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Baseline HIV RNA and the when to start question: time to stop asking this question?
[EPIDEMIOLOGY AND SOCIAL: EDITORIAL COMMENT]

Mussini, Cristina

From the Clinic of Infectious Diseases, Azienda Policlinico and University of Modena and Reggio Emilia, Modena, Italy.
Received 31 January, 2006
Revised 14 March, 2006
Accepted 21 March, 2006
Correspondence to Dr. C. Mussini, Clinic of Infectious and Tropical Diseases, Azienda Policlinico, Via del Pozzo, 71, 41100 Modena, Italy. E-mail: crimuss@unimo.it

HIV specialists represent a rare example of clinicians who believe in medical miracles. For those who started working in this field in the mid-1980s, the introduction of HAART provided evidence that a patient's prognosis could be changed in a single day [1]. Yet, even 10 years after this dramatic change to the management of patients, we are still trying to decide the optimum use of these drugs. As clinicians, we tend to view most of our present concerns, including the side-effects of therapy (even the most serious ones) and the ‘when to start’ question, as mere details that have to be addressed when fine-tuning an individual's therapy. Certainly, these are minor issues compared with the dramatic reduction in mortality that we have seen since the introduction of HAART [2]. However, as most patients no longer live in fear of imminent death (as they would have done in the pre-HAART era), these minor issues often represent major hurdles that they must deal with on a daily basis. The direct correlation between antiretroviral exposure and the onset of major side-effects such as lipodystrophy or cardiovascular disease [3–5] means that ‘when to start’ remains a key question in the management of patients with HIV infection. As yet, no randomized clinical trials have addressed this question and, therefore, the optimal time to start HAART remains uncertain.

Guidelines for starting therapy have changed over the years following the publication of a series of key articles. Initially after the introduction of HAART and the discovery of HIV RNA [6], hopes were raised that HIV might be eradicated within only a few years of starting therapy [7]. With this in mind, it was suggested that antiretroviral therapy should be started as soon as possible after infection [8]. However, increasing awareness of associated side-effects and the difficulties of maintaining the high levels of adherence required to ensure a good long-term outcome raised some doubts about this aggressive approach [9]. Consequently, more recent guidelines have taken a more conservative approach, and it is now recommended that HAART is initiated once the CD4 cell count has fallen to much lower levels [10]. The role of an individual's HIV RNA level when determining their prognosis is still under debate. Cohort studies conducted in the pre-HAART era demonstrated that the HIV RNA level provided prognostic information that was independent of that provided by the CD4 cell count [6,11]. These results were confirmed by several studies, in the HAART era in which baseline plasma HIV RNA levels >= 100 000 copies/ml were independently associated with higher rates of mortality after the initiation of HAART [12,13]. Therefore, despite the fact that most recent international guidelines have become more conservative regarding the CD4 cell count at which HAART should be initiated, there is still a justification for those clinicians who would like to incorporate information on the HIV RNA level when making treatment decisions [10].

In the present issue of AIDS, Wood et al. have contributed to this question [14]. They conducted a study in the HOMER cohort to evaluate the impact of baseline plasma HIV RNA on survival considering only patients naive for antiretroviral drugs at starting HAART with CD4 cell counts >= 200 cells/µl. Patients were again stratified according to their adherence, and a statistical association between plasma HIV RNA >= 100 000 copies/ml and elevated mortality was found only in non-adherent patients. The authors concluded that their findings are not surprising since it is well known that the effect of antiretroviral drugs on HIV natural history is evident only in those who are able to adhere to them. Nevertheless, the message from this study is important. Clinicians should not be scared by elevated HIV RNA values since their detrimental effect on patients' prognosis could be outweighed as long as HAART regimens are correctly taken [15]. This is reflected in the high levels of virological response seen in those presenting with AIDS [16]. Moreover, the HOMER study includes patients who started therapy from 1996 onwards. Since this date, the efficacy of antiretroviral therapy has improved and most antiretroviral drugs currently in use are so potent and convenient to take that adherence and so prognosis could be improved. A possible limitation of the clinical value of these findings is that it requires clinicians to be able to make an accurate assessment of a patient's likely adherence on therapy. Indeed, published studies have shown that clinicians' preconceptions about patient adherence are likely to be incorrect [17], and that they should not use this information when making their decision about when to start therapy. The consequence of this uncorrected perception is that patients more than guidelines should be the centre of our prescription. Indeed, antiretroviral therapy should be started when the patient is ready to take it correctly and it should be tailored on to the patient's lifestyle to improve, at least in theory, adherence. Continuous efforts should be made to motivate patients to stick rigidly to the medication regimen, in order to avoid the emergence of resistance and clinical progression. At present, since adherence to treatment is the most important prognostic factor and it is difficult to maintain for long periods of time, there is no reason why patients with high HIV RNA should be proposed treatment in presence of a CD4 lymphocyte count higher than that recommended by international guidelines: 250–350 cells/µl.

Acknowledgements

Professor Andrea Cossarizza (University of Modena and Reggio Emilia, Italy) kindly contributed critical discussions.

Sponsorship: This work was partially supported by Istituto Superiore di Sanità, Rome (Italy), Progetto Patologia, Clinica e Terapia dell'AIDS (grant 30D.56 to C. Mussini).

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