Although guidelines for the diagnosis and treatment of HIV-1 infection recommend starting therapy when number of CD4+ T cells is < 500-350/μL [16, 17], it is not uncommon in clinical settings to observe a later initiation of HAART in patients who present with advanced HIV-1 disease. The proportion of "late presenters/AIDS presenters" in our series of new HIV-1 diagnoses (28.7%) is fully consistent with the data from the large Italian cohort of antiretroviral-naive patients (Icona), where 29% of 968 patients enrolled between 1997 and 2000 were first tested for anti-HIV-1 antibodies after the onset of an AIDS-defining condition and/or with a number of CD4+ T lymphocytes < 200/μL. In our group of advanced naive patients, median age was 44 years (with 74% younger than 50 years at diagnosis), slightly lower compared to other studies . The route of transmission distribution, characterized by about 70% of heterosexual contacts, is consistent with recent literature data and with the recent trends in the epidemic, increasingly affecting heterosexuals . These findings may also be related to a different risk perception in different groups, with MSM and injecting drug users probably more likely to be aware of the risk and carry out more frequent testing. Finally, the predominant acquisition of HIV-1 infection by unprotected sexual intercourses may explain the low number of patients with hepatitis virus coinfections in our series of recent diagnoses. With regard to nationality, the vast majority of late presenter patients were of Italian nationality (81%). This represents a difference with other reports, that have indicated an association of the "advanced naive" status with foreign nationality, social marginalization, and limited access to clinical investigations [4–8]. Summarizing our findings, the patient defined as "advanced naive" in our context is mainly a person below 50 years, of Italian nationality, who acquired the infection through heterosexual intercourses.
Considering the combined immunovirological outcome, observed response rate in our series was 65%, with a low mortality (3%) during follow up. Although the proportion of responder subjects may appear slightly lower compared to other studies performed in naive patients [26, 27], it is important to note that we considered as responders only those individuals who reached both an undetectable viral load (HIV-1 RNA level < 50 copies/mL) and a CD4+ T cell count above 200/μL after one year of HAART. This strict definition, together with the immunological characteristics of our population and the antiretroviral combinations used, may explain the differences in response rate observed when compared with other studies.
As previously reported, an important goal of the present analysis was to identify predictors of immunovirological success. This outcome was not associated with age, nationality, route of transmission, clinical stage of HIV-1 disease, and HIV-1 viral load at baseline. Conversely, CD4+ T cell count at entry represented a significant predictor: patients starting HAART with CD4+ T cells > 100/μL had a 3 times higher probability to reach an immunovirological response at 12 months. This is consistent with other data showing that starting HAART in a poor immune condition is associated with a delayed, and sometimes partial, immune recovery and suggests that a discordant response to HAART (defined by the immunological non-responder condition) may be more frequent in patients starting therapy with a more severe degree of immune deterioration .
Regarding type of first-line treatment, in terms of treatment response our data showed that PI-based regimens were not superior to those based on efavirenz. These data are consistent with the recent ACTG 5142 study, that showed among treatment-naive patients no significant difference in immune recovery after 48 weeks between lopinavir/ritonavir and efavirenz as initial therapy , and with other studies in patients with CD4+ T lymphocytes < 100/μL, all demonstrating that efavirenz-induced immune reconstitution was not inferior to that induced by boosted PIs [21, 23, 24]. In our study the two treatment approaches also displayed similar virological suppression, with no statistically significant differences in the average reduction of plasma viral load after 12 months of treatment. However, the third drug chosen for first-line therapy was an important determinant for the switch to a second-line treatment: 67% of patients receiving a PI-based therapy changed their treatment, compared to 25% alone of patients receiving an efavirenz-based first-line, with a four-fold higher risk of switching for PI-based compared to efavirenz-based regimens. It is important to note that switch took place in more than half of the cases (57%) with the aim to simplify treatment. In fact, PI-based regimens could be more cumbersome to follow, due to a higher number of pills and to dietary restrictions linked to drug assumption. It is therefore likely that such regimens were more frequently changed because of patient request and in order to avoid compromising adherence and therapeutic effectiveness. Our data also suggest that older age might be associated with a higher risk of changing first-line treatment. Even if we were unable to assess the reasons underlying this association, the increased occurrence of comorbidities and concomitant treatments in older patients might facilitate a change of treatment in order to maintain adherence to complex therapeutic schedules and prevent undesired adverse events.
An important point emerged from our study is represented by the differences in immune recovery after one year of therapy in subjects with different routes of transmission. In particular, the 12 month CD4+ T cell recovery seems to be significantly higher in MSM than in heterosexuals. We evaluated potential confounding factors, such as age or AIDS diagnosis, without detecting significant differences. It could be hypothesized that the two groups differ in terms of adherence to the therapeutic prescriptions. It could be particularly relevant to explore this issue promoting studies on adherence to antiretroviral therapy in late presenters, in order to evaluate this hypothesis and simplify as much as possible the treatment in patients identified as less compliant with drug prescriptions. Selecting a regimen that ensures maximum adherence to get as soon as possible an adequate immune recovery is particularly important in these advanced patients, who may have more compromised clinical and/or immunological conditions.
Our study has some limitations: a limited sample size, that may have reduced the power to detect differences between groups, a non-randomized assignation of treatment, and the lack of adherence measurements. The findings related to treatment should therefore be taken cautiously. Moreover, we cannot extend the validity of these observations to other NNRTIs, such as nevirapine and etravirine. Nonetheless, our data suggest that based on a background of similar immunovirological response, efavirenz-based regimens could have an advantage over PI-based regimens because of their simpler administration characteristics, that might promote better adherence in a sustainable long-term approach. Finally, in terms of possible therapeutic choices, it is important to consider in these particular patients the potential use of other recently available treatment options [27, 29] represented by new classes of antiretroviral drugs (i.e., integrase inhibitors and CCR5 inhibitors) or new NNRTIs (i.e., rilpivirine), characterized by particularly favourable dynamics of viral load reductions and CD4+ T cell recovery, and probably accompanied by less marked metabolic effects.