At the beginning of the HAART era, optimism about the effectiveness of prevention campaigns and the efficacy of the new drugs meant that many believed that clinical AIDS events would cease to occur. Unfortunately, this scenario did not materialize and even now, after more than 10 years of successful HAART , many patients infected with HIV present with an AIDS diagnosis each year; a substantial proportion of these events are among those newly diagnosed with HIV [2–7]. Late presentation with AIDS may be a consequence of denial or ignorance of HIV risk exposure [7,8]. These patients often present a real challenge due to their advanced clinical status and the psychological implications of dealing with an HIV and AIDS diagnosis at the same time. Unfortunately, little is known about the clinical presentation of these patients, their prognosis or responses to antiretroviral treatment [3,4]. In an attempt to answer some of these questions, we pooled information from eight clinical cohorts in four countries on patients who presented with a clinical AIDS event at the time of HIV diagnosis.
Patients and methods
We pooled data on patients newly diagnosed with HIV presenting with a clinical AIDS event from 1997–2004 from the following cohorts: Clinic of Infectious Diseases Modena, Italy; Department of Infectious Diseases, Ferrara, Italy; Clinic of Infectious Diseases, Milan, Italy; Infectious Disease Department, San Raffaele Hospital, Milan (HSR), Italy; INMI Spallanzani, Rome, Italy; Infectious Diseases Service, Hospital Clinic – IDIBAPS. University of Barcelona, Barcelona, Spain; the Ian Charleson Centre, Royal Free Hospital, London, UK; Southern Alberta Clinic Calgary, Canada. Eligible patients from each cohort were those who had an AIDS diagnosis [defined using the Centers for Disease Control and Prevention (CDC) criteria ] from 30 days prior to until 14 days after their first positive HIV test. All AIDS events occurring during this period were considered to be events that occurred ‘at the time of diagnosis’; any AIDS event that occurred more than 14 days after HIV diagnosis was considered to be a ‘subsequent’ event.
Datasets were requested in a common format and included information on patient's demographics (date of birth, sex and risk group), clinical events (dates and type of all AIDS events, date of death and date of HIV diagnosis), laboratory measurements at diagnosis and over follow-up (CD4 cell counts and percentages, CD8 cell counts and percentages, HIV RNA levels and haemoglobin) and information on antiretroviral use (dates of starting and stopping all antiretroviral drugs).
We considered the time from HIV diagnosis to initiation of antiretroviral treatment using standard survival methods. For those not starting treatment, follow-up was censored at death or on the date of last clinic visit. Factors associated with earlier or later initiation of antiretroviral treatment were identified using multivariable Cox regression analyses using a backward selection procedure (PROC PHREG, SAS version 9.1; SAS Institute Inc., Cary, North Carolina, USA). Factors considered in these analyses included the patient's sex, age and risk group, the year of HIV diagnosis, CD4 cell count, HIV RNA and haemoglobin at HIV diagnosis and the specific AIDS conditions that the patient had been diagnosed with. All analyses also adjusted for clinic cohort.
Virological response to therapy was defined in two ways. First, initial response was defined as the time until the first HIV RNA level measured of 500 copies/ml or less; patients who started treatment but who did not achieve an HIV RNA level below this level were censored at the time of death or last clinic visit, as described above. Second, among those with an initial response, virological rebound was defined as the time until the first HIV RNA measurement of more than 500 copies/ml, with follow-up censored as above in those who maintained a suppressed viral load. A threshold of 500 copies/ml was used, as patients were included from a time when ultrasensitive viral load testing was not routinely performed. Factors considered for association with virological response were the same as those listed above.
CD4 cell counts in the first year after start of HAART were summarized by calculating the median values for each individual measured in the periods 0–3, 4–6, 7–9 and 10–12 months after starting HAART. Immunological response to therapy was defined as the time until the first of two consecutive CD4 cell counts of more than 200 cells/μl. Factors associated with an immunological response were identified using Cox regression models as described above. Fifty-seven patients whose CD4 cell count prior to starting HAART was more than 200 cells/μl were excluded from these analyses. Factors associated with mortality were also identified using Cox regression analyses. For these analyses, we considered two sets of variables. The first included only variables available at HIV diagnosis (fixed covariate model), including age, sex, risk group, year of diagnosis and the CD4, HIV RNA and haemoglobin levels at diagnosis. The second (time-updated model) replaced the CD4, HIV RNA and haemoglobin levels at diagnosis with their values over follow-up. We did not incorporate use of treatment into this time-updated model as any impact of treatment is expected to act primarily through changes in the CD4 cell count and HIV RNA level, and as the interpretation of such models that include treatment is complicated by the presence of time-varying confounding.
Seven hundred and sixty patients met the eligibility criteria for this study (Table 1). Overall, patients were followed up for a median of 1.8 years (range 1 day to 8.8 years); 125 (16%) patients died. As expected, given the HIV epidemics in these four countries, there were some differences in the characteristics of patients from the different clinics. For example, the proportion of patients who were male ranged from 66% in London to 93% in Calgary, whereas the proportion that were injection drug users (IDUs) ranged from only 1.5% in London to 30% in Barcelona. The median age of patients at the time of diagnosis did not vary greatly by cohort, though it was slightly higher (medians of 44–45 years) in the Ferrara and Rome clinics compared with other clinics (medians of 36–39 years). The median CD4 cell count was highest in HSR (median of 100 cells/μl) and lowest in Calgary (20 cells/μl), whereas the HIV RNA level at diagnosis was lowest in HSR (4.3 log10 copies/ml) and highest in London (5.5 log10 copies/ml).
Use of antiretroviral treatment
Six hundred and twenty-four patients (82%) started treatment. At the start of treatment, the median CD4 lymphocyte count was 41 cells/μl (range 0, 1584), whereas the median HIV RNA was 5.3 log10 copies/ml (range 1.6, 6.4). Four hundred and nine (66%) patients started a protease-inhibitor-based regimen, 153 (25%) patients a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen and 62 (10%) patients a regimen containing nucleoside reverse transcriptase inhibitors (NRTI) only or a combination of the three drug classes. The most common drugs started being lamivudine (85% of those starting HAART), zidovudine (57%), stavudine (37%), indinavir (28%), ritonavir (23%), efavirenz (20%), nelfinavir (18%) and lopinavir (13%). Treatment combinations varied by clinic, with NNRTI-based regimens being used relatively more frequently in the Calgary, London and Barcelona clinics (56, 42 and 32%, respectively) compared with other clinics (ranging from 8 to 16%) and protease-inhibitor-based regimens being used relatively more frequently in the clinics from Modena, Ferrara, Milan, Rome and HSR (83, 79, 76, 76 and 72%, respectively).
Treatment was started a median of 31 days [95% confidence interval (CI): 30, 34 days] after HIV diagnosis. A quarter of patients (25%) started treatment within the first 2 weeks after HIV diagnosis, 20% started between 2–4 weeks after diagnosis and 21% started within the second month after diagnosis. In unadjusted analyses (Table 2), treatment was initiated sooner in those diagnosed in 2004 (compared with those diagnosed between 1999 and 2003), in those who were older and in those with Kaposi's sarcoma at the time of HIV diagnosis, whereas treatment was started later in those with an IDU risk for infection, in those diagnosed in 1998 or earlier, in those with a higher CD4 cell count at the time of HIV diagnosis and in those with tuberculosis (TB). There were differences between the clinics in the timing of initiation of HAART (data not shown), but no differences by sex, HIV RNA or haemoglobin levels at diagnosis or between the other types of AIDS events. After adjustment, the differences in treatment initiation by calendar year, CD4 cell count, Kaposi's sarcoma and TB remained statistically significant.
Information on subsequent AIDS events was available from five cohorts (584 patients). Over follow-up, 110 (19%) patients developed a new AIDS event. In total, there were 152 new AIDS events [TB: 38; cytomegalovirus (CMV): 34; Candida: 16; lymphoma: 11; Pneumocystis carinii pneumonia (PCP): 16; Kaposi's sarcoma: 9; toxoplasmosis: 5 and other: 23].
Of the 125 patients who died, 102 (82%) were men, the median (range) age at death was 46 (25–78) years and 22 (18%) were IDUs, 15 (12%) were homosexual, 45 (36%) were heterosexual and the remaining 43 (34%) patients had another/unknown risk for infection. Prior to death (and after the first 14 days after diagnosis), 28 (22%) patients had at least one new AIDS diagnosis. CD4 cell counts in the patients who died were 33 (0–522) and 28 (0–730) cells/μl at diagnosis and death, respectively; viral loads were 5.4 (1.9–6.7) and 4.6 (1.6–6.4) log10 copies/ml, respectively. Among those who did not receive treatment, there were 64 deaths, occurring at a median (range) of 21 (0, 1409) days after diagnosis. Among those who did receive treatment, there were 61 deaths, occurring at a median (range) of 372 (0, 2051) days after diagnosis.
Of the baseline factors (Model a, Table 3), only older age and a higher viral load at diagnosis were significantly associated with mortality. When considering factors that changed over follow-up (model b, Table 3), the factors independently associated with a higher risk of mortality were IDU and other risk group, older age at diagnosis and lower CD4 cell counts and haemoglobin levels over follow-up.
Virological response to therapy
Overall, 505 (89%) of the 624 patients starting antiretroviral therapy (ART) experienced at least one viral load of 500 copies/ml or less, a median of 90 (95% CI 83–99) days after starting treatment (Fig. 1). In univariable analyses, there was some evidence that initial virological response was associated with risk group and initial HAART regimen. However, in multivariable analyses (Table 4), after adjusting for clinic, the only factors that were significantly associated with a better initial response to therapy were later calendar year, a lower viral load at the start of therapy and a diagnosis of CMV (compared with other AIDS events).
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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