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Battegay 4/9/07 12:57 Page 841 Antiviral Therapy 12:841–851 Review Late presentation of HIV-infected individuals Manuel Battegay1*, Ursula Fluckiger1, Bernard Hirschel2 and Hansjakob Furrer 3 1 Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Switzerland Division of Infectious Diseases, Geneva University Hospital, Geneva, Switzerland 3 Division of Infectious Diseases, University Hospital Berne, Switzerland 2 *Corresponding author: Tel: +41 61 265 50 72; Fax: +41 61 265 31 98; E-mail: [email protected] Late presentation remains a major concern despite the dramatically improved prognosis realized by ART. We define a first presentation for HIV care during the course of HIV infection as ‘late’ if an AIDS-defining opportunistic µl. In the disease is apparent, or if CD4+ T-cells are <200/µ Western world, approximately 10 and 30% of HIV-infected individuals still present with CD4+ T-cells <50 and <200/µl, respectively; estimates are substantially higher for developing countries. Diagnosis and treatment of opportunistic diseases and intense supportive in-hospital care take precedence over ART. Benefits of starting ART without delay, that is, when opportunistic diseases are still active, include faster resolution of opportunistic diseases and a decreased risk of recurrence. The downside of starting ART without delay could include toxicity, drug interactions and immune reconstitution inflammatory syndrome (IRIS). Among asymptomatic or oligosymptomatic individuals presenting late, where ART and primary prophylaxis are initiated, ~10–20% will become symptomatic from drug toxicity or undiagnosed opportunistic complications, including IRIS, which require appropriate therapies. In this review we describe late presentation to HIV care, the scale of the problem, the evaluation of a late-presenting patient and challenges associated with initiation of potent antiretroviral therapy (ART) in the setting of acute opportunistic infections and other comorbidities. Introduction HIV-1 infection without antiretroviral therapy (ART) destroys the immune system leading to opportunistic diseases and death. The level of CD4+ T-cells in the peripheral blood has proven to be a very valuable marker of the severity of immunodeficiency in HIV infection [1–3]. CD4+ T-cells of 200/µl represent the threshold below which the risk for clinical symptoms and AIDS-defining illnesses starts to increase substantially (Figure 1). Current management of HIV infection aims to prevent opportunistic diseases by starting ART before CD4+ T-cells fall below this critical level, but this relies on patients to seek HIV care early enough. Therefore, we define a presentation as ‘late’ if an AIDS-defining opportunistic disease is present, or if CD4+ T-cells are <200/µl. This includes patients with late testing and/or late presentation for clinical care. Several studies highlight the problem of late HIV diagnosis and late presentation to HIV care in the highly active ART (HAART) era [4–15]. Very late presentation of HIV-infected patients, that is, with a CD4+ T-cell count of <50/µl, often has an immediate clinical effect [15]. Evidence from different studies clearly demonstrates a significant influence on HIV disease course when patients © 2007 International Medical Press 1359-6535 present for first care at lower CD4+ T-cell counts, in particular <200/µl [6]. A strong rationale for special consideration in patients presenting late is given in studies by Egger et al. [16] and Hogg et al. [17], which demonstrate that initiation of ART prior to a CD4+ T-cell decrease <200/µl is associated with improved outcomes. Impressively, a recent study found that earlier diagnoses would have reduced short-term mortality by 56% in England and Wales in the years 2000–2004, resulting in 249 fewer deaths [6]. A US study found that 27% of patients presented with an AIDS-defining illness at initiation of care [4]. Patients presenting with low CD4+ T-cell counts can make large demands on clinical resources [15], particularly over the first few months. Although HIV deaths occurring in the era of potent ART are more diverse and the result of a number of factors (see below) [18,19], most HIV-associated deaths are due to late presentation and delayed uptake of ART [5]. Late presentation - scale of the problem There is ever increasing evidence that ART decreases morbidity and mortality in HIV-infected patients. 841 4/9/07 12:57 Page 842 M Battegay et al. Figure 1. Risk of opportunistic diseases according to CD4+ T-cell counts Moderate immunodeficiency 500 CD4+ T-cell counts, cells/µl Battegay 200 Lymphadenopathy Thrombopenia Oral hairy leukoplakia Herpes zoster Oral thrush Cervical dysplasia Cervical carcinoma Recurrent bacterial pneumonia Tuberculosis Kaposi’s-Sarcoma Severe immunodeficiency Candida oesophagitis Pneumocystis jiroveci pneumonia Malignant lymphoma Persistent ulcerous Herpes simplex Cerebral toxoplasmosis Cryptosporidiosis HIV-encephalopathy Histoplasmosis 100 Profound immunodeficiency Progressive multifocal leukencephalopathy Cryptococcosis Cytomegalovirus retinitis Disseminated Mycobacterium avium infection Disseminated Mycobacterium genavense infection Time Hence, late presentation might strongly effect overall prognoses of HIV-infected patients [20–28]. In the Western world, ~10–30% of HIV-1-infected individuals attend clinics late. For example, in the Swiss HIV Cohort Study from 2001 until 2005 between 5–10% of individuals presented with CD4+ T-cells <50/µl and up to 30% with CD4+ T-cells <200/µl (Figure 2). Similar data exist in other Western countries, for example, in one study of a London clinic between 1996 and 2002, 15.3% of patients presented for first care with CD4+ T-cells <50/µl [15]. In a study conducted in the southeastern US, 50% of individuals had CD4+ T-cells <200/µl at initiation of care; however the authors comment that the rural setting might have contributed to this high rate of delay in accessing care [4]. The Antiretroviral Therapy Cohort Collaboration (ART-CC), report that ~15% of patients start ART with CD4+ T-cells <50/µl compared with 30% in developing countries, as reported by the Antiretroviral Treatment in Lower Income Countries Collaboration (ART-LINC) [29]. Particularly in developing countries, high proportions of patients are starting ART too late because of the still limited access to ART and lack of awareness of HIV infection in many infected individuals [30]. In developing countries the rate of late presentation is likely to be a minimum estimate because of an important lack of HIV testing. Hence, late 842 presentation will be an immense problem in the years to come. The data indicate that a substantial proportion of patients still initiate HIV care with advanced disease, and early presentation and initiation of ART would probably improve mortality, morbidity and costs associated with AIDS-defining illnesses. As a result, understanding what factors are associated with late presentation is important. Heterosexual transmission and Black-African ethnicity were described to be significant risk factors for presenting late [10,15]. Studies have found conflicting evidence about gender, some suggesting female gender while others found that male gender was associated with increased risk of late presentation [4,8–10,15]. Older age is consistently associated with late presentation and may reflect underdiagnosing of HIV in individuals in whom less risky sexual activity is presumed [8–10]. Late presentation and prognosis ART has dramatically decreased morbidity and mortality according to recent and ever increasing evidence, be it from randomized clinical trials or large observational studies [20–28]. The advent of dual ART resulted in a decrease in mortality of 30–50% [20–22], followed by an even more dramatic decrease in mortality with the introduction of triple combination ART [23–25,27,28]. In recent years, further decreases in © 2007 International Medical Press Battegay 4/9/07 12:57 Page 843 Late presentation of HIV-infected individuals HIV-related mortality is probably due to several factors: the advent of more potent therapies including nonnucleoside reverse transcriptase inhibitors (NNRTIs) and boosted protease inhibitors (PIs), better adherence due to more convenient, simplified regimens with lower pill counts and potent salvage therapies. A rough breakdown of the underlying reasons behind HIV/AIDS deaths that still occur in the era of potent ART is difficult to provide. Death may be due to (i) AIDS associated with low CD4+ T-cell counts despite ART, for example, because of poor adherence, toxicity or treatment of insufficient potency leading to insufficient increases or even decreases in CD4+ T-cell counts, (ii) late presentation for HIV care, (iii) resistance to all available drug classes or (iv) HIV-unrelated mortality at high CD4+ Tcell counts. It appears that late presentation, in particular in recent years, explains a significant proportion of deaths from HIV/AIDS in the HAART era [5,6,15]. Prognosis of untreated HIV-infected individuals was investigated in an analysis from the Cascade cohort [31]. From this and other studies, the predicted 6 months’ risk of AIDS in untreated individuals increases exponentially with a decrease of CD4+ T-cells below 200/µl and increasing viral load. Prognosis in untreated individuals is also affected by increasing age [31]. A recent analysis from the ART-CC suggests that AIDS or death rates are lower in individuals who Figure 2. Percentage of ART-naive patients in each CD4+ T-cell count stratum in years 2001–2005 376 344 351 359 2001 2002 2003 2004 351 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% >200 CD4 T-cells/µl + + 101–200 CD4 T-cells/µl 2005 + 51–100 CD4 T-cells/µl <50 CD4+ T-cells/µl Patients are antiretroviral therapy (ART)-naive participants of the Swiss HIV Cohort Study attending clinics. CD4+ T-cell count strata: blue >200 cells/µl; red 101–200 cells/µl; white 51–100 cells/µl; and black <50 cells/µl. Data from the Swiss HIV Cohort Study, compiled by Martin Rickenbach and Olivia Keiser, Datacenter, Swiss HIV Cohort Study, Lausanne, Switzerland. Antiviral Therapy 12:6 initiate ART >350 CD4+ T-cells/µl, compared with those who delay ART until 200 CD4+ T-cells/µl [32]. In the following parts of this review we highlight issues specifically related to the evaluation and management of late presenters, that is, the clinical evaluation, the prevention of opportunistic infections and the initiation of ART, particularly in the setting of acute opportunistic infections and the approach to differential diagnosis. Evaluation of late-presenting HIV-infected individuals Signs and symptoms The first diagnostic approach to an HIV-infected person includes a thorough history of prior HIVassociated symptoms and diseases. Weight loss, diarrhoea or low-grade fever must be noted when taking the patient history. The patient should be asked about comorbidities (in particular hepatitis C infection), substance use and mental illnesses (such as depression), as such conditions could complicate ART and/or negatively influence adherence and thereby alter outcome. Signs and symptoms can be subtle. A patient may suffer from mild, sub-acute onset of exertion dyspnea, fever and non-productive cough indicative of early stage Pneumocystis jirovecii pneumonia (PCP). Mild headache and confusion with motor weakness might suggest Toxoplasma gondii infection of the brain. However, opportunistic infections may be asymptomatic or oligosymptomatic and have an insidious beginning. Exam findings Subtle clinical signs might already give an indication of mild to moderate immunodeficiency, for example, oral candidiasis or oral hairy leukoplakia. In mild cases of PCP, pulmonary examination is usually normal at rest. With exertion, tachypnea, tachycardia and diffuse dry rales might be observed [33]. Physical examination might demonstrate focal neurological abnormalities with a broad differential diagnosis including HIV-specific diseases, such as primary brain lymphoma or T. gondii brain abscesses. Of special concern are cytomegalovirus (CMV) retinitis and mycobacterioses because these subclinical, untreated infections can lead to severe immune reconstitution inflammatory syndromes (IRIS) once ART is started. Therefore, fundoscopic evaluation should be done in all late presenters to rule out peripheral CMV retinitis, in particular in patients who present with CD4+ T-cells <50/µl. Laboratory and diagnostic tests Repeated measurements of CD4+ T-cell counts and the viral load should be performed as soon as possible. 843 Battegay 4/9/07 12:57 Page 844 M Battegay et al. Serologies regarding toxoplasmosis, the hepatitis viruses, CMV and sexually transmitted infections such as syphilis must be included in the initial work-up. Genotypic or phenotypic HIV resistance testing for HIV is recommended if resistant strains are prevalent in >5% of HIV-infected individuals initiating ART in the patient’s country of origin [34,35]. For patients with pulmonary symptoms, a chest radiograph is indicated. For example, for patients with PCP this typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hilar region in a butterfly pattern [33]. A CT scan or magnetic resonance imaging of the brain will typically show multiple contrastenhancing lesions in the case of T. gondii infection or a single lesion suggestive of primary brain lymphoma. Taken together, in patients presenting with CD4+ T-cells <200/µl, the medical history and clinical status are important. Clinical signs, symptoms and laboratory abnormalities have to be evaluated to rule out specific opportunistic diseases. For example, in a patient with low CD4+ T-cells with unspecific symptoms like fever, weight loss, anaemia and increased aminotransferases, radiological evaluation, sputum and blood cultures for mycobacteria should be obtained. The physician has to be knowledgeable about the presentation of opportunistic infections and about the level of immunodeficiency at which they usually occur (Figure 1). Thorough recommendations on treating opportunistic infections among HIV-infected adults and adolescents from Benson et al. at the CDC were published in 2004, which include information on epidemiology, clinical manifestation, diagnosis and other aspects of opportunistic infections [36]. Investigations for a first HIV evaluation are described in detail in the Department of Health and Human Services (DHHS) guidelines 2006 [34]. Importantly, the more profound the immunodeficiency, the higher the probability that the clinical picture of an individual patient is complicated by multiple opportunistic diseases. This is somewhat in contrast with the general clinical approach where a single disease is sought to explain patient symptoms, particularly in younger patients. Prevention of opportunistic infections Data from both randomized, controlled trials and observational cohort studies document that ART reduces the incidence of opportunistic infections and improves survival [23–28,37–40]. Interestingly, the ART-CC found that despite improved initial HIV virological control, there was no further reduction in allcause mortality. Conversely, there was some evidence for an increase in the rate of AIDS in more recent years [39]. This recent increase in the risk of AIDS seems largely due to increased tuberculosis incidence [37,39]. 844 The data from this study indicates the importance of prevention and screening for active opportunistic infections [41–46]. Oesophageal candidiasis, PCP, tuberculosis, cerebral toxoplasmosis and atypical mycobacterial diseases are still the most common opportunistic infections [15,16,36,40]. Importantly, primary prophylaxis against PCP and T. gondii infection has to be initiated in patients with CD4+ T-cells <200/µl (Table 1) [47,48]. In patients with CD4+ T-cells <50/µl primary prophylaxis against Mycobacterium avium complex (MAC) can be used, although this particular prophylaxis might be withheld if ART can be started promptly. Randomized clinical trials indicate that primary and secondary prophylaxis reduces the risk of opportunistic infections by 50–80% [41–45,47]. However, without ensuing ART, HIV disease will progress rapidly, as in the pre-HAART era [24,49,50]. Prophylaxis against opportunistic infections is invaluable in late presenters as ART is often postponed while active opportunistic infections are treated. ART in HIV-infected individuals who present late Prompt start of ART in patients who present late, in particular when CD4+ T-cells are <50/µl, improves midand long-term prognosis more than any other action [16,36]. It is beyond the scope of this review to describe principles and details of commencing antiretrovirals in HIV-infected individuals so we refer to the 2006 DHHS guidelines [34] and IAS-USA guidelines [35]. Nevertheless, there are particularly relevant considerations for patients presenting late, such as mental illness, active substance use and commitment to start of therapy. Empathy and good information is crucial. Depression and active intravenous drug use are risk factors for not starting ART [34,51,52] and special attention has to be given to social support in older individuals, immigrants and intravenous drug users. Late presenters include those who are very sceptical towards therapy. Hence, special attention should be given to the patient’s individual perspective and readiness to start therapy [52] as drug adherence is the most important predictor of survival [34,53]. There is no evidence that recommended regimens for late presenters should be different from those for other patients [34,35]. In the large cohort studies ART-LINC and ART-CC, progression to death after 1 year did not differ between individuals treated with NNRTI- or PIbased ART [29]. It is interesting to note that ART initiation in low- and high-income countries was followed by a very similar CD4+ T-cell gain after 1 year (106 CD4+ T-cells/µl and 103 CD4+ T-cells/µl, respectively) [29]; however, the probability of death after 12 months © 2007 International Medical Press Battegay 4/9/07 12:57 Page 845 Late presentation of HIV-infected individuals Table 1. US guidelines for primary and secondary prophylaxis (initiation and discontinuation) for most frequent pathogens in response to ART [82] Primary prophylaxis (initiation) Primary prophylaxis (discontinuation) Secondary prophylaxis (discontinuation) Pneumocystis jirovecii pneumonia CD4+ T-cells <200 cells/µl (AI) CD4+ T-cells >200 cells/µl for ≥3 months (AI) CD4+ T-cells >200 cells/µl and ≥3 months on ART (BII) Toxoplasmosis CD4+ T-cells <100 cells/µl (AI) CD4+ T-cells >200 cells/µl for ≥3 months (AI) CD4+ T-cells >200 cells/µl sustained for ≥6 months on ART + completed toxoplasmosis therapy and asymptomatic for toxoplasmosis (CIII) MAC CD4+ T-cells <50 cells/µl CD4+ T-cells >100 cells/µl and ≥3 months on ART CD4+ T-cells >100 cells/µl sustained for ≥6 months on ART + completed 12 months of MAC therapy and asymptomatic for MAC (CIII) Cryptococcosis Not applicable Not applicable CD4+ T-cells >100–200 cells/µl and sustained for ≥6 months on ART + completed initial therapy and asymptomatic for cryptococcosis (CIII) CMV retinitis CD4+ T-cells <50 cells/µl; it may be reasonable to observe patients closely and treat if active CMV infection Not applicable CD4+ T-cells >100–150 cells/µl and >6 months on ART. No evidence for active disease (BII) Histoplasmosis Not applicable Not applicable No recommendation for stopping prophylaxis Illness Primary and secondary prophylaxis should be initiated or discontinued for adult and adolescent patients when CD4+ T-cells have decreased or increased to thresholds as indicated. For special situations see [82]. Quality of strength and evidence of recommendations (Centers for Disease Control and Prevention system): A – Both strong evidence for efficacy and substantial clinical benefit support recommendation for use; should always be offered; B – Moderate evidence for efficacy or strong evidence for efficacy, but only limited clinical benefit, supports recommendation for use; should usually be offered; C – Evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweigh adverse consequences (for example, drug toxicity and drug interactions) or cost of the chemoprophylaxis or alternative approaches; use is optional. Rating quality of evidence supporting the recommendation: I – Evidence from ≥1 correctly randomized, controlled trials; II – Evidence from ≥1 well designed clinical trials without randomization, from cohort or case-controlled analytic studies (preferably from ≥1 centre), or from multiple time–series studies, or dramatic results from uncontrolled experiments; III – Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of consulting committees. ART, antiretroviral therapy; CMV, cytomegalovirus; MAC, Mycobacterium avium complex. was much higher in low income countries (6.4% [95% confidence interval (CI) 5.1–7.7] versus 1.8% [95% CI 1.5–2.2] in high income countries). Baseline CD4+ T-cell counts were shown to be the most important risk factor of progression to death during the 1st year of ART and the difference in short-term prognosis between low- and high-income countries could be partly explained by the difference in baseline CD4+ T-cells [29]. Mortality was highest in the 1st month after ART initiation and decreased thereafter [29], as HIV-infected patients who present late often suffer from severe, life-threatening complications. However, even late initiation of ART at <50 CD4+ T-cells/µl still carries quite a good prognosis. One London study investigated such very late presenters from 1996 until the end of 2002 and reported an 87% survival rate at 12 months [15]. In patients with low CD4+ T-cells, primary PCP prophylaxis with trimethoprim-sulfamethoxazol and ART can be started together. However, in case of side effects such as a rash, it can be nearly impossible to distinguish which drug is responsible for this reaction. Therefore, one may start trimethoprim-sulfamethoxazol first and add ART after about 2 weeks. This time period is also helpful to evaluate and increase the patients’ readiness to start ART. In a late-presenting patient in whom ART is indicated, the initial phase of care is most important and might Antiviral Therapy 12:6 include intensive care. The general approach to intensive care of HIV-infected patients has changed because of the dramatically improved long-term prognosis. Several studies indicate that admissions to intensive care units and survival after stay in intensive care units have significantly increased from the pre- to the post-HAART era [54–56]. The gain in CD4+ T-cells during the first 6 months improves prognosis, as shown in an ART-CC analysis [57] where a CD4+ T-cell count increase from <5 to 25–49 CD4+ T-cells/µl cut the probability of AIDS or death by half, even more if CD4+ T-cells increase beyond the 50 cells/µl threshold. Management of ART in the setting of acute opportunistic infections The immediate start of ART helps to contain opportunistic infections, such as cryptosporidiosis and microsporidiosis or progressive multifocal leukencephalopathy, where no effective therapies are available. Also faster resolution of other opportunistic infections might occur and the risk of a second opportunistic infection might be reduced. The risks of immediate start of ART include additive drug toxicity and drug interactions. However, these complications do not always occur and drug interaction with ART can be managed with adequate knowledge (for example, 845 4/9/07 12:57 Page 846 M Battegay et al. with use of www.hiv-druginteractions.org). Upon starting ART HIV-infected patients with profound immunosuppression might experience a syndrome characterized by excessive inflammatory responses, that is, IRIS. IRIS can complicate the clinical picture with fever, and worsening symptoms of opportunistic diseases [58–63]. IRIS usually occurs in the first weeks after starting ART [58,59,61], when plasma viral load drops and the CD4+ T-cell count increases from usually very low levels. It is assumed that newly gained immunity either unmasks latent infections or worsens already apparent acute opportunistic diseases [59]. A retrospective study examined 180 HIV-infected army veterans with median CD4+ cells of 30/µl and known tuberculosis, MAC or Cryptococcus neoformans coinfection [64]. Almost one-third of these patients experienced IRIS after ART initiation. Interestingly, during 2 years of follow up, patients with IRIS symptoms had better virological responses and higher CD4+ cell increases [64]. In a multicentre study patients without prior MAC infection were prospectively followed for new AIDS-defining events occurring after Figure 3. Start of antiretroviral therapy in the setting of an acute opportunistic infection IRIS possible - await response to OI therapy (CIII) CD4+ T-cell count, cells/µl Battegay 200 100 (Toxo), PCP, Crypto, MAC, TBC No data about adverse effects of ART - no delay (BIII) CMV 50 25 Benefits of ART > risk of IRIS - ART as soon as possible (AIII) PML, Kaposi, -Sporidiosis 0 ART 2 4 8 12 Time, weeks Compiled from reference [34,36,73]. Quality of strength and evidence of recommendations (Centers for Disease Control and Prevention system): A – Both strong evidence for efficacy and substantial clinical benefit support recommendation for use; should always be offered; B – Moderate evidence for efficacy or strong evidence for efficacy, but only limited clinical benefit, supports recommendation for use; should usually be offered; C – Evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweigh adverse consequences (for example, drug toxicity, drug interactions) or cost of the chemoprophylaxis or alternative approaches; use is optional. Rating quality of evidence supporting the recommendation: I – Evidence from >1 correctly randomized, controlled trials; II – Evidence from >1 well designed clinical trials without randomization, from cohort or case-controlled analytic studies (preferably from >1 centre), or from multiple time–series studies, or dramatic results from uncontrolled experiments; III – Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of consulting committees. ART, antiretroviral therapy; CMV, cytomegalovirus infection; crypto, cryptococcosis; IRIS, immune reconstitution inflammatory syndrome; MAC, Mycobacterium avium complex; OI, opportunistic infection; PCP, Pneumocystis jirovecii pneumonia; PML, progressive multifocal leukencephalopathy. TBC, tuberculosis; Toxo, Toxoplasma gondii infection. 846 initiation of ART [65]. Focusing on 612 patients with CD4+ T-cell increases of over 100 cells/µl, only 1.75 events per 100 patient-years were observed [65]. As this study did not concentrate on ART initiation but on long-term course, a significant proportion of IRIS events were probably not captured [60]. Symptoms of IRIS occur as early as a few days after starting ART. In patients with baseline CD4+ cells below 50 cells/µl, most events will occur within the first 8 weeks of therapy [66]. However, late IRIS with symptom onset >1 year after starting ART has been described [67–69]. Notably, ART does not directly cause IRIS. Hence, in the case of latent infections for which there is often no prophylaxis given, as, for example, for tuberculosis, delaying ART will probably not prevent IRIS. The start of ART during acute opportunistic infection is still a matter of debate with no randomized clinical trial data to guide informed decision making. For progressive multifocal leukencephalopathy or Kaposi’s sarcoma the benefits of immediate ART outweigh the risk of IRIS (Figure 3) [58,59,61]. Also, there is no contraindication to starting ART simultaneously with treatment of CMV [36]. However, toxicity of the drugs used in the initial phase of CMV disease can be substantial and it is advisable to delay the introduction of ART until the tolerability of CMV therapy is known. In addition, some investigators found a high incidence of immune recovery uveitis in the weeks after starting ART [70]. Therefore, a high level of awareness regarding this complication is warranted and any visual impairment should immediately be investigated by an experienced ophthalmologist. Similarly, the start of ART can be delayed from 2–6 weeks to await the response to therapy for PCP and cerebral toxoplasmosis [36]. IRIS frequently occurs with Mycobacterium tuberculosis and MAC infection as well as cryptococcal meningitis. In this situation, a response to treatment of opportunistic infection should be awaited. A frequent dilemma is whether to start ART while the results of mycobacterial cultures are pending. In patients who present with suspected disseminated mycobacteriosis, antimycobacterial treatment is often started and ART is delayed until culture results are available or until the patient has responded to therapy. If the a priori risk is low, ART is commenced but special attention is focused on the possibility of IRIS unmasking underlying infection [62,64,71–73]. A recent retrospective analysis in 160 patients receiving treatment for tuberculosis demonstrated that the risk of IRIS was strongly associated with early ART initiation and low baseline CD4+ Tcell count. IRIS developed in 32% of those who started ART within 2 months of tuberculosis diagnosis, however it developed infrequently when ART was started thereafter. Importantly, mortality risk from IRIS was low [72]. Immediate treatment for M. tuberculosis © 2007 International Medical Press Battegay 4/9/07 12:57 Page 847 Late presentation of HIV-infected individuals is essential for a favourable prognosis. However, prompt initiation of ART may be crucial in patients with very low CD4+ T-cell counts to prevent AIDSrelated mortality [72]. In these cases, ART should be postponed by at least 4–8 weeks. In our experience nonsteroidal anti-inflammatory drugs and steroids can be given if IRIS occurs [74]. If reactivation of M. tuberculosis is clinically apparent during ART, it is possible to continue ART in most instances if IRIS is not life-threatening and drug interactions are taken into account. Newer results indicate that the frequency of IRIS due to tuberculosis might be overestimated, as shown in a recent study performed in South Africa [75,76]. In this study no IRIS events were identified among 20 patients starting ART who were coinfected with HIV-1 and tuberculosis. The ongoing AIDS clinical trial group study ACTG 5164 is investigating immediate versus delayed ART for HIV-infected adults presenting with acute opportunistic infections. A special challenge is the late presentation of patients with malignancies such as cerebral lymphomas and non-Hodgkin lymphoma. ART is essential to improve the prognosis of these patients. However, concurrent radiation and chemotherapy can hamper the tolerability of ART. In our experience a close interdisciplinary approach facilitates successful ART and is likely to enable concurrent ART and therapy for a malignancy. In summary, ART should be started as soon as possible in late presenters but the decision about the best time point has to be taken on an individual level, considering comorbidities (especially opportunistic diseases), comedication with possible overlapping toxicities and drug interactions, and the patient’s readiness for presumably lifelong ART. Robust data exists about stopping primary as well as secondary prophylaxis for different pathogens (Table 1) once CD4+ T-cell counts have increased over defined thresholds and treatment of opportunistic infections has been completed [48,77–81]. Primary prophylaxis against PCP and toxoplasmosis should be stopped with CD4+ T-cell counts >200 cells/µl for at least 3 months [36]. For stopping secondary prophylaxis in patients treated with ART, CD4+ T-cell counts have to be >200 cells/µl for 3 months after PCP and 6 months after cerebral toxoplasmosis [82]. Diagnostic challenges Not all patients demonstrate a substantial CD4+ Tcell count increase [63,83]. Measuring viral load 2–8 weeks after treatment initiation should show a viral load decrease of more than 1 log10. Insufficient drug adherence leading to suboptimal viral suppression, older age, malnutrition or myelotoxic drug toxicity can be cofactors influencing CD4+ T-cell Antiviral Therapy 12:6 increases, for example, related to trimethoprimsulfamethoxazol toxicity. Overlapping symptoms and findings often complicate the course of disease and are difficult to interpret. Table 2 compiles the differential diagnoses in a structured way with regard to new symptoms and findings in the setting of late presentation and initiation of ART. Following this, new symptoms and findings may be due to (i) HIV, (ii) a defined complication of HIV, for example, opportunistic diseases, (iii) a treatment-related complication, (iv) a concurrent indirect complication, for example, nosocomial infection during hospitalization, (v) IRIS or (vi) unrelated diseases. Prevention of late HIV presentation Ideally, HIV infection should be diagnosed early enough to prevent further transmission and to prevent late presentation. Hence, all patients with symptoms and diseases potentially associated with HIV such as herpes zoster, oral candidiasis, HIVassociated cancers and other CDC B and CDC C diagnoses should be screened for HIV [84]. All individuals presenting with sexually transmitted infections such as syphilis, gonorrhoea, Chlamydia trachomatis infection and genital herpes simplex virus infection should undergo an HIV test. HIV testing should be promoted as a routine element of medical care [47]. HIV testing should be promoted in hospital emergency departments, substance abuse treatment clinics and primary care settings. HIV screening should be included in the routine panel of prenatal screening tests for all pregnant women [85]. There are other aspects regarding late presentation. For example, the risk of transmission in late HIV disease with higher viral loads is increased [86,87]. Hence, patients with late presentation should obtain counselling on HIV prevention which takes into account the increased risk of transmitting HIV to their partners. Also, side effects of ART such as lipodystrophy, and the risk of triple class failure are associated with low nadir CD4+ T-cell counts at presentation [88–91]. Late presentation is still common in HIV-infected patients, particularly in developing countries. This influences the overall prognosis much more than in former times as a result of the dramatically improved prognosis of HIV-infected individuals when treated in a timely fashion, that is, before CD4+ T-cell counts drop below 200 cells/µl. Late presentation remains a major concern and clinicians must be aware of it. A latepresenting patient should trigger a prompt evaluation of the HIV disease status and comorbidities as well as a concrete individual treatment plan for possible opportunistic diseases as well as ART. 847 Battegay 4/9/07 12:57 Page 848 M Battegay et al. Table 2. Differential diagnosis - newly occurring symptoms found in HIV-infected patients presenting late during HIV infection Diagnosis Examples of symptoms Characteristics (A) HIV Weight loss Fever Diarrhoea Dementia Very low CD4+ T-cells/µl High viral load >100 000 copies/ml Diagnosis only possible after ruling out B–E (B) Defined complication of HIV Opportunistic diseases Symptoms typical for opportunistic infections or diseases Symptoms indicating organ specificities Time course of symptoms or findings indicating defined opportunistic diseases (C) Treatment-related complication ART-associated side effects or side effects from treatment of opportunistic and/or nosocomial infections Symptoms and findings typically associated with single antiretroviral drugs (for example, hypersensitivity, skin rash, hepatitis, diarrhoea) Symptoms and findings indicating association with single drugs (for example, sulfadiazine) Time course regarding side effects indicating specific drug (D) Concurrent indirect complications, in particular during hospitalization Nosocomial infections Typical symptoms and findings related to nosocomial infections such as catheter-related infection, Clostridium difficile infection and septicaemia (E) Immune reconstitution syndrome Tuberculosis Non-tuberculous mycobacteria Cryptococcosis Herpes simplex recurrence Hepatitis Progressive multifocal leukencephalopathy Cytomegalovirus infection Typical time point, that is, 1–4 weeks and more after initiation of ART Previous diagnosis of AIDS Low increasing to high CD4+ T-cells/µl Atypical presentation of opportunistic infections Symptoms not explained by normal course of previous or new opportunistic infection or side effect of antiretrovirals (F) Unrelated diseases Frequent diseases, in particular in older patients Symptoms and findings indicating an unrelated cause Completely unrelated diseases in this setting are probably rare, but might occur in higher frequency with older age and in patients in the developing world ART, antiretroviral therapy. 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