The Natural History of HIV Infection

In the years following the time when specif­ic diagnostic molecular assays became avail­able (HIV serology by means of ELISA and Western-Blot techniques), we eventually recognized the rather atypical clinical evo­lution of HIV infection.

Well before HIV was identified as the causative agent of AIDS, a clear-cut correla­tion was established between the downgrad­ing tendency of immune surveillance and the increasingly severe clinical manifesta­tions leading eventually to death [2]. It is worth noting that 26 years after the first five AIDS patients were described as indi­viduals developing unusual opportunistic infections and neoplasms in association to extremely low numbers of circulating CD4+ T-lymphocytes, no immunological markers better than CD4+ cells have been identified as indicator of immune status in patients with HIV infection [3]. Although exceptions are not so uncommon, the relationship between the CD4+ cell count and the likeli­hood of developing specific opportunistic diseases is still the best clinical rule for cli­nicians to rely upon in the diagnostic workup of patients with HIV infection. There are no other human diseases in which the relationship between an immunological marker and a given clinical condition is so coherent. Although the distinction between HIV infection (defined by a positive HIV serology) and AIDS (defined by a positive serology in association with some major associated disorders) is still made on a clin­ical ground, reliance on the number of circu­lating CD4+ cells is pivotal in the process of choosing diagnostic procedures and taking therapeutic decisions [4].

Based on these two markers (serology and CD4+ count), a more than approximate description of the natural history of HIV infection can be easily plotted on a graph, with the time elapsing since infection on the x axis and the absolute number of CD4+ T-lymphocytes∕μl on the y axis (Fig. 1). In the 2nd half of the 90s, a molecular marker representing the plasma concentration of HIV-specific nucleic acids became available (HIV-RNA), which made it possible to quan­tify the presence of HIV in the blood and to successfully relate it to clinical and immune disease progression [5].

In clinical terms, the manifestations of HIV infection can be classified in four sequential phases. In the days following infection, an acute inflammatory syndrome may take place with a rather wide variety of signs and symptoms [6]. In more than 50% of symptomatic cases, fever, pharyngitis (“mononucleosis-like syndrome”), systemic adenopathy, cutaneous rash and diffuse musculoskeletal pain are usually present, but less common disease forms are also described, with involvement of the central nervous system [7]. Acute retroviral syn­drome tends to subside in a few days to sev­eral weeks; and, depending on a variety of circumstantial factors (clinical presenta­tion, physician’s experience), it may actual­ly be recognized or simply interpreted as a common flu-like disease. Today it is common practice to rely upon plasma HIV-RNA assays when serology is still negative and the clinical picture suggests the possibility of acute retroviral syndrome. While anti­HIV antibodies may take up to several months to become detectable, the molecu­lar evidence of HIV infection in the plasma well anticipates seroconversion, thus allow­ing the diagnosis of newly acquired HIV infection in the absence of detectable anti­HIV antibodies [8]. It must be recognized, however, that it is not easy to estimate the rate of newly acquired HIV infection cases producing acute symptomatic disease, and the proportion of newly diagnosed infec­tions presenting with an acute inflammato­ry disease form is rather low.

Fig.

After primary infection (which may thus pass unnoticed in a substantial proportion of cases) a prolonged asymptomatic phase follows, which usually lasts several years

[9]. With progression of immune decline, an early symptomatic phase may be recog­nized, with some minor clinical manifesta­tions like pharyngeal candidiasis, systemic lymphadenopathy, seborrhoeic dermatitis

[10]. When immune deterioration gets below the threshold of 200 CD4+ T-lympho- cytes∕μl, the patient enters in the phase of highest vulnerability to opportunistic disor­ders, as the risk of developing overtly symp­tomatic opportunistic disorders increases in inverse relationship with decreasing CD4+ T-lymphocytes [11]. The clinical phase cor­responding to a CD4+ cell count 10% of normal body weight), chronic fatigue and fever [16-18].

A particularly relevant position in the spectrum of the HIV-associated opportunis­tic infection is that of tuberculosis (TB). Active TB may develop in any human being regardless of the presence of specific immunosuppressant conditions, but as is the case with other predisposing factors, in the case of HIV infection, the risk increases sev­eral fold as compared to the general popula­tion [19]. In patients with HIV infection, the risk of developing active TB increases when the individual immune surveillance declines and such increased individual vul­nerability has been demonstrated both in the case of reactivation of a pre-existing (latent) infection as well as in case of de novo exposure [20, 21]. Further to play the role of the most powerful factor predispos­ing to active TB, HIV infection was also found to alter the clinical presentation of the disease [22]. In a sizeable proportion of patients with low values of circulating CD4+ cells (have described a rather steady immunological condition up to 20 years since HIV was acquired [25, 26].

In the years preceding the release of effective antiretroviral regimens, the only therapeutic measures available to counter­act the effects of the downgrading tendency of immune surveillance were drugs specifi­cally active against opportunistic patho­gens. Further to be used in the treatment of specific opportunistic infections, these drugs were also administered as prophylac­tic agents both for primary (e.g. for prevent­ing P. jirovecii pneumonia in patients with less than 200 CD4+ T-lymphocytes/ö²) or sec­ondary prophylaxis (following the treat­ment of the first episode of opportunistic infection) of otherwise frequently occurring opportunistic infectious processes [27]. Although neither treatment or prophylaxis were able to reverse the tendency to lose immune competence over time, the life expectancy of HIV-infected patients who were carefully monitored on this basis was significantly increased in the years before HAART became available [15]. It is unclear to what extent the release of the first anti­retroviral drugs contributed to this pre- HAART improvement in the life expectancy of AIDS patients. The use of azidothimidine (AZT) alone was found to delay the onset of AIDS, but no advantages were seen in terms of life duration [28].