Vih todo 2019.pdf

e540 www.thelancet.com/hiv Vol 6 August 2019
Review
Introduction
Substantial progress has been made in the identification
of individuals with HIV and starting them on anti
retroviral therapy (ART): 21·7 million of the estimated
36·9 million people living with HIV worldwide are now on
treatment.1
The number of AIDS-related deaths in 2017
was the lowest ever in the 21st century and the incidence
of HIV infections has been decreasing.1
However, these
seemingly promising statistics obscure the full story. The
estimated 21·7 million individuals starting ART includes
those who are lost to follow-up and who are double
counted when they return to care. Furthermore, CD4
count at ART initiation has now plateaued, suggesting
that progress towards earlier HIV diagnosis has effectively
stalled.2
Updates and future directions in preventing,
diagnosing, and treating advanced HIV and associated
co-infections are the focus of this Review.
In this Review, we define advanced HIV using the
WHO definition,3
which for adults, adolescents, and
children older than age 5 years, is a CD4 cell count less
than 200 cells per µL or a WHO clinical stage III or IV
event.4
Any child younger than age 5 years with HIV is
considered to have advanced HIV disease. Individuals
presenting to care with a CD4 count of less than 350 cells
per µL or presenting with an AIDS-defining illness
(regardless of CD4 count) are considered to have late
presentation of HIV, according to the European Late
Presenter Consensus definition.5
Scope of the problem
Two broad groups of individuals present with advanced
HIV: individuals who are ART-naive and those who are
ART-experienced.
ART-naive patients have never had ART and have
advanced disease at the time of initial HIV diagnosis.
Several studies have identified risk factors for these
individuals, including male gender, older than age
50 years, heterosexual, and a migrant.6–14
These risk
factors emphasise groups not traditionally considered to
be at high risk of acquiring HIV. Consequently, countries
should initiate or strengthen HIV screening programmes
for all individuals, and encourage health-care providers
to offer provider-initiated counselling and testing without
bias towards perceived risk. The poor linkage between
inpatient and outpatient care in low-income and middle-
income countries also needs to be highlighted. Many
individuals who are aware of their HIV status and are
admitted to hospital are never linked to outpatient care.
This can result in large proportions of late presenters
with prior interactions with the health system for whom
HIV diagnosis was either missed or not linked to
outpatient care.15
A renewed emphasis on better linkage
from inpatient to outpatient care is necessary to identify
HIV infection at earlier stages, when outcomes are more
favourable.
A new but alarming trend noted in countries that rolled
out ART early is that higher proportions of individuals
with advanced disease are ART-experienced compared
with those who are ART-naive. In one study in South
Africa, the ART-experienced group went from being 14·3%
with CD4 counts less than 50 cells per µL in 2008 to 56·7%
in 2017. Similarly, high proportions of ART-experienced
individuals were noted in studies among inpatients in
the Democratic Republic of the Congo and Kenya.16
This
finding suggests that successful scale-up of ART initiation
has not been followed by sustained retention and
adherence. The most widely used ART regimens for first-
line patients feature non-nucleoside reverse transcriptase
inhibitors (NNRTIs), which are susceptible to resistance
during periods of poor adherence. Patients with poor
adherence and receiving less robust NNRTI-based ART
can be expected to progress to advanced disease, especially
in settings where monitoring for treatment failure is not
available or routinely done, which is all too common in
low-resource settings.
Implications of advanced HIV
A high incidence of advanced HIV leads to adverse
effects for patients and health systems. Compared with
people with less advanced disease, individuals who start
ART at low CD4 counts have a high risk of mortality,
which is related to their poor immunological status when
ART is initiated.17
Given that these patients tend to
be sicker and often admitted to hospital, the fact that
Advanced HIV: diagnosis, treatment, and prevention
Sandeep Prabhu, Joseph I Harwell, Nagalingeswaran Kumarasamy
Substantial progress has been made this century in bringing millions of people living with HIV into care, but progress
for early HIV diagnosis has stalled. Individuals first diagnosed with advanced HIV have higher rates of mortality
than those diagnosed at an earlier stage even after starting antiretroviral therapy (ART), resulting in substantial costs
to health systems. Diagnosis of these individuals is hindered because many patients are asymptomatic, despite being
severely immunosuppressed. Baseline CD4 counts and screening for opportunistic infections, such as tuberculosis
and cryptococcus, is crucial because of the high mortality associated with these co-infections. Individuals with
advanced HIV should have rapid ART initiation (except when found to have symptoms, signs, or a diagnosis of
cryptococcal meningitis) and those in treatment failure should switch treatment. Overcoming barriers to testing and
adherence through the development of differentiated care models and providing psychosocial support will be key in
reaching populations at high risk of presenting with advanced HIV.
Lancet HIV 2019; 6: e540–51
Published Online
July 5, 2019
http://dx.doi.org/10.1016/
S2352-3018(19)30189-4
University of California,
San Diego School of Medicine,
La Jolla, CA, USA (S Prabhu MD);
Clinton Health Access
Initiative, Boston, MA, USA
(J I Harwell MD); and Chennai
Antiviral Research and
Treatment Clinical Research
Site,Voluntary Health Services,
Chennai, India
(N Kumarasamy PhD)
Correspondenceto:
DrNagalingeswaranKumarasamy,
ChennaiAntiviral Research and
TreatmentClinical Research Site,
Voluntary Health Services,
Chennai 600113, India
kumarasamyn@gmail.com

www.thelancet.com/hiv Vol 6 August 2019 e541
Review
advanced HIV places burden on already strained health-
care systems is not surprising; although high-resource
settings are also affected.9,11
In addition to high rates of mortality, patients with
advanced HIV disease are also more likely to be lost to
follow-up than are those with less advanced disease.
One study from Zimbabwe found low baseline weight and
WHO stage IV were associated with an increased
likelihood of becoming lost to follow-up.18
Another study
from Ethiopia reported that baseline functional status and
CD4 count at ART initiation were significantly associated
with retention in care.19
A systematic review of 33 data
sources covering more than 200000 patients found low
baseline CD4 counts to be associated with attrition,
concluding that increases in baseline CD4 counts should
be associated with increases in retention.20
Although many
patients with advanced disease are lost to follow-up
because of mortality, one study that successfully traced
86% of a subset of lost to follow-up cases found that
advanced WHO stage was significantly associated with
stopping care while alive.21
Earlier diagnosis provides an opportunity to prevent
secondary transmissions. The HPTN 052 study22
showed
conclusively that effective ART can successfully prevent
sexual transmission of HIV. This finding agrees with
those from the PARTNER and PARTNER2 studies,23,24
which found zero transmission of within-couple HIV
transmissions when the seropositive partner was on
suppressive ART. Therefore, delays in diagnosis and ART
initiation are likely to translate into missed opportunities
to prevent secondary transmissions.
Diagnosis
An important first step in the management of advanced
HIV disease is case-finding. Although many individuals
are diagnosed on presentation with a concurrent
symptomatic opportunistic infection, many others remain
asymptomatic despite severe immunosuppression. Studies
of patients in Africa and Asia indicate that between 6% and
8% of patients with CD4 counts of less than 100 cells
per µL have asymptomatic cryptococcal antigenaemia.25–29
In the REALITY Trial30
done in Kenya, Malawi, Uganda,
and Zimbabwe, the median CD4 counts of patients was
37 cells per µL, yet half were asymptomatic. CD4 counts
are necessary to identify patients with advanced disease
and additional screening tests are needed to identify
opportunistic infections. WHO’s advanced disease guide
lines recommend specific interventions for patients with
certain CD4 thresholds, so it follows that CD4 count is
important for identifying candidates for these screening
tests and other interventions. Many countries do not
emphasise CD4 testing because it is no longer necessary to
determine ART eligibility. Estimates suggest that CD4
capacity is sufficient to meet the programmatic needs, but
less than 14% of testing capacity is used.31
To optimise
management of advanced HIV disease, countries need to
ensure that instruments and reagent supply chains are
maintained and that clinicians are reminded of the
importance of baseline CD4 in advanced HIV disease
management.
Screening for key opportunistic infections in
advanced HIV
Tuberculosis
Tuberculosis is the leading cause of death among people
living with HIV, not only among patients admitted to
hospital, but also for outpatients, as noted by autopsy
results in those with advanced HIV. One study from
South Africa found evidence of tuberculosis in 47% of
patients who underwent a minimally invasive autopsy,
38% of whom had not started treatment.32
Despite the morbidity and mortality associated with
co-infection with tuberculosis and HIV, most individuals
are not screened; even among those who are screened,
few have complete evaluation with treatment initiation.33,34
Treatment often does not follow the 2008 WHO
recommendations for starting isoniazid preventive
therapy (IPT), intensified case-finding, and infection
control.35
Symptom screening remains the primary
strategy for identifying patients eligible for IPT, despite
most patients being asymptomatic and thus missed by
this approach. In a study from southeast Asia, of more
than 1700 new patients screened, only 31% admitted to
having symptoms, meaning that 69% required additional
diagnostic tests.36
Unfortunately, the necessary diagnostics
are often unavailable at low-resource facilities, leaving
most patients as neither eligible for IPT nor tuberculosis
treatment. Even at facilities where a sputum smear can be
used for confirmation, same-day diagnoses do not occur.37
Diagnosis is even more difficult in certain populations,
such as in older patients and children, for whom
obtaining sputum samples is difficult. Consequently,
high quality point-of-care diagnostic tests are urgently
required. WHO established the following diagnostic
targets to screen for tuberculosis: sensitivity of at least
90%, specificity of at least 70%, and cost per test of no
more than US$2.
Such a test would ideally be non-sputum based, point-
of-care, administered by a minimally trained health-care
provider, and diagnose both pulmonary and extra
pulmonary tuberculosis.38
The point-of-care C-reactive
protein test was investigated as an alternative test to the
symptom screen.39
The rise of these newer technologies
(table 1)40–43
creates new opportunities for rapid tubercu
losis identification following a symptom screen. We
recom
mend more widespread implementation of the
lipoarabinomannan (LAM) test, which is a true point-of-
care test and one with a mortality benefit.
In the absence of a specific microbiological diagnosis,
one potential strategy for managing suspected tubercu
losis
in patients with advanced HIV is empirical initiation of
therapy. Although WHO has not specifically recommended
this practice, they have offered guidelines for how it
could be deployed.44
Presumptive treatment of tuberculosis

Review
in patients with advanced HIV is supported by a retro
spective study from Uganda, which found a significant
44% reduction in mortality at 8 weeks.45
However,
the REMEMBER study46
compared empirical tuberculosis
therapy with IPT in people with HIV and CD4 counts of
less than 50 cells per µL. The study showed no difference
in mortality between the two groups, but people with active
tuberculosis were excluded. Thus, presumptive treatment
does not appear to be beneficial for asymptomatic patients.
Diagnostic tests for tuberculosis in children are low
yielding as it is difficult to obtain a sputum specimen
from a child, and children typically experience tuberculosis
symptoms with low organism burdens. A study from
Kenya found that LAM had sensitivity of 43% among
children admitted to hospital with HIV,47
compared with
sensitivity of 56% in adults.42
The rapid turn-around time,
low cost, ease of specimen collection, and high specificity,
suggest that LAM could be useful in diagnosing
tuberculosis, but not in excluding it in patients with HIV.
Cryptococcus
Cryptococcal meningitis is a leading cause of mortality
among people living with HIV, especially in sub-Saharan
Africa. Screening for cryptococcal antigen (CrAg) before
symptom onset is important as antigenaemia can precede
symptoms by several weeks (up to a third of asymptomatic
patients can have cryptococcal meningitis) and delaying
treatment can increase mortality.48
Furthermore, ascer
taining a diagnosis provides guidance on when to start
ART as it is one of the few opportunistic infections for
which a delay in starting ART is recommended, with early
ART associated with increased mortality.49
Evidence to support screening for CrAg comes from
several studies, including the REMSTART trial50
done in
Tanzania and Zambia with HIV-positive, ART-naive adults.
The intervention group consisted of CrAg screening,
preemptive antifungals for those who tested positive,
and home visits to provide support; the control group had
no home visits. Mortality was 28% lower in the intervention
group than in the control group. A meta-analysis48
showed
mortality benefit of providing pre
emptive fluconazole
to CrAg-positive individuals.48
WHO guidelines call for
screening for CrAg in all HIV-positive individuals with a
CD4 count of 100 cells per µL or less with a provisional
recommendation for 200 cells per µL or less, before
starting ART.3
A meta-analysis found the prevalence of cryptococcal
antigenaemia (ie, CrAg-positive patients) to be 6·5%
among individuals with CD4 counts of 100 cells per µL or
less and 2% among those with counts of 200 cells per µL
or less.51
However, large regional variations in CrAg
prevalence exist (from as low as 0·3% in Iran to 13·3% in
the western Pacific). Ethiopia and Tanzania have already
adopted a threshold of 150 cells per µL to screen
individuals.52
We recommend increasing the cutoff to
200 cells per µL in settings with a high prevalence of
cryptococcal meningitis (eg, sub-Saharan Africa) and
among inpatients.51
Implementation of CrAg screening in HIV clinics is
not enough for diagnosis. Patients who screen positive
for CrAg need to have a lumbar puncture for cryptococcal
meningitis. However, this is challenging because a
high proportion of patients refuse the procedure (eg,
75% of CrAg-positive patients in the REMSTART trial).50
Type of test Advantages Disadvantages Sensitivity38
Specificity38
Screening test
Point-of-care
C-reactive protein39
Point-of-care test that checks for
the presence of C-reactive
protein in the blood
Tests available within minutes; cost is US$2 per assay; fewer
patients require Xpert confirmatory testing if this test is
implemented as a screening test
C-reactive protein testing might
not be available at all peripheral
centres
90–95% 50–70%
Diagnostic test
Xpert Mycobacterium
tuberculosis or
rifampicin resistance40
Quantitative PCR test that
assesses for presence of
Mycobacterium tuberculosis DNA
Can also test for rifampicin resistance; requires minimal
training to use; same day result
Requires continuous use of
electricity; high unit cost, unless
high volumes achieved; lower
specificity in patients with
tuberculosis
89% 99%
Xpert Ultra38
Quantitative PCR test that
assesses for presence of
Mycobacterium tuberculosis DNA
Can also test for rifampicin resistance; requires minimal
training to use; same day result
Requires continuous use of
electricity; high unit cost, unless
high volumes achieved; lower
specificity in patients with
tuberculosis
95% 96%
Lateral flow LAM
test40–42
Point-of-care test that assesses
patient’s urine for the presence
of LAM (a component of
mycobacterial cell walls)
Useful in children because urine samples are easy to obtain
(obtaining sputum samples can be hazardous); use of LAM has
a mortality benefit; most useful in seriously ill patients with
sputum negative (individuals whose sputum smears are
negative for acid-fast bacilli but are known to have
tuberculosis)
Highest sensitivity with lowest CD4
counts, making it less useful in
patients with high CD4 counts
44% 92–99%
LAM=lipoarabinomannan.
Table 1: Point-of-care tuberculosis diagnostic modalities appropriate for people living with HIV

Review
Additionally, asymptomatic patients can have neuro
cognitive deficits, so without signs or symptoms,
adherence without support is challenging.53,54
The low
acceptance of lumbar puncture affects management as
those with asymptomatic cryptococcal antigenaemia can
be treated with fluconazole alone, but patients with
cryptococcal meningitis require amphotericin-based and
flucytosine-based treatments.52
Timely availability of CD4 testing to determine which
patients need screening, locally available CrAg screening,
and appropriate preemptive treatment are important
elements of an effective advanced HIV disease programme.
Detection of CrAg in a time-sensitive manner has been
enhanced with the availability of point-of-care lateral flow
assays.55
However, logistical challenges exist. High rates of
patients lost to follow up and medication stockouts are
common in many parts of sub-Saharan Africa.56
Staff
motivation, difficulty contacting individuals who test
positive, and inadequate medication supplies are other
practical challenges that have been noted.56
Now that point-
of-care CrAg testing is available, health worker motivation
and training to run these tests is necessary to immediately
provide therapy to those who test positive.
Other fungal infections
Fungal infections, including cryptococcus, are responsible
for at least a quarter of AIDS-related mortality among
people living with HIV worldwide.57
However, tests for
other mycoses (which are often geographically endemic)
are lacking.
PCR can identify colonisation (and even infection) with
Pneumocystis jirovecii, a common cause of pneumonia in
people living with HIV.58
However, a point-of-care tool to
diagnose Pneumocystis infection is of crucial importance,
especially in low-resource settings. Most cases are
diagnosed clinically, but substantial overlap with other
diseases exists. Because high-dose corticosteroids are
an important adjunct to Pneumocystis pneumonia,
misdiagnosis can be hazardous.
Histoplasma is an endemic fungus and diagnosis has
been facilitated in the USA with various antigen detection
tests, but these have been predominantly used in research
studies and are inaccessible in low-resource settings.59
Further work on point-of-care tests is necessary before a
truly affordable and reliable point-of-care test is available
in low-resource settings. However, given the unrecognised
true burden of histoplasmosis and its underdiagnosis,
this remains an area of insufficient research.
Taloromycosis is a fungal infection endemic to southeast
Asia, where point-of-care diagnostics remain an unfulfilled
gap and should be developed.58
Treatment
ART regimens for advanced HIV
The CADIRIS study60
assessed if the addition of a CCR5
antagonist (eg, maraviroc) to a tenofovir, emtricitabine,
and efavirenz regimen could reduce the incidence of
immune reconstitution inflammatory syndrome (IRIS)
in patients with CD4 counts of 100 cells per µL or
less who were starting ART. Unfortunately, this strategy
showed no difference in frequency of or time to IRIS
between the experimental and placebo groups.
Concerns have been raised regarding the risk of IRIS
among patients on integrase strand transfer inhibitor
(INSTI)-based ART. Two cohort studies from northern
Europe suggested a two to three fold increased risk of
IRIS among patients receiving INSTIs.61,62
However, this
result has not been observed in prospective randomised
trials. The INSPIRING study,63
a randomised trial
comparing dolutegravir-based ART with efavirenz-based
ART in patients treated for tuberculosis, reported that
6% of patients in the INSTI group (dolutegravir) met
criteria for tuberculosis-associated IRIS, compared with
9% in the efavirenz group. The REALITY trial64
examined
the effect of 12 weeks of intensified initial ART (with the
INSTI raltegravir) on reduction in early mortality among
patients with advanced HIV and CD4 counts of 100 cells
per µL or less. Although mortality was similar between
groups, no significant association with IRIS was reported,
supporting the safety of INSTI-based ART use in
advanced HIV.
Treatment switch
Treating advanced HIV among those returning to care
poses additional challenges because of the high risk of
acquired resistance, which can occur in up to a quarter of
all patients.65
Even among individuals in care, long delays
occur in recognising and responding to treatment failure,
amplified by a paucity of resources to identify treatment
failure, often resulting in disease progression and
mortality.66
In these cases, the next steps include increasing
availability of viral load monitoring, strengthening
adherence interventions, and streamlining procedures for
rapid treatment switching for patients. However, external
factors such as political instability affect many countries,
some of which still have drug or reagent shortages and
even a lack of second-line treatments.67,68
Dolutegravir is
now a first-line medication in high-resource settings and
is being promoted in low-income and middle-income
countries, where it is a popular option because of its high
genetic barrier to resistance and superior efficacy.69
In
2016, Botswana became the first sub-Saharan African
nation to make dolutegravir available as part of a national
health programme.70
However, data showing an association
between dolutegravir use at conception and neural tube
defects is likely to diminish uptake of this medication
despite pricing agreements that have made a generic
version more affordable to low-income and middle-income
countries.69,71
Prophylaxis
The high mortality rate among people with advanced HIV
within 6 months of starting ART has encouraged further
studies investigating optimal prophylactic regimens for

Review
these patients at high risk of opportunistic infections.
The REALITY trial30
enrolled individuals with CD4 counts
of 100 cells per µL or less, aged 5 years or older, and who
had not previously received ART. The experimental group
in this open-label trial received a single dose of
albendazole, five doses of azithromycin, 12 weeks of
fluconazole (100 mg daily), and 12 weeks of a fixed-dose
formulation containing co-trimoxazole, isoniazid, and
pyridoxine. The control group received co-trimoxazole
only. The study found a 27% lower rate of mortality in the
experimental group compared with the control group at
24 weeks (8·9% vs 12·2%; p=0·03). Notably, only
1·5% of patients in the experimental group had to
discontinue prophylaxis because of toxic effects. This
study provides compelling evidence for a comprehensive
prophylaxis regimen for all patients who are diagnosed
with advanced HIV, and has been recognised by the 2017
WHO guideline group. WHO recommendations include
co-trimoxazole prophylaxis for individuals with CD4
counts of 350 cells per µL or less, or WHO clinical
stage III or IV; tuberculosis prophylaxis in those without
symptoms or a full work-up in those with symptoms; and
preemptive treatment with fluconazole for those who
screen CrAg positive (and do not have symptoms of
meningitis).3
Further work is needed to clarify if azithromycin
prophylactic regimens are appropriate, especially among
individuals with low CD4 counts. Although azithromycin
has been recommended specifically for prophylaxis
against infection with Mycobacterium avium complex in
high-income countries, routine use in newly diagnosed
patients in low-income and middle-income countries is
uncommon. However, severe bacterial infections are an
important cause of hospital admission among people
living with HIV.57
Severe bacterial infections might have
contributed to the unknown causes of death in the
REALITY trial and were probably most reduced by
enhanced, azithromycin-containing prophylaxis.30
Mass
azithromycin administration (twice a year) was associated
with a significant reduction in mortality among young
African children regardless of HIV infection.72
Therefore,
azithromycin prophylaxis in certain populations and
settings might be useful, but the optimal dose, frequency,
and duration have not been determined, and the exact
mechanism by which this drug influences mortality has
not been identified.
The most effective use (ie, optimal dose) of fluconazole
also requires further investigation. The REALITY trial30
provided low-dose fluconazole (100 mg daily) to all patients
without the use of CrAg triage. A retrospective analysis of
outcome according to baseline CrAg status found that
new cryptococcal disease developed in only 7·8% of CrAg-
positive patients receiving low-dose fluconazole, compared
with 20·3% who received co-trimoxazole prophylaxis
only.73
Universal low-dose fluconazole for patients with
advanced HIV might be an alternative option if CrAg
screening is not available.
ART initiation
Principles of ART initiation
Patients with advanced HIV have a high risk of mortality,
particularly in the first 6 months of ART initiation.17,74
WHO has recommended that patients with advanced
HIV should be offered rapid initiation of ART.
As recently as 2010, patients’ readiness was assessed
before starting therapy.75
This practice stemmed from
historical beliefs that all patients with HIV must
complete extensive adherence training before ART
initiation, which often required months to complete.
A secondary analysis of a prospective cohort study in
Uganda did not identify a benefit in terms of adherence
or viral suppression among patients who completed their
adherence counselling before ART, compared with
patients who received ART concurrently with their
counselling.76
Patients who completed counselling before
ART initiation did have an additional 1-month delay in
starting their treatment. New data from the past decade
looking at timing of ART initiation have helped
guidelines evolve.
Approaches to ART initiation required adaptation
because of a lack of standardisation of preparation
activities. Myer and colleagues77
did an analysis of
different education and counselling activities in different
health-care settings in Cape Town, South Africa, finding
that clinics varied substantially in their activities, with
little evidence supporting different approaches.78
Data
from Malaysia show that deferred ART is substantially
higher among certain key populations (such as people
who inject drugs), suggesting that physician bias might
have a role in delaying ART.79
Studies have investigated
the timing of ART among patients with HIV and other
co-infections (table 2),49,80–87
two of which have helped
bring about guideline changes among individuals newly
diagnosed with HIV.
Both the RapIT and GHESKIO studies80,81
show that
starting ART on the day of diagnosis has benefits for both
viral suppression and retention, but the applicability of
these results to individuals with advanced HIV disease is
questionable. The Haitian study (GHESKIO) excluded
patients at advanced stages (WHO stage III or IV
disease). Increased ART uptake among groups started on
ART immediately following diagnosis was probably
driven by healthy individuals who would have not started
treatment if further clinic visits were needed. Additionally,
the cost of enrolling patients in the group starting ART
treatment immediately was 41% higher than in the
standard ART group, but only 4% higher among those
who achieved viral suppression.78
The higher cost in the
immediate ART group was driven by two factors:
individuals were on therapy for a slightly longer time,
and the higher cost of the rapid visit (primary health-care
nurse was present for the entire visit). However, these
costs could easily be reduced with more familiarity with
immediate ART (fewer senior staff members could be
present for the visit), and the overall cost benefits offered

Review
Inclusion
criteria
Type
of
study
Location
Number
of
participants
in
final
analysis
Intervention
group
Control
group
Primary
outcome
Results
Implications
Generalisability
Individuals
newly
diagnosed
with
HIV
RapIT
(Rapid
Initiation
of
Treatment)
Trial
80
Age
>18
years;
CD4
count
<350
cells
per
µL;
non-pregnant
Unblinded
RCT
2
urban
health
centres
in
Johannesburg,
South
Africa
377
Rapid
group:
point-of-care
CD4
count,
point-of
care
tuberculosis
test
if
symptomatic,
point-of-care
blood
tests,
physical
examination,
education,
counseling,
antiretroviral
drugs
provided
Standard
care:
3
clinic
visits
over
2–4
weeks
before
starting
ART
Viral
suppression
after
10
months
Participants
in
the
standard
group
were
1·26
times
(95%
CI
1·05–1·50)
more
likely
to
be
virally
suppressed
than
those
in
the
rapid
group;
participants
in
the
rapid
group
had
a
36%
increased
probability
of
initiating
ART
RR
1·36
(95%
CI
1·24–1·49)
within
90
days
of
study
entry
Starting
ART
on
the
same
day
as
diagnosis
has
benefits
for
viral
suppression
and
retention
Median
CD4
count
was
about
200
cells
per
µL;
unclear
if
these
results
can
be
extended
to
patients
with
advanced
HIV
disease
GHESKIO
(Haitian
Study
Group
for
Kaposi’s
sarcoma
and
OI)
study
81
Age
>18
years;
WHO
stage
I
or
II
disease;
CD4
count
<350
cells
per
µL
(later
increased
to
<500
cells
per
µL)
Unblinded
RCT
1
urban
clinic
in
Port-au-Prince,
Haiti
703
Same-day
group:
ART
initiated
on
day
of
HIV
diagnosis
Standard
care:
initiated
ART
3
weeks
after
HIV
testing
Retention
in
care
12
months
after
HIV
testing
and
viral
suppression
(<50
copies
per
mL
of
HIV-1
RNA)
80%
of
individuals
in
the
same-day
ART
group
remained
in
care,
compared
with
72%
in
the
standard
care
group;
viral
suppression
was
also
higher
in
same-day
group
(53%
vs
44%);
adjusted
RR
for
being
in
care
at
12
months
and
achieving
viral
suppression
was
1·24
(95%
CI
1·06–1·41)
Starting
ART
on
the
same
day
as
diagnosis
has
benefits
for
viral
suppression
and
retention
Only
patients
with
WHO
stage
I
or
II
disease
were
included;
study
used
a
generalised
non-
cohort
population,
making
it
more
representative
of
the
general
population
Individuals
with
HIV
and
co-infections
ACTG5164
study
82
Men
or
women
with
HIV
aged
>13
years
with
AIDS-defining
OI
or
serious
bacterial
infection
Open-label
RCT
39
AIDS
Clinical
Trials
Units
in
the
USA
and
Johannesburg,
South
Africa
282
Immediate
group
started
ART
within
48
h
of
study
enrolment
Deferred
group
started
ART
between
6
weeks
and
12
weeks
of
study
enrolment
Ordered
outcome:
alive
without
AIDS
progression
and
HIV
viral
load
<50
copies
per
mL
at
48
weeks,
or
alive
without
AIDS
progression
with
detectable
viral
load
>50
copies
per
mL
at
48
weeks,
or
AIDS
progression
or
death
at
any
time
Starting
ART
within
14
days
of
diagnosis
versus
after
OI
treatment
showed
a
decrease
in
composite
outcome
of
AIDS
progression
or
death
(24·1%
in
the
late
ART
group
and
14·2%
in
the
early
ART
group)
but
the
mortality
difference
alone
was
not
significant
Early
initiation
of
ART
(before
completing
OI
treatment)
is
associated
with
decreased
AIDS
progression
or
death
compared
with
late
initiation
of
ART
These
results
are
generalisable
to
an
advanced
HIV
population,
such
as
those
with
an
AIDS-defining
OI
or
a
CD4
count
<200
cells
per
μL
Individuals
with
HIV–tuberculosis
co-infection
CAMELIA
(Cambodian
Early
versus
Late
Introduction
of
Antiretrovirals)
study
83
ART-naive
adults
with
CD4
count
<200
cells
per
µL
and
tuberculosis
Open-label
RCT
5
hospitals
in
Cambodia
661
Early
treatment:
ART
2
weeks
after
beginning
ATT
Later
treatment:
ART
8
weeks
after
beginning
ATT
Survival
at
end
of
study
The
earlier
ART
group
had
significantly
improved
long-term
survival
compared
with
the
later
ART
group
(HR
0·62,
95%
CI
0·44–0·86);
risk
of
IRIS
increased
2·51-fold
(95%
CI
1·78–3·59)
in
the
earlier
treatment
group
Early
ART
among
those
receiving
ATT
confers
a
mortality
benefit
that
might
be
more
pronounced
among
those
with
CD4
count
<50
cells
per
µL,
despite
an
increase
in
IRIS
associated
with
tuberculosis
Study
done
in
advanced
HIV
patient
population
(median
CD4
of
only
25
cells
per
µL)
making
these
results
generalisable
to
advanced
HIV
populations
(Table
2
continues
on
next
page)

Review
Inclusion
criteria
Type
of
study
Location
Number
of
participants
in
final
analysis
Intervention
group
Control
group
Primary
outcome
Results
Implications
Generalisability
(Continued
from
previous
page)
SapIT
(Starting
Antiretroviral
Therapy
at
Three
Points
in
Tuberculosis)
trial
84
Age
>18
years
with
confirmed
HIV;
positive
smear
for
acid-fast
bacilli;
CD4
<500
cells
per
µL;
no
contraindications
to
ART
(women
required
to
be
taking
contraceptive
measures)
Open-label
RCT
HIV–tuberculosis
clinic
in
Durban,
South
Africa
642
Early
integrated-therapy
group:
initiated
ART
therapy
within
4
weeks
of
starting
ATT;
sequential-therapy
group:
initiated
ART
within
4
weeks
of
completing
ATT
Late
integrated-
therapy
group:
initiated
ART
within
4
weeks
of
completing
the
intensive
phase
of
ATT
Death
from
any
cause
Individuals
in
the
combined
(early
and
late)
integrated-therapy
groups
had
a
significant
reduction
in
mortality
compared
with
the
sequential
group
(HR
0·44,
95%
CI
0·25–0·79);
IRIS
was
significantly
more
common
in
the
combined
integrated-therapy
groups
(12·4%
vs
3·8%;
p<0·001);
no
medication
changes
required
because
of
IRIS;
no
deaths
attributable
to
IRIS;
mortality
benefit
with
integrated-therapy
was
maintained
regardless
of
CD4
count
stratum
Early
ART
among
those
receiving
ATT
confers
a
mortality
benefit
that
might
be
more
pronounced
among
those
with
CD4
count
<50
cells
per
µL,
despite
an
increase
in
IRIS
associated
with
tuberculosis
The
subgroup
analysis
suggests
that
early
ART
improved
survival
even
among
those
at
the
most
advanced
stage
of
HIV
disease
ACTG
A5221
study
85
Age
>13
years
with
HIV-1;
CD4
<250
cells
per
µL;
ART-naive;
confirmed
or
probable
tuberculosis
Open-label
RCT
Multiple
sites
in
Asia,
Africa,
South
America,
and
North
America
809
Early:
ART
started
within
2
weeks
of
ATT
initiation
Late:
ART
started
between
8
weeks
and
12
weeks
after
ATT
initiation
Proportion
of
patients
who
survived
and
did
not
have
a
new
AIDS-defining
illness
No
significant
difference
in
outcome
among
those
in
the
early
ART
group
compared
with
the
late
ART
group
(12·9%
vs
16·1%;
percentage
difference
95%
CI
1·8–8·1%;
p=0·45)
except
in
subset
of
those
with
CD4
<50
cells
per
µL
(15·5%
in
the
early
ART
group
vs
26·6%
in
the
late
ART
group;
percentage
difference
95%
CI
1·5–20·5%;
p=0·002);
tuberculosis-associated
IRIS
was
more
common
in
the
early
ART
group
(5%
vs
11%;
p=0·002)
Early
ART
is
beneficial
among
individuals
with
CD4
<50
cells
per
μL
compared
with
late
ART
The
subgroup
analysis
emphasises
the
mortality
benefit
of
early
ART
among
those
with
advanced
HIV
disease
receiving
ATT
(Table
2
continues
on
next
page)

Review
Inclusion
criteria
Type
of
study
Location
Number
of
participants
in
final
analysis
Intervention
group
Control
group
Primary
outcome
Results
Implications
Generalisability
(Continued
from
previous
page)
Meta-analysis
86
RCTs
that
investigated
timing
of
ART
initiation
among
people
living
with
HIV,
with
newly
diagnosed
pulmonary
tuberculosis
Systematic
review
and
meta-analysis
··
8
trials
were
included
··
··
··
A
decrease
in
all-cause
mortality
was
noted
among
individuals
with
CD4
<50
cells
per
µL
(RR
0·71,
95%
CI
0·54–0·93);
no
significant
mortality
difference
among
those
with
CD4
>50
cells
per
µL
(RR
1·05,
95%
CI
0·68–1·61);
individuals
receiving
early
ART
had
more
than
double
the
incidence
of
tuberculosis-associated
IRIS
(RR
2·31,
95%
CI
1·87–2·86)
··
Findings
specifically
applicable
to
patients
with
advanced
HIV
and
tuberculosis
Individuals
with
HIV–cryptococcus
co-infection
COAT
(Cryptococcal
Optimal
ART
Timing)
Trial
87
Age
>18
years;
known
diagnosis
of
HIV;
ART-naïve;
CSF
culture
or
CSF
CrAg
confirmed
diagnosis
of
cryptococcal
meningitis
Open-label
RCT
Two
urban
hospitals
in
Kampala,
Uganda
and
one
hospital
in
Cape
Town,
South
Africa
177
Early
ART,
within
1–2
weeks
after
diagnosis
Deferred
ART,
within
5
weeks
after
diagnosis
Survival
at
25
weeks
At
26
weeks,
HR
of
mortality
among
those
in
the
early
ART
group
was
1·73
times
(95%
CI
1·06–2·82)
increased
compared
with
in
the
later
ART
group;
cryptococcal
occurrence
of
IRIS
was
not
significantly
different
between
the
two
groups
(20%
in
early
ART
group
vs
13%
in
deferred
ART
group;
p=0·32)
ART
should
be
deferred
among
individuals
with
confirmed
cryptococcal
meningitis
as
it
is
associated
with
increased
mortality
Earlier
ART
was
not
favourable
even
in
the
subgroup
of
individuals
with
CD4
<50
cells
per
µL
(although
this
result
was
not
statistically
significant)
Cochrane
review
49
RCTs
investigated
people
living
with
HIV
with
cryptococcal
meningitis
who
initiated
ART
within
4
weeks
of
cryptococcal
meningitis
diagnosis
and
those
who
initiated
it
4
weeks
after
diagnosis
Systematic
review
and
meta-analysis
··
4
trials
were
included
··
··
··
Early
ART
might
increase
mortality,
but
it
is
unclear
if
this
is
due
to
cryptococcal
IRIS,
and
review
was
unable
to
determine
if
early
ART
affects
viral
suppression
at
6
months
ART
should
be
deferred
among
individuals
with
confirmed
cryptococcal
meningitis
as
it
is
associated
with
increased
mortality
The
small
number
of
studies
analysed
make
conclusions
difficult,
but
early
ART
is
suggestive
of
increased
mortality
among
people
living
with
HIV
with
cryptococcal
meningitis
ART=antiretroviral
therapy.
RCT=randomised
controlled
trial.
OI=opportunistic
infection.
RR=relative
risk.
ATT=anti-tuberculosis
therapy.
HR=hazard
ratio.
IRIS=immune
reconstitution
inflammatory
syndrome.
CrAg=cryptococcal
antigen.
Table
2:
Studies
investigating
early
versus
late
initiation
of
ART
among
people
living
with
HIV

Review
by a person being virally suppressed, compared with a
person who is not virally suppressed.
Broadly, the data suggest that early ART among
patients with co-infections improves outcomes with
two important caveats (table 2). In the case of patients on
ART and anti-tuberculosis therapy, early ART confers a
mortality benefit, despite an increase in tuberculosis-
associated IRIS. The main exception to this rule is
cryptococcal meningitis. Increasing evidence is showing
that initiation of ART early in the course of treatment for
cryptococcal meningitis is associated with higher
mortality, so increased availability of CrAg screening is
important to facilitate decisions about rapid ART
initiation.83
Challenges moving forward
Implementation of immediate ART has operational
challenges, such as changing long-standing beliefs at the
primary clinic level. Amanyire and colleagues88
did an
open-label randomised controlled trial that targeted
an intervention to change health-care worker behaviour
to assess whether it increased the likelihood of initiating
ART within 14 days of diagnosis. Interventions included
face-to-face didactics, a new approach to counselling that
emphasised an individual patient approach to ART
readiness rather than the previous approach of multiple
adherence counselling sessions for all patients. Finally,
the intervention sites were also given machines to
provide real-time CD4 cell count results. Individuals at
intervention sites were more likely to start ART within
14 days of eligibility than were those at the control sites.
This study uncovered beliefs that delays in ART initiation
were not harmful, which emphasises the need for
education among health-care providers. Point-of-care
CD4 cell count reduced the need for multiple visits,
which was a key advantage. Implementing ART quickly
requires aware
ness of real-world challenges beyond just
the availability of appropriate therapies. However, further
behavioural and evaluation work needs to be done in the
coming years to understand the extent to which
immediate ART is being scaled up and to understand
challenges that are encountered in this process.
Prevention of advanced HIV
Moving forward, sustained progress is needed in
preventing advanced HIV by extending the reach of
testing, and reducing barriers to care.
Many cases of HIV remain undiagnosed, and several
groups in particular tend to be late presenters, including
men, older individuals, and migrants.6–8,10–12
Therefore,
understanding the reasons for this discrepancy must
precede developing strategies for mitigation. To encourage
individuals to seek testing at earlier asymptomatic stages
of disease rather than waiting for the onset of a disabling
illness, strategies to generate interest while removing
barriers to accessing care are needed. One qualitative study
found that structural factors and gender norms were
important determinants for HIV testing behaviours.89
Key
themes from this study included that men are away for
large portions of the year because of jobs elsewhere, strong
societal perceptions exist that health seeking is for
women and not men, and that traditional power structures
normalise men’s high sex-risk behaviours. Clearly, the
previously successful so-called one-size-fits-all approach
to HIV diagnosis will be insufficient in reaching men
in these communities. Instead, targeted interventions
occurring during the months that men return to the
community and provided by local practitioners, irrespective
of cultural beliefs about health seeking, are required.
Another successful strategy for improving access to
testing for men includes self-testing. For example,
in Uganda, peer-distribution of HIV self-tests among
fishermen found an 82% acceptance of this approach,
with 25% of participants having never been tested
previously.90
Differentiated care has been defined as “a client-
centered approach that simplifies and adapts HIV
services across the cascade, in ways that both serve the
needs of PLWH [people living with HIV] better and
reduce unnecessary burdens on the health system”.91
This can include interventions such as community ART
groups collecting medications for a group of patients
whose individual transportation costs preclude regular
visits, or 6-month refills instead of 3-month refills for
stable patients to reduce wait times at facilities.92,93
These
interventions reduce barriers to care, increase efficiency
of health-care providers by enabling them to focus on
patients at more advanced stages, and save money for
health systems.92–94
Further expansion of differentiated
care models, especially in regions and for populations in
which uptake of HIV care services is low, will be
important in diagnosing asymptomatic infection earlier.
Psychosocial support can improve the likelihood of
treatment success. A study in rural Rwanda showed that
those who had financial costs associated with going to a
clinic had lower odds of negative outcomes if they
received a community-based accompaniment (including
daily home visits).94
Similar results were seen for those
who were unable to access services in the previous
6 months: those with community-based accom
paniment
had better outcomes than those without.94
Therefore,
psychosocial support, especially for high-risk populations,
will play an integral role in improving adherence and
subsequent outcomes in these populations.
WHO guidelines for advanced HIV disease manage
ment recommend that community-based support should
be used during initiation of ART. The investigators
from the REMSTART study50
concluded that of the
28% reduction in mortality they observed, about half was
attributable to four weekly home visits by lay health-care
workers to provide personalised adherence support and
manage side-effects. However, further work is needed
to determine the most cost-effective strategies for
community support.

Review
Conclusion
Tremendous progress has been made in bringing millions
of individuals living with HIV into care, but late diagnosis
remains a pressing issue in key populations. Most new
infections in several regions of the world are among key
populations, and data-driven approaches to understand
risk and improved epidemiological surveillance for these
populations are crucial.1
Such an approach was used in
Kenya, with a survey that sought to measure outcomes
following a national HIV prevention programme for key
populations.95
Although the initial results have been mixed,
such a targeted approach could serve as a model for other
countries to diagnose and reliably link these populations to
care. Doing so would not only help optimise their
outcomes by diagnosing individuals early, but might also
be cost-effective.1,96,97
Most importantly, this approach will
be crucial to reaching the UNAIDS 90-90-90 goals.1
Contributors
SP, JIH, and NK all contributed to the literature search and drafting
sections of the text. SP, JIH, and NK made crucial revisions to and
approved the final draft of the manuscript. SP and NK prepared the tables.
Declaration of interests
We declare no competing interests.
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340 articles published in English from Nov 1, 2013,
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