Review
Advanced HIV: diagnosis, treatment, and prevention
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)
Correspondence to:
Dr Nagalingeswaran Kumarasamy,
Chennai Antiviral Research and
Treatment Clinical Research Site,
Voluntary Health Services,
Chennai 600113, India
kumarasamyn@gmail.com
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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.
Introduction to offer provider-initiated counselling and testing without
Substantial progress has been made in the identification bias towards perceived risk. The poor linkage between
of individuals with HIV and starting them on anti­ inpatient and outpatient care in low-income and middle-
retroviral therapy (ART): 21·7 million of the estimated income countries also needs to be highlighted. Many
36·9 million people living with HIV worldwide are now on individuals who are aware of their HIV status and are
treatment.1 The number of AIDS-related deaths in 2017 admitted to hospital are never linked to outpatient care.
was the lowest ever in the 21st century and the incidence This can result in large proportions of late presenters
of HIV infections has been decreasing.1 However, these with prior interactions with the health system for whom
seemingly promising statistics obscure the full story. The HIV diagnosis was either missed or not linked to
estimated 21·7 million individuals starting ART includes outpatient care.15 A renewed emphasis on better linkage
those who are lost to follow-up and who are double from inpatient to outpatient care is necessary to identify
counted when they return to care. Furthermore, CD4 HIV infection at earlier stages, when outcomes are more
count at ART initiation has now plateaued, suggesting favourable.
that progress towards earlier HIV diagnosis has effectively A new but alarming trend noted in countries that rolled
stalled.2 Updates and future directions in preventing, out ART early is that higher proportions of individuals
diagnosing, and treating advanced HIV and associated with advanced disease are ART-experienced compared
co-infections are the focus of this Review. with those who are ART-naive. In one study in South
In this Review, we define advanced HIV using the Africa, the ART-experienced group went from being 14·3%
WHO definition,3 which for adults, adolescents, and with CD4 counts less than 50 cells per µL in 2008 to 56·7%
children older than age 5 years, is a CD4 cell count less in 2017. Similarly, high proportions of ART-experienced
than 200 cells per µL or a WHO clinical stage III or IV individuals were noted in studies among inpatients in
event.4 Any child younger than age 5 years with HIV is the Democratic Republic of the Congo and Kenya.16 This
considered to have advanced HIV disease. Individuals finding suggests that successful scale-up of ART initiation
presenting to care with a CD4 count of less than 350 cells has not been followed by sustained retention and
per µL or presenting with an AIDS-defining illness adherence. The most widely used ART regimens for first-
(regardless of CD4 count) are considered to have late line patients feature non-nucleoside reverse transcriptase
presentation of HIV, according to the European Late inhibitors (NNRTIs), which are susceptible to resistance
Presenter Consensus definition.5 during periods of poor adherence. Patients with poor
adherence and receiving less robust NNRTI-based ART
Scope of the problem can be expected to progress to advanced disease, especially
Two broad groups of individuals present with advanced in settings where monitoring for treatment failure is not
HIV: individuals who are ART-naive and those who are available or routinely done, which is all too common in
ART-experienced. low-resource settings.
ART-naive patients have never had ART and have
advanced disease at the time of initial HIV diagnosis. Implications of advanced HIV
Several studies have identified risk factors for these A high incidence of advanced HIV leads to adverse
individuals, including male gender, older than age effects for patients and health systems. Compared with
50 years, heterosexual, and a migrant.6–14 These risk people with less advanced disease, individuals who start
factors emphasise groups not traditionally considered to ART at low CD4 counts have a high risk of mortality,
be at high risk of acquiring HIV. Consequently, countries which is related to their poor immunological status when
should initiate or strengthen HIV screening programmes ART is initiated.17 Given that these patients tend to
for all individuals, and encourage health-care providers be sicker and often admitted to hospital, the fact that
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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 200 000 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
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Review
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
recom­mend 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 tubercu­losis
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

Type of test Advantages Disadvantages Sensitivity38 Specificity38

Screening test
Point-of-care Point-of-care test that checks for Tests available within minutes; cost is US$2 per assay; fewer
C-reactive protein39 the presence of C-reactive
protein in the blood
Diagnostic test
Xpert Mycobacterium Quantitative PCR test that
tuberculosis or assesses for presence of
rifampicin resistance40 Mycobacterium tuberculosis DNA
Xpert Ultra38 Quantitative PCR test that
assesses for presence of
Mycobacterium tuberculosis DNA
Lateral flow LAM Point-of-care test that assesses
test40–42 patient’s urine for the presence
of LAM (a component of
mycobacterial cell walls)
C-reactive protein testing might 90–95% 50–70%
patients require Xpert confirmatory testing if this test is not be available at all peripheral
implemented as a screening test centres
Can also test for rifampicin resistance; requires minimal Requires continuous use of 89% 99%
training to use; same day result electricity; high unit cost, unless
high volumes achieved; lower
specificity in patients with
tuberculosis
Can also test for rifampicin resistance; requires minimal Requires continuous use of 95% 96%
training to use; same day result electricity; high unit cost, unless
high volumes achieved; lower
specificity in patients with
tuberculosis
Useful in children because urine samples are easy to obtain Highest sensitivity with lowest CD4 44% 92–99%
(obtaining sputum samples can be hazardous); use of LAM has counts, making it less useful in
a mortality benefit; most useful in seriously ill patients with patients with high CD4 counts
sputum negative (individuals whose sputum smears are
negative for acid-fast bacilli but are known to have
tuberculosis)

LAM=lipoarabinomannan.

Table 1: Point-of-care tuberculosis diagnostic modalities appropriate for people living with HIV

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

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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
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Review
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.
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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
 Inclusion criteria Type of study Location Number of Intervention Control group Primary outcome Results Implications Generalisability
participants in group
final analysis

Individuals newly diagnosed with HIV

RapIT (Rapid Age >18 years; Unblinded RCT 2 urban health 377 Rapid group: Standard care: Viral suppression Participants in the standard Starting ART on Median CD4 count
Initiation of CD4 count centres in point-of-care CD4 3 clinic visits after 10 months group were 1·26 times the same day as was about 200 cells
Treatment) <350 cells per µL; Johannesburg, count, point-of care over 2–4 weeks (95% CI 1·05–1·50) more diagnosis has per µL; unclear if
Trial80 non-pregnant South Africa tuberculosis test if before starting likely to be virally suppressed benefits for viral these results can be
symptomatic, ART than those in the rapid suppression and extended to patients
point-of-care blood group; participants in the retention with advanced HIV
tests, physical rapid group had a 36% disease
examination, increased probability of

www.thelancet.com/hiv Vol 6 August 2019

education, initiating ART RR 1·36
counseling, (95% CI 1·24–1·49) within
antiretroviral drugs 90 days of study entry
provided
GHESKIO Age >18 years; Unblinded RCT 1 urban clinic in 703 Same-day group: Standard care: Retention in care 80% of individuals in the Starting ART on Only patients with
(Haitian Study WHO stage I or II Port-au-Prince, ART initiated on initiated ART 12 months after same-day ART group the same day as WHO stage I or II
Group for disease; CD4 Haiti day of HIV 3 weeks after HIV testing and remained in care, compared diagnosis has disease were included;
Kaposi’s count <350 cells diagnosis HIV testing viral suppression with 72% in the standard benefits for viral study used a
sarcoma and per µL (later (<50 copies per mL care group; viral suppression suppression and generalised non-
OI) study81 increased to of HIV-1 RNA) was also higher in same-day retention cohort population,
<500 cells per µL) group (53% vs 44%); making it more
adjusted RR for being in care representative of the
at 12 months and achieving general population
viral suppression was 1·24
(95% CI 1·06–1·41)
Individuals with HIV and co-infections
ACTG5164 Men or women Open-label RCT 39 AIDS Clinical 282 Immediate group Deferred group Ordered outcome: Starting ART within 14 days Early initiation of These results are
study82 with HIV aged Trials Units in started ART within started ART alive without AIDS of diagnosis versus after OI ART (before generalisable to an
>13 years with the USA and 48 h of study between progression and treatment showed a completing OI advanced HIV
AIDS-defining OI Johannesburg, enrolment 6 weeks and HIV viral load decrease in composite treatment) is population, such as
or serious South Africa 12 weeks of <50 copies per mL outcome of AIDS progression associated with those with an
bacterial infection study at 48 weeks, or or death (24·1% in the late decreased AIDS AIDS-defining OI or a
enrolment alive without AIDS ART group and 14·2% in the progression or CD4 count <200 cells
progression with early ART group) but the death compared per μL
detectable viral mortality difference alone with late initiation
load >50 copies was not significant of ART
per mL at
48 weeks, or AIDS
progression or
death at any time
Individuals with HIV–tuberculosis co-infection

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CAMELIA ART-naive adults Open-label RCT 5 hospitals in 661 Early treatment: Later treatment: Survival at end of The earlier ART group had Early ART among Study done in
(Cambodian with CD4 count Cambodia ART 2 weeks after ART 8 weeks study significantly improved those receiving advanced HIV patient
Early versus Late <200 cells per µL beginning ATT after beginning long-term survival ATT confers a population (median
Introduction of and tuberculosis ATT compared with the later mortality benefit CD4 of only 25 cells
Antiretrovirals) ART group (HR 0·62, that might be per µL) making these

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study83 95% CI 0·44–0·86); risk of more pronounced results generalisable
IRIS increased 2·51-fold among those with to advanced HIV
(95% CI 1·78–3·59) in the CD4 count populations
earlier treatment group <50 cells per µL,
despite an increase
in IRIS associated
Review

with tuberculosis
(Table 2 continues on next page)

e545
 e546
Review

Inclusion criteria Type of study Location Number of Intervention Control group Primary outcome Results Implications Generalisability
participants in group
final analysis

(Continued from previous page)

SapIT (Starting Age >18 years Open-label RCT HIV–tuberculosis 642 Early Late integrated- Death from any Individuals in the combined Early ART among The subgroup analysis
Antiretroviral with confirmed clinic in Durban, integrated-therapy therapy group: cause (early and late) those receiving suggests that early
Therapy at HIV; positive South Africa group: initiated initiated ART integrated-therapy groups ATT confers a ART improved
Three Points in smear for acid-fast ART therapy within within 4 weeks had a significant reduction in mortality benefit survival even among
Tuberculosis) bacilli; 4 weeks of starting of completing mortality compared with the that might be those at the most
trial84 CD4 <500 cells ATT; the intensive sequential group (HR 0·44, more pronounced advanced stage of HIV
per µL; no sequential-therapy phase of ATT 95% CI 0·25–0·79); IRIS was among those with disease
contraindications group: initiated significantly more common CD4 count
to ART (women ART within 4 weeks in the combined <50 cells per µL,
required to be of completing ATT integrated-therapy groups despite an increase
taking (12·4% vs 3·8%; p<0·001); in IRIS associated
contraceptive no medication changes with tuberculosis
measures) required because of IRIS;
no deaths attributable to
IRIS; mortality benefit with
integrated-therapy was
maintained regardless of
CD4 count stratum
ACTG A5221 Age >13 years Open-label RCT Multiple sites in 809 Early: ART started Late: ART Proportion of No significant difference in Early ART is The subgroup analysis
study85 with HIV-1; CD4 Asia, Africa, within 2 weeks of started between patients who outcome among those in beneficial among emphasises the
<250 cells per µL; South America, ATT initiation 8 weeks and survived and did the early ART group individuals with mortality benefit of
ART-naive; and North 12 weeks after not have a new compared with the late ART CD4 <50 cells early ART among
confirmed or America ATT initiation AIDS-defining group (12·9% vs 16·1%; per μL compared those with advanced
probable illness percentage difference with late ART HIV disease receiving
tuberculosis 95% CI 1·8–8·1%; p=0·45) ATT

For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
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

Downloaded for Anonymous User (n/a) at National Autonomous University of Mexico from ClinicalKey.com by Elsevier on June 27, 2020.
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)
(Table 2 continues on next page)

www.thelancet.com/hiv Vol 6 August 2019

 Inclusion criteria Type of study Location Number of Intervention Control group Primary outcome Results Implications Generalisability
participants in group
final analysis

(Continued from previous page)

Meta-analysis86 RCTs that Systematic ·· 8 trials were ·· ·· ·· A decrease in all-cause ·· Findings specifically
investigated review and included mortality was noted among applicable to patients
timing of ART meta-analysis individuals with CD4 with advanced HIV
initiation among <50 cells per µL (RR 0·71, and tuberculosis
people living with 95% CI 0·54–0·93);
HIV, with newly no significant mortality
diagnosed difference among those
pulmonary with CD4 >50 cells per µL

www.thelancet.com/hiv Vol 6 August 2019

tuberculosis (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)
Individuals with HIV–cryptococcus co-infection
COAT Age >18 years; Open-label RCT Two urban 177 Early ART, within Deferred ART, Survival at At 26 weeks, HR of mortality ART should be Earlier ART was not
(Cryptococcal known diagnosis hospitals in 1–2 weeks after within 5 weeks 25 weeks among those in the early deferred among favourable even in the
Optimal ART of HIV; ART-naïve; Kampala, diagnosis after diagnosis ART group was 1·73 times individuals with subgroup of
Timing) Trial87 CSF culture or CSF Uganda and (95% CI 1·06–2·82) confirmed individuals with CD4
CrAg confirmed one hospital in increased compared with in cryptococcal <50 cells per µL
diagnosis of Cape Town, the later ART group; meningitis as it is (although this result
cryptococcal South Africa cryptococcal occurrence of associated with was not statistically
meningitis IRIS was not significantly increased significant)
different between the mortality
two groups (20% in early
ART group vs 13% in
deferred ART group; p=0·32)
Cochrane RCTs investigated Systematic ·· 4 trials were ·· ·· ·· Early ART might increase ART should be The small number of
review49 people living with review and included mortality, but it is unclear if deferred among studies analysed
HIV with meta-analysis this is due to cryptococcal individuals with make conclusions
cryptococcal IRIS, and review was unable confirmed difficult, but early ART
meningitis who to determine if early ART cryptococcal is suggestive of
initiated ART affects viral suppression at meningitis as it is increased mortality
within 4 weeks of 6 months associated with among people living
cryptococcal increased with HIV with
meningitis mortality cryptococcal
diagnosis and meningitis
those who
initiated it 4 weeks
after diagnosis

For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
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

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Review

e547
 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 aware­ness 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
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For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
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 accom­paniment
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.

Search strategy and selection criteria
We searched PubMed for original research, reviews,
and viewpoint articles describing advanced HIV among adults,
using the term “advanced HIV” in the title or abstract.
340 articles published in English from Nov 1, 2013,
to Oct 31, 2018, were reviewed, in addition to references of
relevant articles. Papers were retained for this scoping review if
they discussed the diagnosis, treatment, or prevention of
advanced HIV; also included were those that discussed
antiretroviral therapy (ART) initiation strategies and ART
regimens specific to individuals with advanced disease or those
with treatment failure. We also reviewed WHO treatment
guidelines and reports, and conference abstracts that were
cited in WHO treatment guidelines or reviewed articles.
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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