The Effects of Highly Active Antiretroviral Therapy (HAART) in the Clinical Aspects of HIV Infection
It took a few months to realize how the use of existing nucleoside analogues inhibitors of the HIV reverse transcriptase (NRTIs) in combination with the newly released protease inhibitors (PIs) was associated to a spectacular reversal of the otherwise inescapable deterioration of immune competence [29, 30].
To better understand the changes that occurred with the introduction of HAART in those years, we must also consider the importance of the concomitant release of the test for measuring the amount of circulating HIV (plasma HIV- RNA by polymerase chain reaction-PCR) [31, 32].Until that time we were dealing with a poorly active treatment (one or two NRTIs) whose efficacy was rather difficult to establish, since the rise in CD4+ cell count (of scarce extent, if any) took several weeks or months to became apparent and a short time to vanish. In the years preceding the use of HIV-RNA, the measurement of plasma p24 antigen levels, as a surrogate marker of the circulating viral burden, was employed to some extent but it never became part of the routinary analyses in HIV-infected patients, mostly for its limited clinical value [33]. In few months we acquired both much more potent therapeutic weapons and a pharmacodynamic marker more sensitive to treatment effects. Furthen to produce a quicker and more consistent effect on CD4+ cell count, HAART was also found to determine a rapid drop of logarithmic magnitude of the plasma HIV- RNA, which was demonstrable well before any rise in CD4+ cells [34]. The almost contemporary release of these two new instruments made it thus possible to both effectively treat HIV infection and to monitor treatment effects more timely and precisely than before. With the early evidence of HIV- RNA fall as indicator of therapeutic efficacy, with CD4+ cell increase ensuing thereafter, physicians administering HAART to their patients had thus increased confidence in this new treatment modality.
From a more popular perspective, the now fully demonstrable and consistent association taking place between immunovirological and clinical benefit under HAART was the final and definitive answer to those persisting minor rumours against the role of HIV infection in the pathogenesis of AIDS [35]. The importance of relying upon plasma HIV-RNA as early efficacy marker is today emphasized by the common habit of designing short-lasting (10-14 days) phase I therapeutic trials aimed at assessing, as “proof of concept”, the antiretroviral properties of new compounds before proceeding to conventional clinical studies [36].In the years 1995-1997, with minor delays in some western regions, the introduction of combination therapy consisting of two NRTIs and one of the new PIs, determined a dramatic change in the natural course of HIV infection. In less than 2 years, according to the HIV Outpatient Study, mortality in patients with HIV infection dropped from 29.4 per 100-person-years to 8.8 [1]. In Italy the mortality of AIDS patients (determined as the number of yearly AIDS deaths per number of AIDS diagnoses in the same year) dropped from 67.3% in 1995 to 9.0% in 2005 [37]. A decline of similar magnitude was also seen in terms of lower incidence of opportunistic infections like P. jirovecii pneumonia, CMV retinitis and atypical mycobacteriosis, whose overall rate declined from 21.9 per 100-person- years to 3.7 in the period 1995-1997 [1]. The latter findings gave a working confirmation that immune recovery under HAART was not only numerical but also functional, thus leading to regained effective immune surveillance [38]. This was also testified by the spontaneous recovery from some opportunistic infections (without specific chemotherapy) in patients undergoing HAART-associated immune reconstitution, which implies that the sole CD4+ cell increase may be sufficient to get rid of the ongoing active disorder by simply restoring a protective level of immune surveillance [39].
With few exceptions, which are likely to be attributable to some specific clonal deletion in immune reconstitution [40], the number of CD4+ to be restored in order to confer spontaneous protection against opportunistic pathogens was found to be the same as the one established before HAART was available. On this basis, once a patient has undergone a numerical recovery of CD4+ cells known to be sufficient to keep the patient out of a CD4+ defined risk of opportunistic infection, prophylaxis or maintenance therapy against specific opportunistic infections may be safely interrupted [41, 42].A number of cohort studies have subsequently confirmed the unambiguous and sustained survival advantage provided by HAART. In the years following the astonishing debut of HAART in the HIV scenario, the exciting new wave of pharmaceutical research in antiretrovirals made it also possible to find the appropriate answers to a series of problems emerging from the ordinary antiretroviral practice such as resistance to existing drugs, insufficient antiretroviral potency, side effects and adherence, thus substantially keeping the initial promise of a really effective treatment. The effects of HAART in the clinical manifestations of HIV infection also translated into the emergence of new, HIV-unrelated, causes of death in patients with HIV infection [43]. This is to say that concomitant diseases like HCV chronic hepatitis, which were neglected in the pre-HAART era, became a priority in the management of patients with HIV infection. A number of pathophysiological factors well describe the complex pathogenetic interaction of diseases coexisting with HIV, but the single simple fact that HIV-infected patients receiving adequate antiretroviral therapy have many more years to live, clearly implies that these conditions have a longer time to fully develop to clinically significant manifestations.
Today the management of HIV-infected patients has switched from mostly inpatient to mostly outpatient, since the most frequent service to be delivered is that of monitoring efficacy and toxicity of HAART in patients whose average quality of life has greatly improved and who do not require, in most circumstances, to be assisted in the hospital.
A sizeable proportion of patients, however, still require intensive hospitalbased treatment, as treatment failures occur for a variety of reasons: lack of patients’ adherence to treatment, real treatment failures due to resistance to antiretrovirals, symptomatic chronic virus hepatitis, neoplastic diseases and other concurrent infectious and non-infectious conditions requiring close monitoring (e.g. active tuberculosis). In addition to these occurrences, we have also to face the increasingly important issue of the “late presenters” such as patients who present with a major opportunistic disorder without any prior clinical or serologic evidence of HIV infection. These are truly AIDS patients as we were accustomed to seeing in the pre- HAART era, and require the same therapeutic measures we had been applying in those years. Although HAART may be highly efficacious also in these cases, a measurable rate of early mortality is recorded in these patients, mainly due to the nature of the AIDS-defining disorder they present with. In Italy, the proportion of new cases of HIV infection meeting the case definition for AIDS increased from 18% in 1995 to nearly 50% in 2005 [37]. The reason why this has happened has probably some epidemiologic reasons, at least in countries like Italy, where the responsibility of sexual transmission as a risk factor for acquiring HIV infection increased from 27.5% in 1995 to 61.7% in 2005, while parenteral transmission among heroin addicts decreased from 66.7% in 1995 to 30.8% in 2005 [37]. Whereas, in the case of intravenous drug abusers, the outpatient facilities are able to detect HIV infection in earlier stages (as part of the ordinary serologic screening) in the majority of cases, the STD clinics can only screen that minority of the sexually active population who present with some disturbances. Although such a significant switch in HIV epidemiology might only be representative of regions like Italy, France and Spain, the phenomenon of “late presenters” is well present in most western countries. As a consequence, in order to curb this wave of AIDS presenters, efforts should clearly be made in the setting of the screening strategy, since the effectiveness of today’s available HAART might prove to be useless in this not-so sizeable proportion of patients.