side effects of the
therapy. It follows that further researches are needed to establish the non-conventional use of HIV PIs. Furthermore, the study of PIs against specific
aspartyl proteases of those opportunistic protozoa that cause severe and intractable diseases, could be considered an alternative way towards the development of new drugs that may prove effective against these
infections.