Of the 505 patients who experienced an initial response to therapy, 186 (37%) experienced a viral rebound of more than 500 copies/ml over follow-up, a median of 3.8 years after their initial response. Factors independently associated with an increased risk of viral rebound were treatment with a NRTI-based regimen, a diagnosis of TB at the time of AIDS (compared with other AIDS events) and initiation of treatment in or before 1999, whereas those who were initially treated with a protease inhibitor, those who were older and those who started treatment in 2003 or 2004 were less likely to experience viral rebound.
Immunological response to therapy
Overall, median CD4 cell counts increased from 111 cells/μl in the first 3 months of HAART to 157, 190 and 221 cells/μl in months 4–6, 7–9 and 10–12, corresponding to median increases from pretherapy levels of 41, 93, 120 and 147 cells/μl, respectively (Fig. 2). Among those who achieved a viral load of less than 500 copies/ml within the first 6 months after starting HAART and maintained this for at least a year from initial response, the respective CD4 cell count increases were 49, 90, 120 and 148 cells/μl. Of the 567 individuals whose pre-HAART CD4 cell count was less than 200 cells/μl, CD4 cell counts were increased above 200 cells/μl on two consecutive occasions in 331 (58%), a median of 421 (95% CI 374–511) days after starting HAART. The only factors that were independently associated with a more rapid increase in CD4 cell count were a higher pretreatment level (adjusted relative hazard 1.57 per 50 cells/μl higher, 95% CI 1.32–1.86, P = 0.0001) and a higher pretreatment viral load (adjusted relative hazard 1.28 per log10 copies/ml higher, 95% CI 1.02–1.59, P = 0.03).
To our knowledge, this is the largest collaborative study (aside from surveillance studies) of outcomes among individuals diagnosed with HIV at the same time as a clinical AIDS diagnosis. The large size and geographic diversity of participating clinics has allowed us to describe the heterogeneity between these patients, in terms of their demographic characteristics, stage of HIV infection at diagnosis, approaches and subsequent response to treatment. The heterogeneity in patients' characteristics is largely a consequence of the characteristics of the HIV epidemics in different countries but may also reflect local prevention campaigns that have targeted specific groups and differences in the ease of accessing an HIV test in different countries.
The wide variability in the time to initiation of HAART in this group is not surprising given lack of data from randomized studies to support any guidelines for the management. On one hand, there is an urgent need to start antiretroviral treatment as rapidly as possible to prevent the development of subsequent AIDS events in this high-risk group. On the other hand, a short delay in initiation of treatment, to allow clinicians to treat the opportunistic infection and obtain a more accurate assessment of prognosis, may be beneficial. Thus, a balance has to be reached between the immediate clinical benefits of starting HAART, the possibility that concomitant illnesses (particularly gastrointestinal conditions) may limit the effectiveness of HAART or of treatment for opportunistic infections , and the possible detrimental effects of multiple medications (particularly relating to drug–drug interactions and sub-optimal adherence) on the responses to both anti-opportunistic medications and HAART.
Recently, a randomized trial was conducted to compare immediate HAART (given within 14 days of the start of treatment for acute opportunistic infections) with deferred ART (started once any acute opportunistic infections had been treated). Preliminary results showed no significant difference between the strategies for the primary combined clinical/virological endpoint, though by 48 weeks, patients in the immediate arm were less likely to have experienced clinical progression (AIDS or death) and had experienced greater CD4 cell count increases, leading the authors to conclude that consideration should be given to early use of ART in these patients . Further analyses of the timing of HAART and possible implications of this in this patient group are currently underway.
The type of opportunistic infection determined the rate of initiation of HAART in our study – in particular, patients with Kaposi's sarcoma (which may respond positively to HAART alone) tended to start treatment soon after diagnosis , whereas those with TB tended to start treatment later. The latter finding may reflect the real possibility of immune reconstitution disease in those patients starting HAART with untreated TB [12,13] as well as the possible effect of TB itself on the CD4 cell count  and also concerns about overlapping drug side effects. Thus, it is likely that clinicians will prefer to treat TB first before initiating HAART in these patients.
The variation in initial HAART regimens reflects the different clinical presentation of the patients and the absence of guidelines on when and with which antiretroviral regimen such patients should be treated. The choice of nucleoside backbone in these patients reflects not only the availability of these drugs in different years, but also decisions surrounding the penetration of some NRTIs into the central nervous system . There are some data from randomized controlled trials [16,17] that protease inhibitors may have a more potent effect on immune reconstitution than NNRTIs among individuals with low CD4 cell counts even if in the ACTG 5142 study , 35% of patients had less than 100 CD4 cell count at baseline and there is no clear difference regarding immunological reconstitution between the two arms at 48 weeks (efavirenz vs. lopinavir) and among patients with HIV-1 RNA levels of 100 000 copies per ml or more at screening.
On the contrary, the use of a NNRTI as the ‘third’ drug may have been favoured because of a lower pill burden (particularly among individuals receiving treatment for their AIDS event), or because of the reduced chance of drug–drug interactions with TB treatment [19,20].
Although this study was retrospective, the immunological and virological responses to HAART seen in these patients did not differ greatly from those reported in patients with similar CD4 cell counts without a concomitant AIDS event . Indeed, the vast majority of patients in this study (almost 90%) attained a viral load of less than 500 copies/ml and experienced an increase in CD4+ lymphocytes. In line with other studies [3,22], virological response to treatment was improved among patients starting treatment in more recent years, possibly as a result of the use of more potent antiretroviral regimens, greater understanding of drug–drug interactions, improved toxicity management and adherence support, the use of resistance testing and other improvements in clinical care. Information on the treatment for opportunistic infections was not collected, but it is possible that foscarnet, used to treat CMV, may have some direct anti-HIV activity  that may explain why a diagnosis of CMV was associated with virological success. In these patients who already have a high pill burden, the use of triple NRTI regimens with their reduced pill burden and lack of drug–drug interactions may have been favoured. However, our data, as well as that from other studies , suggest that this combination is associated with a higher risk of viral rebound.
Around 19% of patients followed up in the five cohorts who provided follow-up clinical data developed a new opportunistic infection during follow-up. This finding, in line with a previous report , confirms that despite a good response to HAART, these patients do remain at high risk of clinical progression and should be monitored carefully . On the contrary, a limitation of our study is that we did not collect data on immune reconstitution syndrome (IRIS); some of the opportunistic infections seen in this cohort may be a consequence of IRIS or, alternatively, may reflect preexisting infections that were simply unmasked by the use of HAART. Thus, our event rate may be overestimated in the first few months after initiation of HAART.
The importance of early diagnosis of HIV infection is well recognized. In addition to the public health implications for prevention of transmission to sexual partners, early diagnosis allows steps to be taken to prevent the development of opportunistic infections. Furthermore, with current trends favouring earlier treatment , treatment can only be initiated once patients have been diagnosed with HIV. Our study highlights the fact that patients who present for the first time with an AIDS event are likely to remain a clinical problem for the foreseeable future and deaths remain common in this group. Steps to encourage earlier HIV testing among all risk groups and to increase clinician awareness of the possibility of an AIDS diagnosis among individuals who are not perceived to be at risk of HIV infection are required.
C. Mussini takes overall responsibility for the study. J.M.M., C. Manzardo, M.J., A.d'A.M., C.U.-F., A.A., M.J.G., L.S., V.B. and A.L. all contributed to discussions on the design and analysis of the study, identified eligible patients for inclusion, extracted datasets in a common format and commented on initial study results and early article drafts. C.S. performed all statistical analyses. C. Mussini drafted the initial article with input from C.S. and J.M.M.; all authors commented on and approved the final article. A full listing of all contributors to the study is provided below.
Financial support: Partially supported by Istituto Superiore di Sanità, VI Programma Nazionale di ricerca sull'AIDS 2006, Italy, Projects: ‘Eziopatogenesi, studi immunologici e virologici dell'HIV/AIDS’ - Grant: 40G.43 (Mussini), ‘Ricerca clinica e terapia della malattia da HIV’ - Grant 30G.3 (Antinori), by the ‘Fundación Máximo Soriano Jiménez’ (Barcelona, Spain) and the ‘Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (FIS),’ and grant ISCIII-RETIC RD06/006 from the Instituto de Salud Carlos III, Madrid (Spain)(Manzardo, Miro). J.M.M. was a recipient of a Research Grant from the ‘Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)’ and the ‘Conselleria de Salut de la Generalitat de Catalunya, Barcelona (Spain)’.
There are no conflicts of interests.
Late presenters investigators
Clinic of Infectious Diseases, Modena (Italy)
F. Prati, F. Sabbatini, R. Esposito.
Hosp. Clinic of Barcelona (Spain)
F. García, J.L. Blanco, E. Martínez, J. Mallolas, E. de Lazzari and J.M. Gatell.
Royal Free Centre for HIV Medicine, London (UK)
Clinical: S. Bhagani, P. Byrne, A. Carroll, Z. Cuthbertson, A. Dunleavy, A.M. Geretti, B. Heelan, M. Johnson, S. Kinloch-de Loes, M. Lipman, S. Madge, N. Marshall, D. Nair, G. Nebbia, B. Prinz, L. Swaden, M. Tyrer, M. Youle
Data management: C. Chaloner, H. Grabowska, J. Holloway, J. Puradiredja, D. Ransom, R. Tsintas
Biostatistics/Epidemiology: C. Sabin, W. Bannister, L. Bansi, A. Cozzi-Lepri, Z. Fox, E. Harris, T. Hill, F. Lampe, R. Lodwick, A. Mocroft, A. Phillips, J. Reekie, C. Sabin, C. Smith
Laboratory: E. Amoah, C. Booth, G. Clewley, A. Garcia Diaz, B. Gregory, W. Labbett, F. Tahami, M. Thomas
Clinic of Infectious Diseases, Università Vita e Salute, Milan (Italy)
C. Uberti-Foppa, A. Lazzarin, L. Galli, S. Salpietro, A. Castagna.
National Institute for Infectious Diseases ‘L. Spallanzani’, IRCCS, Rome (Italy)
A. Antinori, P. Lorenzini, P. Marconi, M.P. Trotta and M. Zaccarelli.
Department of Infectious Diseases, S.Anna Hospital, Ferrara (Italy)
L. Sighinolfi, R. Roda, F. Ghinelli
Southern Alberta Clinic, Calgary (Canada)
Clinic of Infectious Diseases, San Paolo University Hospital, Milan (Italy)
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
AIDS; AIDS presenters; opportunistic infections; prognosis