Download Review Late presentation of HIV

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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.
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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
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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.
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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].
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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
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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,
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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
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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
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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.
Acknowledgements
No financial support was given for this work. The
authors thank Dr Martin Rickenbach and Olivia Keiser
from the Datacenter Lausanne of the Swiss HIV
Cohort Study for data shown in Figure 2. Regarding
the content of this paper all authors have no conflict of
interest. The authors thank Andrew Phillips, London,
Hans H Hirsch, Basel, and Tracy Glass, Basel, for stimulating discussion and carefully reading this manuscript and Michèle Girard for outstanding secretarial
assistance in preparing this manuscript. We sincerely
thank the two anonymous reviewers for their very
valuable comments.
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