nature reviews disease primers https://doi.org/10.

1038/s41572-023-00452-3

Primer Check for updates

HIV infection
Linda-Gail Bekker    1  , Chris Beyrer2, Nyaradzo Mgodi    3, Sharon R. Lewin    4,5,6, Sinead Delany-Moretlwe7,
Babafemi Taiwo8, Mary Clare Masters8 & Jeffrey V. Lazarus    9,10
Abstract Sections

The AIDS epidemic has been a global public health issue for more than Introduction

40 years and has resulted in ~40 million deaths. AIDS is caused by the Epidemiology
retrovirus, HIV-1, which is transmitted via body fluids and secretions. Mechanisms/pathophysiology
After infection, the virus invades host cells by attaching to CD4
Diagnosis, screening and
receptors and thereafter one of two major chemokine coreceptors, prevention
CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte,
Management
as it replicates. If unchecked this can lead to an immune-deficient state
Quality of life
and demise over a period of ~2–10 years. The discovery and global
roll-out of rapid diagnostics and effective antiretroviral therapy led Outlook

to a large reduction in mortality and morbidity and to an expanding

group of individuals requiring lifelong viral suppressive therapy. Viral
suppression eliminates sexual transmission of the virus and greatly
improves health outcomes. HIV infection, although still stigmatized,
is now a chronic and manageable condition. Ultimate epidemic control
will require prevention and treatment to be made available, affordable
and accessible for all. Furthermore, the focus should be heavily
oriented towards long-term well-being, care for multimorbidity and
good quality of life. Intense research efforts continue for therapeutic
and/or preventive vaccines, novel immunotherapies and a cure.

1
The Desmond Tutu HIV Centre, University of Cape Town, RSA, Cape Town, South Africa. 2Duke Global Health
Institute, Duke University, Durham, NC, USA. 3University of Zimbabwe Clinical Trials Research Centre, Harare,
Zimbabwe. 4Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute
for Infection and Immunity, Melbourne, Victoria, Australia. 5Victorian Infectious Diseases Service, The Royal
Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
6
Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
7
Wits RHI, University of the Witwatersrand, Johannesburg, South Africa. 8Division of Infectious Diseases,
Northwestern University, Chicago, IL, USA. 9CUNY Graduate School of Public Health and Health Policy, New York,
NY, USA. 10Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona,
Spain.  e-mail: Linda-Gail.Bekker@hiv-research.org.za

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Primer
Introduction
Four decades into the AIDS epidemic, HIV-1 has infected an estimated
84 million people worldwide and caused the death of ~40 million. This
retrovirus is transmitted human to human via infected body fluids,
for example, blood or sexual fluids, and gains access to host cells via
the CD4 receptor, and coreceptors such as CCR5 or CXCR4, which are
expressed on the surface of the host cells. Most often these host cells
are CD4+ T cell lymphocytes, which are then destroyed by the repli-
cating virus. Over months to years, if untreated, the attrition of CD4+
T cells leads to AIDS, whereby the infected individual becomes suscep-
tible to opportunistic infections and cancers. This leads to the demise
of an adult often within 2–10 years of disease acquisition1. In the case of
newborns infected via vertical transmission in utero, peri-partum or
during lactation, the course of the infection is more rapid, with one
in two babies dying within 24 months2,3. Antiretroviral therapy (ART;
usually a cocktail of antiviral agents with different drug targets) can
alter this course by suppression of viral replication and immune resto-
ration. In many cases a return to a near normal life expectancy can be
achieved as long as treatment is started early and viral suppression is
maintained4. As HIV treatment has improved, in many cases being now
a single pill taken just once a day, the prospect of treating all who live
with HIV around the world is within reach. However, viral transmission
still occurs, especially among those who for reasons of stigma, dis-
crimination, conflict or other structural barriers cannot access testing,
prevention or treatment. In 2021 another 1.5 million people globally
became infected, of which 160,000 were children5.
In this Primer, we discuss the natural history of HIV-1 infection and
transmission, including infection in key populations. We also discuss
the recent progress made in both treatment and prevention of HIV,
patient quality of life (QoL) and the progress that is still needed to bring
this global epidemic to an end.
Epidemiology
Natural history of HIV and SIV
In contrast to the global, highly pathogenic HIV-1, HIV-2 is found mostly in
West Africa, with another known area of significant prevalence in India6;
it is morphologically and biologically similar but only distantly related
to HIV-1. Both HIV-1 and HIV-2 are related to a group of retroviruses
called simian immunodeficiency viruses (SIVs), which are largely
non-pathogenic in their natural non-human primate hosts. Phylogenetic
data have demonstrated that HIV-1 evolved from a SIV, through transmis-
sion to a chimpanzee (Pan troglodytes) and then to humans7,8. HIV-1 com-
prises four distinct lineages, termed groups M, N, O and P, each thought
to be the result of an independent cross-species transmission event in
central western Africa. M, N and O were identified at the beginning of
the twentieth century whereas P has been identified only within the past
three decades9,10 (Fig. 1). Passage from monkey species to the chimpanzee
seemed to have been essential in the zoonosis from non-human primates
to humans, giving rise to group M. Group M is the lineage that gave rise to
pandemic HIV-1 and has subsequently been found in virtually every
country in the world (Fig. 2) and is the subject of this Primer.
Host proteins that provide natural immunity to viruses, known as
restriction factors, may be highly effective at preventing infection of
poorly adapted viruses from other species, thereby frequently repre­
senting potent barriers to successful cross-species transmission. In
the case of HIV evolution, SIV is hypothesized to have accumulated
multiple mutations that enabled evasion of restriction factors to over-
come the species barrier11. It is thought that dissemination of HIV-1
from central West Africa may have resulted from increased human to
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human contact through societal changes, rapid urbanization and an
increased prevalence of sexually transmitted infections, including geni-
tal ulcers12–17. Genital ulcers likely facilitate more rapid and efficient HIV
transmission between individuals owing to disruption of the protective
mucosa. As HIV-1 group M spread globally, its dissemination involved
several population bottleneck founder events, which led to the predom-
inance of different group M lineages, now called subtypes, in different
geographical areas18. There are nine subtypes (A–D, F–H, J, K), as well as
more than 40 different circulating recombinant forms (CRFs), which are
distributed around the world. CRFs occur when a viral genome is derived
from two or more subtypes as a result of genetic recombination19.
It has been possible to trace the migration pathways of some of these
subtypes and CRFs. For example, subtypes A and D originated in West
Africa, but ultimately established epidemics in eastern Africa, Russia
and Central Asia whereas subtype C was introduced to, and predomi-
nates in, southern Africa from where it spread to India and other Asian
countries20. Subtype B, which accounts for most of HIV-1 infections in
Europe and the Americas, arose from a single African strain that seems
to have first spread to Haiti in the 1960s and then onward to the USA
and other Western countries20. The recombination event that created
CRF01 (a recombinant of A and E subtypes) probably occurred in West
Africa and has gone on to dominate the Southeast Asian epidemic21.
Global incidence
HIV infection is transmitted within human populations by sexual, par-
enteral and perinatal routes including breastfeeding; however, ~80%
of adolescents and adults acquire HIV via either vaginal or anal sex22,23.
As the HIV epidemic has matured, spread across virtually all human
populations and interacted with multiple health-care, policy and social
environments, it has shown remarkable diversity. Although truly a
global epidemic, subtypes vary, predominant modes of transmission
vary and population-level prevalence and incidence vary most dra-
matically between all these features. Figure 3 illustrates the incidence
curves for HIV by region globally and underscores this diversity5. Two
regions show rising incidence, Eastern Europe and Central Asia, and the
Middle East and North Africa (MENA), albeit from much lower baseline
HIV incidence than the African epidemics (Fig. 3).
Eastern and southern Africa. Eastern and southern Africa represent
the only region in which HIV infection is hyperendemic: high levels
of disease are consistent, and HIV infection prevalence rates among
all adults of reproductive age are above a (somewhat arbitrary) 5%
prevalence level5. This region also has a distinct epidemiology of female
predominance; indeed, this is the only region of the epidemic where
HIV infection is significantly higher in adult women than adult men24.
In South Africa, a country that also has the largest number of people
living with HIV anywhere, 60% of the newly infected are women25.
Lifetime acquisition probabilities for girls and women in this region are
very high and remain at more than 20% despite years of investment in
treatment and prevention26. The very high force of infection (the rate
at which susceptible individuals acquire HIV) in this region is most
clearly illustrated by recent results from a large phase III efficacy trial
of an HIV vaccine candidate in the region (HVTN 702, which assessed
efficacy of an ALVAC-HIV + subtype C gp120/MF59 candidate)27. The
vaccine was not successful — incidence densities were almost identi-
cal across immunization and placebo arms, but the incidence was a
very high 4.2 per 100 person-years (95% CI 3.4–5.2) among women
in 2020, just before the onset of the coronavirus disease 2019 (COVID-19)
pandemic27 (also see Box 1). The 2022 reports from UNAIDS indicate
2
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that key populations such as men who have sex with men (MSM), sex
workers and people who use and inject drugs accounted for half of the
new infections in sub-Saharan Africa28.
Western and central Africa. Western and central Africa present
a more complex epidemiological picture. HIV infection rates have long
remained lower, attributed at least in part to the protective effects of
male circumcision, which is ubiquitous among the Muslim and other
communities in which circumcision is part of traditional or cultural
practice29. Despite low overall infection rates, there are high-burden
micro-epidemics among sex workers and clients and among MSM; how-
ever, weak surveillance and reporting systems in many of these coun-
tries make assessment of HIV burdens complex30. Nigeria, Africa’s most
populous nation, has a relatively low prevalence but, owing to its weak
health system and complex gender dynamics, further compli­cated by
criminalization of same-sex sexual relationships, now accounts for
approximately one-third of all perinatal HIV infections worldwide31.
Nigeria has not kept up with the rate of progress made in reduction of
vertical HIV transmission that has been reported in East and southern
Africa. In 2020, fewer than 30% of pregnant women in Nigeria under-
went HIV testing despite a 90% antenatal care attendance rate, and as
such the goal of elimination of vertical transmission in sub-Saharan
Africa has still not been realized32.
Western and central Europe and North America, and Asia and Pacific.
In contrast to eastern and southern Africa and western and central Africa,
the regions of the Americas, Western Europe, Australia and much of East
Asia, have much lower-burden HIV epidemics that are highly concen-
trated in specific populations, primarily among MSM and transgender
women (TGW) who have sex with men33. The highest burdened industrial-
ized country, the USA, is a good example of this epidemiological context.
The overall prevalence in US adults is ~0.6–0.8%, however, more than
two-thirds of new infections in 2021 were among MSM, and among Black
MSM prevalence rates are consistently ~50%34. Across the Americas, over-
all prevalence is <1%, but a higher prevalence is reported in MSM, TGW
and among people who inject drugs in some cities such as Lima, Peru34.
Middle East and North Africa. HIV prevalence in the MENA region is <0.1%
of adults, nevertheless incidence has been rising in some populations,
largely due to expanding epidemics among MSM, TGW, people who inject
drugs and sex workers28. Strong cultural, legal and social sanctions against
the communities most at risk have challenged the outbreak response.
Among these countries, Iran and Pakistan are of particular concern as
they have among the highest population rates of opioid dependency
worldwide, and severely restricted (in the case of Pakistan) or suboptimal
(in the case of Iran) harm reduction programmes. Although Iran provides
extensive and successful access to needle exchange programmes, sus-
tained programmatic efforts with scaled access to methodone for opioid
agonist therapy (OAT) is urgently needed35,36.
Key affected populations
HIV in women. Women (including all people who identify as female)
globally face significant risk of HIV infection, owing to biological risk
factors associated with receptive sex and increased social risk factors
stemming from gender inequality, reduced power to negotiate safe
sex practice and access to HIV care, and vulnerability to gender-based
violence28. In particular young women and adolescent girls (aged
15–24 years) are disproportionately affected37. In sub-Saharan Africa,
young women and girls are three times more likely to acquire HIV than
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B
D HIV-1 group M
G C
A H
F1
F2
SIVcpzLB7
K
J
HIV-1 group N
SIVcpzUSA
SIVcpzGAB
SIVgor
SIVgor
HIV-1 group P
SIVgor2139
HIV-1 group O
ANT70
Fig. 1 | The phylogenetic origins of HIV-1. Phylogenetic tree derived from
nucleotide alignment of genome sequences shows the relatedness of HIV
group M, N, O and P sequences and those of non-human primate simian
immunodeficiency virus strains. HIV-1 group M is represented by single
sequences for each subtype A through H and J and K; group N and group O
are each represented by five sequences, and SIVgor (from which subtype P is
derived) is represented by three sequences. The phylogeny of various HIV-1
groups and their relatedness to SIV in primates suggest that multiple crossover
events with group M are the main cause of large-scale infection and evolution in
humans, resulting in the HIV pandemic we know today.
their male counterparts28. Women, however, generally fare better
than their male counterparts when they have access to HIV care, with
higher rates of HIV testing uptake, increased adherence and persistence
on HIV medication, and increased virus control38,39. Women also have
varying associated needs throughout their life course from the time of
puberty to menopause related to contraception, child-bearing and the
burdens of motherhood. Ensuring that sexual and reproductive health
services are integrated with HIV prevention and treatment services
enhances differentiated service delivery for women. In addition, women
who live with HIV who are pregnant or are at risk of HIV acquisition dur-
ing pregnancy or breastfeeding face the potential prospect of onward
transmission of HIV to their child. Evidence has shown that if women
who are living with HIV are virally suppressed on ART then the risk of
vertical transmission is mitigated to fewer than 50 per 100,000 live
births, below the threshold for elimination of perinatal transmission
set by the WHO40. The same applies to women who live with HIV who
are breastfeeding, although there remains a very small risk of vertical
transmission despite plasma viral suppression as breast milk is a highly
cellular fluid; however, only a handful of cases have been documented
globally41. Women who are at risk of HIV acquisition should be offered
regular HIV testing during pregnancy and effective prevention such
as pre-exposure prophylaxis (PrEP)42. Women living long with HIV also
3
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100

90
A
80 B
Subtype prevalence (%)

70 C
D
60 F
50 G
H
40
J
30 K
CRF01_AE
20
CRF01_AE
10 Other
URFs
0
ic l

an

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ia

ca

ia

sia

ia

sia
er tra

ic

ric

ric

ric

di
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As

an
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fri
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be

tA

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er

In
Am cen

Af

Af

Af

ce
hi

lA

st
e
Am
ib

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as
dl

Et
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st

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Ea

O
ar

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er

id

en
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he
C

en
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No a

es

C
ut
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So

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So
an

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pe
pe e

ric
la
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Af
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No

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Eu

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Fig. 2 | The geographical spread of HIV-1 subtypes. Stacked bar chart shows the percentage of each subtype that circulates within a region279. URFs, unique
recombinant forms. Data from ref. 279.

have specific needs as they enter menopause including considerations
around osteoporosis, cancer screening and cardio­vascular well-being43.
This makes access to HIV education, care, treatment and prevention for
women a particularly pertinent issue.
HIV in the ageing population. As a result of the development and
improved access to ART, the number of people ageing with HIV globally
is increasing. Although there is a higher proportion of people living with
HIV who are >50 years of age in high income countries (for example,
in the USA in 2016, more than 50% of people living with HIV were older
than 50 years), a higher number of people living with HIV aged >50 years
overall live in low and middle income countries (LMICs) (that is, 80%
of all people older than 50 years living with HIV in 2016 lived in LMICs,
with most in eastern and southern Africa, where the majority of people
living with HIV reside)44. People ageing with HIV remain at higher risk
of comorbidities than their HIV-negative counterparts, despite and
potentially in some cases because of the use of ART45. A longitudinal,
observational study in the USA over 35 years (for men) and 25 years
(for women) illustrated a significant increase in the prevalence of
metabolic syndrome, diabetes, kidney disease, liver fibrosis, depres-
sion, impaired instrumental activities of daily living, and hepatitis
B virus (HBV) and HCV infection among participants living with HIV
compared with HIV-seronegative participants, with recent alcohol
and tobacco use separately identified as key risk factors46. In some
conditions, however, the results have been more mixed, with strong
regional trends. For example, in North America the risk of hyperten-
sion is higher among people living with HIV (risk ratio (RR) 1.12, 95% CI
1.02–1.23) whereas in Africa and Asia, the risk is lower (RR 0.75, 95% CI
0.68–0.95 and RR 0.77, 95% CI 0.63–0.95, respectively) when compared
with non-infected populations47. This may reflect lifestyle differences,
age of HIV acquisition and/or use of particular ART. With the evolu-
tion of ART, many of the adverse events such as dyslipidaemia and
metabolic syndromes related to ART have been mitigated; however,
new first-line treatment options, specifically integrase strand transfer
inhibitors (INSTIs), including dolutegravir (DTG), have been associated
with increased weight gain and an increased risk of hypertension com-
pared with previous non-nucleoside reverse transcriptase inhibitor
(NNRTI) treatments (such as efavirenz (EFV))48. The long-term effect
of such weight gain on non-communicable disease risk remains to be
determined. HIV infection leads to premature immune dysfunction,
which in turn leads to low-grade chronic inflammation and the result-
ant premature effects of ageing, including comorbidities, cancers and
degenerative conditions49. It is now understood that this phenomenon
occurs in both adults and children living with HIV50.
HIV in people who inject drugs. Parenteral exposure among people
who inject drugs who do not have access to sterile injection equipment
remains a key contributor to HIV transmission globally, comprising
18% of new HIV infections in 2021 (ref. 5). Transmission of HIV through
injecting drugs was identified in 1981, early in the HIV epidemic, yet its
occurrence remains stubbornly persistent in many epidemiological
contexts, almost entirely owing to the failure to implement inter-
ventions known to be effective at high coverage, despite their dem-
onstrated ability to bring HIV transmission rates down to low rates
(<5 per 1,000 person-years at risk). Such interventions include the
provision of sterile injection equipment and OAT to this highly margin-
alized and stigmatized community51. The rate of HIV infection in peo-
ple who inject drugs was very low in 2022 in Western Europe, yet people
who inject drugs accounted for 39% of new infections in Eastern Europe
and Central Asia. In Central and East Asia, harm reduction services
remain highly constrained, OATs are illegal in the Russian Federation
and disrupted in Ukraine, and the HIV epidemic among people who
inject drugs remains severe. This together with the MENA region are
the only two regions globally where HIV incidence is rising52 (Fig. 3).
Mechanisms/pathophysiology
Viral structure, viral entry and tropism
The mature HIV particle is a 120 nm diameter spherical structure with an
innermost cone-shaped viral core and the capsid, which surrounds two
identical, non-covalently linked, positive-sense single-stranded RNA

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(ssRNA) strands. The outer lipid bilayer membrane of the virion contains enables binding to either of the two major chemokine coreceptors:
envelope glycoprotein (gp), which includes gp120 and gp41 (ref. 53). CCR5 or CXCR4 (refs. 55–57). Envelope protein is also important in
HIV infects a limited number of immune cells in the body, pre- syncytium formation, which is the fusion of infected CD4+ T cells with
dominantly activated CD4+ T cells, but can infect other important cells, uninfected T cells, a phenomenon observed in cultured cells in the
including macrophages and microglial cells (a cell specific to the central laboratory, which may enable virus replication and also account for
nervous system)54. The HIV envelope glycoprotein initially binds to the CD4+ T cell loss in vivo55. Some HIV strains rarely form syncytia and are
target CD4 receptor and, following conformational change of gp120, referred to as non-syncytium inducing. These strains depend on binding

Asia and the Pacific Caribbean Eastern and southern Africa

500 500 1,500
Number of new HIV infections (per 1,000)

Number of new HIV infections (per 1,000)

450 450
1,400
400 400

350 350 1,300

300 300
1,200
250 250

200 200
1,100
150 150

Number of new HIV infections (per 1,000)

100 100 1,000

50 50
900
0 0
2015 2016 2017 2018 2019 2020 2021 2015 2016 2017 2018 2019 2020 2021
800
Year Year

700
Eastern Europe and Central Asia Latin America
500 500
Number of new HIV infections (per 1,000)

Number of new HIV infections (per 1,000)

600
450 450

400 400 500

350 350
400
300 300

250 250 300

200 200

150 150 200

100 100
100
50 50

0 0 0
2015 2016 2017 2018 2019 2020 2021 2015 2016 2017 2018 2019 2020 2021 2015 2016 2017 2018 2019 2020 2021
Year Year Year

Western and central Europe

Western and central Africa and North America Middle East and North Africa
500 500 500
Number of new HIV infections (per 1,000)

Number of new HIV infections (per 1,000)

Number of new HIV infections (per 1,000)

450 450 450

400 400 400

350 350 350

300 300 300

250 250 250

200 200 200

150 150 150

100 100 100

50 50 50

0 0 0
2015 2016 2017 2018 2019 2020 2021 2015 2016 2017 2018 2019 2020 2021 2015 2016 2017 2018 2019 2020 2021
Year Year Year

Fig. 3 | New HIV infections by region 2015–2022. UNAIDS epidemiological estimates. Adapted with permission from ref. 28, UNAIDS.

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Box 1
People living with HIV and
COVID-19
With the onset of the coronavirus disease 2019 (COVID-19)
pandemic there was a lot of initial concern that people living
with HIV would be more susceptible to severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection and more prone to
poor outcomes owing to inherent immune deficiency associated
with HIV infection. Large studies have now confirmed that although
infection susceptibility is not enhanced, there is an increased risk
of more severe COVID-19 disease (adjusted odds ratio 1.13)280 and
death (adjusted hazard ratio 2.14)281 in people living with HIV. In all
cases this is further exacerbated in people living with HIV who are
older and who have comorbidities such as hypertension, diabetes
mellitus, obesity and steatotic liver disease282. In some studies,
these risks are also increased in individuals who have unsuppressed
viral load. Studies have confirmed that COVID-19 vaccines are safe
in people living with HIV and, although few efficacy studies have
specifically included people living with HIV, the study Ubuntu
in Africa and evidence from real-world settings confirm their
effectiveness. Therefore, the COVID-19 vaccination and booster
recommendations are relevant and not different for people living
with HIV. In addition, influenza and pneumococcal vaccinations
are also recommended and can be coadministered with COVID-19
vaccinations. It is not yet clear whether boosting intervals may need
to be shortened in people living with HIV.
to the β-chemokine receptor CCR5 for fusion and entry and are called
R5 strains. R5 strains can infect both macrophages and CD4+ T cells56.
X4 viruses depend on binding to the α-chemokine receptor CXCR4
and replicate primarily in CD4+ T cells. X4 viruses are more pathogenic
and can induce greater destruction and depletion of CD4+ T cells58–60.
Dual tropic strains can bind to either chemokine coreceptor. About 5%
of people of European descent fail to express CCR5 protein owing to
homozygosity for a 32 bp deletion in the CCR5 gene (CCR5Δ32) resulting in
resistance to R5 strains of HIV60. The Envelope precursor gp160 is heav-
ily modified by N-linked glycosylation and assembles into trimers. This
trimeric structure is the major target for HIV immune interventions such
as vaccines and broadly neutralizing antibodies (bNAbs)61.
After fusion, the virus releases HIV RNA into the cytoplasm. The
positive-sense ssRNA is then transcribed into a cDNA molecule by
virally encoded reverse transcriptase62. Reverse transcription is prone
to error and results in a high level of mutation and change, a highly
favourable setting for the emergence of drug-resistant mutations
and immune evasion63. The double-stranded viral DNA arising from
cDNA and a complementary strain is then transported into the host
cell nucleus and integration occurs into the host DNA by the integrase
enzyme64. The integrated HIV DNA (provirus) is transcribed into viral
RNA and mRNA by RNA polymerase. It is then assembled into new virus
particles that bud from the host cell as new virions capable of infect-
ing another cell as a free virion (cell-free spread) or by spread from an
infected to an uninfected cell (cell-to-cell spread)53.
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As a result of the highly error-prone reverse transcriptase, HIV is
a highly polymorphic virus with multiple quasispecies (genetically
related variants) resulting from an RNA replication error rate of about
1 in 10E4 bases and complex cDNA formation65. The rapid replication
cycle produces and clears roughly 1010 virions per day, and the recombi-
nant nature of reverse transcriptase has resulted in diverse and complex
HIV-1 subtypes distributed around the world66. The difficulty in target-
ing multiple subtypes has complicated diagnostic testing, biomedical
prevention and treatment, and vaccine design.
Immunopathogenesis and natural history of HIV infection
In the absence of ART, viral replication occurs predominantly in acti-
vated CD4+ T cells in blood and tissue sites . The initial burst of viral rep-
lication is characterized by an increase in viral load in blood. The viral
load then declines and this is temporally associated with an increase in
HIV-specific CD8+ T cells, which are important for killing HIV-infected
T cells67. This acute phase is commonly referred to as primary infection
and is followed by a chronic phase characterized by progressive decline
in CD4+ T cells. On average, declines occur at 50–100 cells/μl per year
but these declines can be faster or slower depending on multiple viral
and host factors68. Some examples of factors that drive accelerated
CD4+ T cell decline include infection with an X4 virus, co-infection with
HCV or being heterozygous for the CCR5Δ32 allele69.
At the same time as CD4+ T cells decline, there is hyperactivation
of other parts of the immune system including activation of B cells,
leading to high levels of circulating immunoglobulin, called hypergam-
maglobulinaemia, often associated with auto-immune defects, macro­
phage activation and dysfunction leading to impaired phagocytosis
and clearance of intracellular organisms such as Salmonella, Mycobac-
terium tuberculosis and Toxoplasmosis gondii70 (Table 1). The destruc-
tion of CD4+ T cells in the gastrointestinal tract results in increased
microbial translocation and elevated levels of circulating lipopoly-
saccharide (LPS)71. LPS is a potent activator of the innate immune sys-
tem via activation of toll-like receptor 4 (TLR4), further exacerbating
immune activation and immune dysregulation72. Finally, HIV RNA itself
can bind to both TLR7 and TLR8, which are expressed in plasmacytoid
dendritic cells, driving increased production of interferon-α and acti-
vation of multiple interferon-stimulated genes73. Increased systemic
immune activation has multiple adverse effects including enhanced
fibrosis of lymphoid tissue74. This results in reduction in the produc-
tion of cytokines crucial for T cell proliferation and differentiation,
including IL-7. Reduction in IL-7 impedes T cell production, further
exacerbating T cell decline74.
Progression to acquired immunodeficiency syndrome
The progressive loss of CD4+ T cells results in multiple distinct phases
of clinical illness. This acute phase is also referred to as primary infec-
tion. The symptoms are similar to an Epstein–Barr virus-associated
infectious mononucleosis-like illness, including self-limiting fever,
myalgias, mild rash and headache and occasionally serious manifesta-
tions including meningo-encephalitis75,76. During primary infection,
although individuals may look healthy, the virus is actively replicating
in the lymph nodes and bloodstream of infected individuals77. Exactly
what triggers the change from a situation of balance to one of viral
superiority is not clear but factors that are inherent to the virus itself,
for example, tropism switch (CX4 versus CCR5), loss of CD4+ T cell help
and exhaustion of CD8+ cytotoxic T cells as a result of loss of prolifera-
tive capacity or senescence may contribute78. AIDS, defined as a range
of specific clinical presentations or a CD4+ T cell count of <200 cells/μl,
6
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occurs later as normal immune protection begins to fail. Individuals
then become susceptible to opportunistic infections79 such as infec-
tions with Mycobacterium avium, M. tuberculosis, Pneumocystis jirovecii,
T. gondii and many others. In addition, cancers such as Kaposi sarcoma
occur80. At this stage the viral load is high, and the CD4+ T cell count is
reduced (<350 cells/m3) (Fig. 4). The pace at which HIV progresses to
AIDS in untreated individuals varies, but in most, the time to progres-
sion is around 8–10 years. However, some people can progress more
quickly, for example, if infected with an X4 virus. Effective ART has
significantly altered this time line, but in individuals who are unable to
take ART consistently and/or develop multiresistant virus, persistent
viraemia will ultimately lead to AIDS and death.
Impact of ART on immunopathogenesis
ART has a profound impact on the natural history of HIV infection. Inter-
ruption of viral replication leads to a halt in direct CD4+ T cell infection
and destruction, a decline in immune activation and a recovery of CD4+
T cell production in the thymus66,81. CD4+ T cell recovery has biphasic
kinetics with an initial rapid increase (thought to be largely secondary
to tissue redistribution) followed by a slow increase related to increased
thymic output, with naive and memory T cell expansion82. Similar to
rates of CD4+ T cell decline, recovery of CD4+ T cells on average occurs
at 50–100 cells/μl per year; however, CD4+ T cell recovery can also be
highly variable, dependent on both host and viral factors83.
Control of virus replication leads to a significant decline in all
markers of immune activation and exhaustion, including T cell markers
(surface expression of activation markers including HLA-DR, CD38, PD1
and others), markers of macrophage activation, microbial transloca-
tion (reduction in LPS) and innate immune markers (C-reactive protein,
IL-6 and d-dimer)84. However, it is now clear that immune activation
remains persistently elevated in people with HIV on ART85. ART during
acute infection, compared with established chronic infection, has been
associated with achieving lower levels of immune activation, with some
people living with HIV achieving levels of immune activation similar to
those in HIV-uninfected controls86. Elevation of immune activation on
ART has been associated with a higher risk of cardiovascular disease,
renal disease, neurological disease and malignancy, commonly termed
non-AIDS-defining events, compared with age-matched controls87. This
is another compelling reason for early initiation of ART at the time of
diagnosis, and preferably early after infection.
The viral reservoir
HIV, like other retroviruses, can establish both productive and latent
forms of infection in CD4+ T cells88. Whereas productive infection
results in the production of viral RNA, viral proteins and release of
virions from the cell surface, latent infection is defined as the integra-
tion of viral DNA but the absence of viral transcription or translation
(Fig. 5a). However, the integration of an intact virus means that virus
can reactivate from a latently infected T cell at any time following T cell
activation89.
HIV hijacks the normal process of T cell activation, differentiation
and formation of memory. In brief, T cells are generated in the thy-
mus and circulate in a quiescent or resting state (called a naive T cell).
Once foreign antigen is encountered, the cell is activated and prolif-
erates, forming activated effector memory T cells. Following antigen
exposure, the activated effector memory T cell reverts to a resting state
(central memory) and provides lifelong recognition of that foreign
antigen. Latent infection classically occurs in resting memory CD4+
T cells and can be established following direct infection of a resting
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memory T cell or of an activated CD4+ T cell transitioning to a memory
cell (pre-activation latency)90,91. HIV preferentially infects activated
CD4+ T cells, resulting in productive infection, and these productively
infected activated CD4+ T cells can also revert to a resting state as
another pathway to establishing latency (post-activation latency)88.
Latency can be established in vivo immediately after HIV infection of
the host; however, latently infected cells represent only a tiny fraction
of the total pool of infected cells before initiation of ART92,93. Before
initiation of ART, this pool of latently infected cells seems to be turn-
ing over and not stable, given that the sequence of viruses detected
in latently infected cells in people living with HIV on suppressive ART
have the closest match to viral sequences detected in plasma at the time
of ART initiation, compared to earlier time points years before ART94.
Latent virus can persist indefinitely in multiple T cell subsets (naive,
stem cell memory, central memory, effector memory, transitional
memory) as intact or defective virus94 and in various transcriptional
states, even when ART is administered in people living with HIV (Fig. 5b).
This is due to several reasons: latency can be established in long-lived
naive and central memory T cells, which are designed to persist for
life95; latently infected cells can proliferate or undergo what is com-
monly called clonal expansion96; clonally expanded cells can produce
infectious virus and arise largely from expansion of antigen-specific
T cells, after re-exposure to antigen97,98; clonally expanded infected
cells that contain the identical provirus in the identical site can account
for >50% of the reservoir and are capable of producing virions that
can be detected as low-level viraemia, even in the face of excellent
adherence to ART99.
There is a spectrum of transcriptional activity from integrated
proviruses, ranging from integrated provirus that is deeply latent
(transcriptionally silent and/or requiring multiple rounds of T cell
activation to activate virus) to having constitutive levels of HIV tran-
scription (detected as HIV RNA+ using RNA probes) and translation
(expression of viral proteins)100. When ART is stopped and virus
rebounds, usually within 2–3 weeks, it is unclear whether the source
of virus is from transcriptionally active cells (the active reservoir) or
activation of deeply latent cells (the silent reservoir), although time
Table 1 | Factors associated with immune dysfunction other
than destruction of CD4+ T cells
Cell type Immunopathological effects
CD8 cytotoxic
+
Above the normal range during acute phase (normal CD8+
T lymphocytes T cell range: 150–1,000 cells/mm3)
Decline at later stages
Natural killer Impaired numbers
cells
Impaired function
Monocytes and Defects in chemotaxis
macrophages
Inability to promote T cell proliferation (normal CD4+
T cell range: 460–1,600 cells/mm3)
Defects in Fc receptor function, which is an important
requirement for monocytes and macrophages to
recognize and eliminate antibody bound to a foreign
antigen
B cells Increased production of IgG and IgA
Antibody responses to multiple pathogens, after either
prior infection or vaccination, are low compared with
people without HIV infection
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a Primary Fig. 4 | HIV infection and disease progression.

infection Death a,b, The course of HIV infection and disease. Viral
load (part a) and levels of CD4+ T cells (part b) are
• Acute HIV syndrome
• Wide dissemination of virus shown to correlate with the progression of HIV
109
• Seeding of lymphoid organs infection. Adapted from ref. 248, Springer Nature
Limited.
106
HIV RNA copies/ml plasma

Clinical latency
Opportunistic
105 disease

104 Constitutional
symptoms

103

102
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 12
Weeks Years

b <350 cells/mm3 <200 cells/mm3 <100 cells/mm3

The risk for a number of The risk of more Increased risk of
infectious complications serious opportunistic coccidioidomycosis,
begins to rise, including infections, cryptococcosis,
Primary varicella zoster infection, particularly cryptosporidiosis,
infection severe bacterial infections pneumocystis cytomegalovirus disease
and tuberculosis pneumonia and (particularly retinitis),
1,200 oesophageal encephalopathy,
candidiasis, histoplasmosis,
1,100 HIV-associated disseminated
1,000 malignancies Mycobacterium avium
CD4+ T cell count (cells/mm3)

complex, progressive
900
multifocal
800 leukoencephalopathy,
700 toxoplasmosis of brain and
a HIV-associated wasting
600 syndrome, HIV-associated
500 malignancies
400
300
200
100
0
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 12
Weeks Years

to viral rebound after cessation of ART has been associated with levels
of cell-associated HIV RNA, a marker of transcriptional activity of the
reservoir, before cessation of ART101.
Multiple factors determine the transcriptional activity of a pro-
virus, including site of integration102, the transcriptional environ-
ment of the host cell, that is, resting or activated, and certain host or
environmental factors. For example, cell-associated viral RNA has
been shown to vary with time, potentially because of the variation of
circadian proteins CLOCK and BMAL1 acting as direct transcriptional
activators103. In addition, women have a lower level of transcriptional
activity per provirus than men, potentially explained by the effects of
oestrogen binding protein on the HIV long terminal repeat104.
Although there is no distinct surface marker for the HIV reservoir,
new capabilities in single-cell technologies have demonstrated that
latently infected cells that persist on ART have features of immune eva-
sion, specifically expression of immune checkpoints105. Furthermore,
latently infected cells express molecules that limit viral transcrip-
tion and enhance survival106,107. Using conventional sequencing as
well as high-throughput assays that can distinguish intact virus from
viruses with defects in the packaging signal or the envelope protein
gene108, it is now clear that most virus that persists on ART is defective109.
In addition, intact virus decays at a faster rate than defective forms110.
As a result, accurate quantification of the reservoir that matters, that
is, infected cells that contain rebound-competent virus, now requires
quantification of intact rather than total or integrated viral DNA.
Using new tools that can accurately determine viral sequence, inte-
gration site and whether HIV transcription is present or not (parallel
analysis of integration site and proviral sequence, PRIP-seq)102 has been
cause for some optimism that the viral reservoir may not persist in all
people indefinitely. In two individuals who naturally control HIV in the
absence of ART (referred to as elite controllers), no detectable intact virus
was found despite analysis of billions of cells111,112. Similarly, in other elite

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controllers, intact virus is detected but the virus seems to be preferentially
located in centromeres or gene deserts, in which transcription is less likely
to occur112. Using the same assay in people living with HIV on ART, there is,
over time, a greater proportion of latently infected cells with lower levels
of virus transcription and with provirus in transcriptionally silent parts of
the genome102. It remains to be determined whether a transcriptionally
silent reservoir is less likely to rebound once ART is stopped.
Natural viral control
A small subset of infected individuals, known as HIV controllers, can
suppress viral replication without antiretroviral medications. These
unique persons have been broadly defined by sustained levels of
viraemia below 2,000 RNA copies per millilitre of plasma. They can
be subdivided into elite controllers, defined as those with the capac-
ity to control virus replication to <50 copies/ml in the absence of ART,
and viraemic controllers, who control virus replication to between
50 and 2,000 copies/ml in the absence of ART113,114. Although multiple
viral and host factors have been attributed to elite control, the domi-
nant factor is HLA type and, therefore, the capacity to generate highly
functional HIV-specific T cells that have good proliferative capacity
and target favourable epitopes115. A small group of people living with
HIV from France who could control virus to <50 copies/ml after a short
period on ART initiated during primary infection, were first described in
2010 (ref. 116). Further studies of post-treatment control have shown
a Productive infection Latent infection
b
Proliferation
Latent infection
Defective
virus
Integration
sites
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that these individuals do not commonly have HLA alleles described with
elite control117. Post-treatment control seems to occur more commonly
after initiation of ART in acute rather than chronic infection118. Compari-
sons of post-treatment control with non-controllers at the time of ART
cessation have shown a smaller and more stable HIV reservoir and lower
levels of T cell activation and higher frequency of HIV-specific CD4+
T cells and natural killer cell function in post-treatment controllers119.
Although immunological correlates of post-treatment control clearly
differ from those of elite control, the immunological determinants of
post-treatment control are less well understood120.
Diagnosis, screening and prevention
HIV diagnosis
HIV testing is an essential first step in the early diagnosis of HIV infec-
tion and linkage to appropriate care, including rapid initiation of ART
to provide benefit to both the individual in terms of improved health
and the population by interrupting onward HIV transmission. Although
acute HIV infection may present as a short flu-like illness (with features
of fever, sore throat, rash, fatigue, muscle and joint pain, and lymphad-
enopathy) at 2–6 weeks after infection, thereafter the infection may
remain asymptomatic for years, and testing is the only way to confirm
an HIV diagnosis121,122.
HIV infection may not be immediately detected after exposure;
this period in which HIV cannot be detected by any existing diagnostic
Fig. 5 | Key features of cells in productive and
latent HIV infection. a, There are two major
forms of HIV-infected cell: productive infection,
which occurs in activated CD4+ T cells, and latent
infection, which primarily occurs in resting CD4+
T cells that are long lived, including naive and central
memory cells. There is a spectrum of transcriptional
activity in all HIV-infected cells in the reservoir.
b, Latently infected cells have multiple features
that contribute to their capacity for long-term
persistence, including capacity to proliferate,
distinct integration sites, a mixture of defective
and intact virus, varying states of transcriptional
Primed
activity, expression of immune checkpoints to
to survive evade immunity and expression of host factors that
favour survival.
Evade
immunity
Reservoir
‘activity’
9
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test is known as the eclipse period123. The Fiebig staging system (2003) ≥98% specificity127. As this approach can be achieved using either two
classifies early HIV infection into six stages based on test results for point-of-care (PoC) tests, two laboratory tests or a combination of
markers of viral replication and the evolution of antibody responses. these, selecting an HIV test for a given situation requires client char-
Stage I is defined as the emergence of HIV RNA and stage VI is defined acteristics and programmatic concerns to be balanced against test
as full western blot reactivity124. HIV RNA is the first reliable marker performance. In high-burden HIV settings, PoC tests have enabled
of infection and is detectable within 10–11 days after exposure, fol- expansion of community-based HIV testing services because they
lowed usually by p24 antigen (the most abundant HIV protein), which are relatively simple to administer, do not require skilled personnel, are
is detected about 4–10 days after emergence of HIV RNA123,125. IgM cheaper on average, have a rapid turnaround time, use small specimen
antibodies begin to rise around day 20 after exposure, and then shift to volumes and do not require venepuncture130. There is, however, some
a more mature IgG response that can be detected 2–6 weeks after HIV loss of sensitivity when compared with laboratory-based assays; in
RNA emergence123,125. Over the past four decades, serological assays that particular tests using oral transudate (fluid derived from the passive
detect these antigens have improved in terms of both performance and transport of serum components through the oral mucosa into the
the window of detection126. Diagnosis of acute HIV infection, however, mouth) are significantly less sensitive than those using whole blood,
remains a blind spot for antibody-only assays (Table 2). and tests using whole blood are less sensitive than those using serum or
All HIV diagnostic algorithms are based on a common principle, plasma129. Despite this, HIV self-testing using PoC tests is now a recom-
that is, to first screen with a highly sensitive test and then to confirm mended HIV testing approach that is feasible and acceptable and has
reactive results with a different test that is both sensitive and highly been shown to improve HIV testing coverage among stigmatized, previ-
specific127–129. As HIV testing and treatment coverage expand, and test ously hard to reach populations131. HIV self-testing does not provide a
positivity rates fall below 5%, this may influence the positive predictive definitive HIV-positive diagnosis. Individuals with a reactive test result
value (PPV) of a testing algorithm and the likelihood that a positive should receive further confirmatory testing before ART initiation92.
test reflects a true HIV infection. Currently, the WHO recommends WHO recommends that HIV testing is offered to all populations in
that all HIV testing algorithms achieve at least 99% PPV and use a all services in high-HIV burden settings and in low-burden settings to
combination of two or three tests in series with ≥99% sensitivity and populations with evidence of signs, symptoms or medical conditions
that indicate HIV infection, including HIV-exposed infants and chil-
dren, key populations and their partners, and all pregnant women132.
Table 2 | HIV test characteristics The optimal frequency of re-testing is somewhat unknown owing to
limited data. Several guidelines recommend annual re-testing for
Type Antigen source Window Test characteristics ongoing risk unless specific aspects of risk behaviour warrant more
period frequent testing, or when required by programmes, for example, PrEP
First generationa Crude viral 8–10 weeks IgG sensitive only services125,126,132. There is increasing emphasis on the provision of con-
lysate cise pre-test information as opposed to pre-testing counselling, with
Indirect ELISA (HIV-1)
some evidence that pre-testing counselling could be a barrier to HIV
Second generation Lysate and 4–6 weeks IgG sensitive only testing133. A short pre-test assessment has been shown to be as effec-
recombinant
Indirect ELISA HIV-1, tive as a long session for a patient’s decision to take an HIV test134. In the
HIV-2 USA, separate written consent for HIV testing is no longer required,
Differentiates HIV-1 and opt-out testing is recommended for in-patients132. Instead, the
and HIV-2 emphasis has shifted to the post-test package of care to ensure that
Third generation Recombinant 2–3 weeks IgG/IgM sensitive individuals receive information and linkage to care.
and synthetic
peptides Sandwichb ELISA HIV-1,
HIV-2 IgG, IgM Special diagnostic situations. There are some special diagnostic situ-
ations in which the considerations above may require modification.
Fourth generation Recombinant 2 weeks IgG/IgM sensitive
and synthetic For example, antibody-based tests may not be useful in early infant
peptides Sandwich ELISA diagnosis of HIV infection (<18 months of age) when passively trans-
HIV-1, HIV-2 IgG, IgM
and p24
ferred maternal HIV antibodies may be detected123. The WHO recom-
mends PoC nucleic acid testing for infant diagnosis under 18 months
Does not differentiate
of age, whereas routine serological testing may be used in those aged
antibody from
antigen 18 months or older127. Diagnosis of HIV infection in individuals using
PrEP, particularly long-acting PrEP, may be difficult because of low
Fifth generation Recombinant 2 weeks IgG/IgM sensitive
and synthetic viraemia leading to low levels of antibody production and delayed
peptides Sandwich ELISA detection of infection135. Delays in detection of infection may be asso-
HIV-1, HIV-2 IgG, IgM
and p24
ciated with the emergence of resistance in the context of ART mono-
therapy. More data are needed to guide the optimal approach to testing
Separate antibody
in this context, particularly in LMIC settings where routine use of HIV
and antigen results
RNA detection tests may not be feasible135–137.
Nucleic acid testing Detection of 10 days Might not detect
HIV-1 RNA HIV-2 infection
HIV prevention
a
The word generation refers to age, that is, first-generation tests were the earliest tests
Condoms. Condom promotion and supply was one of the earliest
developed and fifth-generation tests are the most recent tests. bSandwich enzyme-linked
immunosorbent assay (ELISA) measures antigen between two layers of antibodies (a capture interventions to be mobilized to address the HIV epidemic. Condoms
and a detection antibody). Data from ref. 278. are inexpensive and provide protection against the transmission of

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HIV and other sexually transmitted infections (STIs). Condoms have
been the cornerstone of HIV prevention for several decades, and as
many as 16 billion condoms may be used annually in all LMICs135. Male
condoms have been estimated to reduce heterosexual HIV transmission
by 71% and HIV transmission through anal sex in MSM by 70% when used
consistently138,139. Laboratory studies have shown that latex condoms
are impermeable to particles the size of sperm or sexually transmitted
pathogens including HIV, so lower than expected estimates of condom
effectiveness likely reflect over-reporting of use or incorrect use140.
A global review of condom use errors and problems found that break-
age and slippage combined or complete failure was reported by 25–45%
of condom users141. A recent mathematical model has estimated that
a scale-up of condom use over the past three decades in 77 high-HIV-
burden countries may have averted about 117 million HIV infections142.
The female condom accounts for only 1.6% of total condom distribu-
tion worldwide143, despite evidence from laboratory studies that it is as
effective as the male condom in protecting against HIV and other STIs.
Currently, there are four female condoms that have been prequalified
by the WHO/United Nations Population Fund (UNFPA). Partner accept-
ability, functionality, aesthetics and access have been identified as key
barriers to female condom acceptability144. However, clinical data on
female condom effectiveness for HIV are limited145.
Voluntary medical male circumcision. Three large randomized con-
trolled trials demonstrated that voluntary medical male circumcision
(VMMC) reduced the risk of HIV infection in self-identified heterosexual
men by 59% compared with uncircumcised men, an effect that was
sustained years after the procedure29. VMMC reduces HIV infection
through surgical removal of foreskin tissue dense with HIV-susceptible
CD4+ T cells and subsequent changes to the foreskin microbiome146.
A trial of VMMC in men living with HIV showed an excess risk (hazard
ratio 1.49, 95% CI 0.62–3.57) of HIV infection in female partners in the
first 6 months after the procedure, likely due to resumption of sexual
activity before wound healing; this is consistent with data that show
higher penile HIV shedding immediately after VMMC147,148. As these
studies were conducted before recommendations for immediate ART, it
is believed that this early HIV transmission risk may become negligible if
the male partner is virally suppressed on ART. Although no randomized
trials in MSM have been conducted, a recent meta-analysis showed that
VMMC may also reduce the risk of HIV infection in MSM by 23% overall;
with greater reductions in risk of up to 42% for MSM living in LMICs149.
VMMC also reduces the risk of non-HIV STIs in circumcised men and
their partners150. In addition, female partners of circumcised men
experience lower rates of trichomoniasis and bacterial vaginosis151,152.
Currently, it is estimated that ~23 million men have been circumcised in
15 countries in Africa prioritized by WHO and UNAIDS with generalized
HIV epidemics and previously low rates of VMMC153, averting ~250,000
new HIV infections and projected to prevent 1.5 million HIV infections
by 2030 (ref. 154). VMMC remains a crucial intervention to achieve
epidemic control even as other interventions are scaled up.
Harm reduction. There is strong evidence that the use of harm reduc-
tion interventions are effective in reducing HIV, as well as viral hepatitis B
and C, transmission among people who inject drugs155. Such interven-
tions include drug treatment (for example, OAT with methadone or
buprenorphine), needle and syringe programmes (NSPs), as well as
psychosocial interventions. Although evidence in favour of these
interventions has grown over time, the implementation of and access
to OAT and NSPs remains limited in most countries. In 2017, only
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93 and 86 of 179 countries provided some level of NSP and OAT cover-
age, respectively, and it is estimated that fewer than 1% of people who
inject drugs live in countries with high coverage of both interventions156.
A further concern is the paucity of evidence to support harm reduction
efficacy and implementation in LMICs, which, alongside low political
support, stands to further hinder progress in these areas157. Without
significant scale-up, HIV transmission is certain to continue among
people who inject drugs.
Pre-exposure prophylaxis. PrEP involves the use of antiretrovirals by
HIV-negative individuals before sexual exposure to prevent HIV infec-
tion. In 2015, the WHO recommended that tenofovir-based daily oral
PrEP be included as part of a comprehensive package of HIV prevention
for individuals at substantial risk of HIV infection158. A systematic review
of ten randomized controlled trials confirmed the overall benefit of
daily oral PrEP in reducing HIV acquisition compared with placebo,
although effectiveness estimates ranged widely across trials, variations
were largely explained by differences in adherence as measured by drug
detection. Among trials with adherence of ≥80%, oral PrEP reduced the
risk of infection by 70% compared with placebo159. In participants with
measurable plasma tenofovir, HIV protection ranged from 86% to 92%,
suggesting high levels of efficacy associated with high adherence160.
Trials of tenofovir alafenamide (TAF) with emtracitabine as oral PrEP
have shown efficacy comparable to that of tenofovir with emtracit-
abine in MSM. Trials are in progress to assess TAF safety and efficacy
in cisgender women.
The WHO has issued recommendations regarding event-driven
PrEP (ED-PrEP) in MSM and two novel PrEP modalities, the dapivirine
vaginal ring (DVR) and injectable cabotegravir (CAB)161–163. ED-PrEP con-
sists of a double dose (two tablets) of tenofovir-based oral PrEP 2–24 h
before anticipated sex, followed by a third dose 24 h after the first
two doses if sex occurs, and a fourth dose 48 h after the first two
doses (also known as 2 + 1 + 1) and is recommended for MSM163. Data
to support this recommendation come from the IPERGAY trial and
open-label extension, which showed that ED-PrEP in MSM can reduce
HIV infection risk by 86–97%164. There is insufficient evidence cur-
rently to support this strategy in other populations. The DVR is a flex-
ible silicone vaginal ring that can be self-inserted monthly and gives
low systemic dapivirine absorption. The DVR has been shown in two
phase III randomized controlled trials to be well tolerated and to reduce
HIV risk by 30% compared with placebo165,166. Subsequent open-label
extension studies showed greater use and an estimated 50% HIV risk
reduction165,167. In July 2020, the EMA issued a favourable opinion on
the DVR but recommended additional research in younger women
(18–25 years) given low adherence that led to an absence of efficacy in
the 21 years and under age group168,169. The DVR was generally safe and
well tolerated with no difference in adverse events between the DVR
and placebo165–167.
CAB has been shown to be highly effective in preventing HIV infec-
tion in a range of populations. The combined results of two phase III trials
(HPTN 083 and HPTN 084) showed that CAB injections administered
every 8 weeks reduced HIV incidence by 79% compared with oral teno-
fovir disoproxil fumarate (TDF)/emtricitabine (FTC)169,170. Importantly,
these protective benefits were consistent across genders and age
groups. In a substudy of CAB in adolescent girls and young women
<18 years of age (HPTN 084-01; NCT04824131), none of the participants
discontinued study product because of adverse events or because of
lack of acceptability. The FDA approved CAB for PrEP in December 2021.
Both DVR and CAB are longer-acting agents, are administered for
11
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1–2 months and may overcome some of the adherence challenges
associated with daily pill use for oral PrEP. Other PrEP formulations
and delivery systems are in late-stage trials, including an alternative
daily oral pill in women (F/TAF), 6-monthly injectable (lenacapavir,
a capsid inhibitor) and a dual prevention pill that combines PrEP and
contraception171. Global PrEP uptake has continued to increase, despite
the COVID-19 pandemic, with ~940,000 people in 83 countries receiv-
ing PrEP in 2020, a 254% increase since 2018 (ref. 172). Yet, substantial
gaps in PrEP availability remain, with only 28% of the global target of
3 million people on PrEP by 2020 being achieved. Barriers to PrEP cover-
age include inadequate knowledge or risk perception, stigma, limited
access, cost and concerns related to adverse effects162. An expanded set
of PrEP options may help to overcome these barriers.
Post-exposure prophylaxis. Post-exposure prophylaxis (PEP) is also
an antiretrovirus-based prevention intervention, but it differs from
PrEP in that it is taken after a high-risk exposure to HIV, preferably
within 72 h, and it usually requires triple therapy. PEP was initially
conceptualized as a preventive intervention following occupational
exposure to HIV such as needle stick injuries173. Subsequently, PEP has
also been recommended in the setting of sexual assault in which the
HIV status of the perpetrator is positive or unknown. In all cases, PEP
is most effective if commenced as soon after exposure as possible, and
most guidelines recommend integrase-inhibitor-based triple antiviral
therapy, which should be continued for 28 days174. There have been no
definitive randomized controlled studies to support PEP but animal
studies and prevention of vertical transmission studies have provided
the rationale175–178.
HIV vaccines and monoclonal antibodies. The development of an
effective HIV vaccine remains a goal for achieving HIV epidemic con-
trol, with even a partially effective vaccine having the potential for a
substantial public health impact179. However, HIV vaccine development
has numerous challenges, including the rapid establishment of a viral
reservoir, extraordinary genetic diversity and high rate of variability
of the viral envelope glycoprotein, the primary target of neutralizing
antibodies, immune evasion during latent infection, an incomplete
understanding of correlates of protection and lack of appropriate
animal models180.
The RV144 Thai trial is the only study to date to demonstrate HIV
protection181. RV144 assessed a pox-protein prime–boost (using an
immunogen to prime the immune system and then a different immuno-
gen to boost the response) strategy in >16,000 participants at relatively
low heterosexual risk of HIV infection and showed 31% reduction in
HIV infection risk at 3.5 years181. The rationale for this approach was
to induce both humoral and cellular responses182. The vaccine did not
elicit neutralizing antibodies, suggesting non-neutralizing mechanisms
of protection.
Building on the success of RV144, the HVTN 702 (Uhambo) trial
was a phase IIB/III trial to evaluate the safety and efficacy of a prime–
boost strategy using ALVAC-HIV vaccine plus a bivalent gp120 protein
adjuvanted with MF59 regimen in sexually active men and women aged
18–35 years in South Africa (NCT02968849)27. An interim analysis in
5,404 participants met pre-specified criteria for non-efficacy and further
vaccinations were discontinued27. Differences in the two trials in terms
of vaccination schedule, clades, subtypes of proteins, lack of tagging of
proteins, genes in immunogens or adjuvants may explain the different
results, and ongoing immunological, viral and genetic analyses will
provide further insights for these different outcomes183. An alternative
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approach to vaccine design is the Ad26 mosaic programme, which com-
bines viral vectors, protein boosts and immunogen sequences optimized
to address global HIV diversity. The HVTN 705/HPX2008 (Imbokodo)
trial assessed the Ad26 mosaic vaccine plus a gp140 protein vaccine in a
phase IIB study in 2,637 adult women in southern Africa. Vaccine efficacy
was 25% but did not achieve statistical significance184. A second effi-
cacy trial of Ad26 mosaic, HVTN 706/HPX3002/Mosaico (NCT03964415)
evaluated a very similar prime–boost regimen in 3,800 cisgender men
and transgender people aged 18–60 years in the Americas and Europe.
The trial was stopped early for futility, with the vaccine regimen shown
to be ineffective in preventing HIV185.
Only one late-stage HIV vaccine trial remains in the field. PrEPVacc
(NCT04066881) is a phase IIB study underway in four countries in Africa
aimed at assessing the efficacy of two vaccine regimens (DNA/AIDSVAX
B/E and DNA/CN54gp140 + MVA-/CN54gp140 boost) in combination
with PrEP in 1,668 adults aged 18–40 years. The two vaccine regimens
will be compared against placebo, and participants are offered PrEP
with emtracitabine/TDF (F/TDF) or F/TAF during the period of the first
three immunizations. The study is estimated to be completed in 2023.
In parallel with several of these vaccine studies, two proof-of-
concept passive immunization studies that enrolled 4,623 participants
on four continents were completed. The trials HVTN 703/HPTN 081
and HVTN 704/HPTN 085 demonstrated the feasibility of blocking HIV
infection with bimonthly infusions of a single bNAb, VRC01 (ref. 186).
Although VRC01 did not reduce HIV infection incidence overall, it
reduced acquisition of VRC01-sensitive HIV strains by 75%; however,
only 30% of circulating strains were VRC01 sensitive. These studies
provided insights into the magnitude of antibody responses required
for vaccines to induce a protective response187. bNAbs that are more
potent, broader or longer-lasting than VRC01 are currently in early
clinical testing. Combinations of complementary bNAbs with adequate
scope and potency are likely to be required for HIV protection.
Management
Historically, ART initiation was delayed given concerns about limited
efficacy, drug resistance, toxicities and inconvenience of the early
regimens188. Large trials in diverse resource settings, such as Temprano
ANRS 12136 and the Strategic Timing of Antiretroviral Treatment
(START) studies, have since consistently demonstrated lower risk of
progression to severe illness or death with early ART189–191. As such, rapid
ART initiation is now recommended after HIV diagnosis144.
Six classes of antiretroviral medication, which each target unique
steps of the HIV life cycle, have been approved for clinical use: entry
inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs), NNRTIs, INSTIs, protease inhibitors (PIs) and capsid inhibi-
tors (Fig. 6 and Table 3). In most contexts, initial ART for treatment-naive
people living with HIV consists of an INSTI, PI or NNRTI in combination
with a backbone of two NRTIs192–195. A few select two-drug regimens have
also been shown to be safe and effective for initial therapy or as a switch
regimen following virological suppression to reduce cumulative expo-
sure to antiretroviral drugs, reduce the risk of some long-term toxicities
or to personalize the regimen to the patient’s preference. However,
there are caveats to this strategy, and the WHO has not incorporated
them in its guidelines192–195. Owing to their high barrier to resistance and
favourable adverse effect profile, INSTI-based regimens are considered
first line across global HIV treatment guidelines192–194.
ART is strongly indicated in persons with advanced HIV disease
(CD4+ T cell count <200 cells/mm3) and requires additional manage-
ment considerations. In particular, people living with HIV with low
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HIV
gp120 CD4+ T cell
gp41
Protein
Capsid
• NRTIs
and/or
1 Nucleus
NtRTIs
2 • NNRTIs
3 INSTIs
4 5
Coreceptor
CD4
Entry inhibitors
• Attachment inhibitor
• CCR5 antagonist
• Anti-CD4 binding antibody
Env GagPol
8
Fig. 6 | The HIV life cycle and sites of action of the major classes of
antiretroviral medication. HIV uses its envelope glycoprotein 120 (gp120)
and gp41 to bind with the CD4+ target cell (step 1) and enters the cell via the
CD4 receptor, using CCR5 or CXCR4 as a coreceptor (step 2). After entry,
the viral RNA is reverse transcribed into DNA (step 3). The viral DNA is then
imported into the nucleus (step 4) and integrated into the host genome
(step 5). Once integrated in the CD4+ cell DNA, transcription and replication
of viral mRNA occurs (step 6), which is then exported to the cytoplasm where
translation occurs to make viral proteins (step 7). The newly formed viral proteins
assemble (step 8), forming immature virions that are pushed out of the cell
(budding, step 9) and subsequently mature into infectious virions (step 10).
Antiretroviral medications target various steps of the HIV life cycle. Entry
inhibitors prevent HIV from entering the cell. Nucleoside reverse transcriptase
CD4+ T cell count need prophylaxis against opportunistic infections
and have an increased risk of immune reconstitution inflammatory
syndrome (IRIS)192–195. Diagnosis of certain opportunistic infections,
such as cryptococcal meningitis or tuberculosis involving the central
nervous system, requires a delay in ART initiation to mitigate potential
complications from IRIS196.
Incomplete adherence to ART can result in ongoing HIV replica-
tion, which in the presence of drugs enables the emergence of resist-
ance. Development of resistance can lead to virological failure (the
inability to maintain viral suppression below 200 copies/ml)192. Once
resistance emerges, it can be transmitted to others. Some guidelines
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6
Viral RNA
8 10
8
9
Protease
inhibitors
Capsid
inhibitors
inhibitors (NRTIs) or nucleotide reverse transcriptase inhibitors (NtRTIs)
are nucleoside/nucleotide analogues that are preferentially incorporated
into HIV DNA, leading to termination of DNA synthesis and blocking reverse
transcription. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind
near to the active site of reverse transcriptase, which causes a conformational
change in the enzyme and inhibition of reverse transcription.  Integrase strand
transfer inhibitors (INSTIs) prevent integration of the HIV genome into the host
genome. Protease inhibitors prevent the HIV enzyme protease from cleaving
HIV virions into mature functional proteins. Capsid inhibitors interfere with HIV
capsid, the protein shell that protects the HIV genetic and enzymatic content.
The new nucleoside reverse transcriptase translocation inhibitor (NRTTI) class
is not shown in this figure as the first NRTTI (islatravir) is still undergoing clinical
development. Image courtesy of R. L. Redondo and C. Reis Vieira.
recommend genotyping the virus in new cases of HIV infection to
assess for drug resistance before initiation of ART as well as those
with virological failure, but routine resistance testing capacity is
not available worldwide192–195. When selecting ART, particularly in
those with a history of virological failure, all available resistance test
results and prior treatment history must be considered. Notably, in
cases in which the non-adherence is the cause of virological failure,
the absence of selective drug pressure may cause drug-resistant virus
to revert to wild type, hence the circulating resistant strains may
become lower in numbers and not detectable by standard resistance
testing197.
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Table 3 | Commonly used antiretroviral medications

Class Drug Route of Notes and adverse effects

administration

NRTI Lamivudine and p.o. Active against HBV but resistance develops if used alone
emtricitabine
Tenofovir p.o. Available in two forms: TDF and TAF
TDF can cause decreases in bone mineral density and renal function; TAF has less bone and kidney
toxicity
TAF has been associated with weight gain in some studies but not in others
Active against HBV
Abacavir p.o. Has been associated with increased risk of myocardial infarction
Requires pre-treatment testing for HLA-B*5701 allele to avoid hypersensitivity reaction
INSTI Bictegravir and p.o. Higher barrier to resistance than first-generation INSTIs (elvitegravir and raltegravir)
dolutegravir
Associated with weight gain
Elvitegravir p.o. Coformulated with a pharmacological booster (cobicistat), which increases potential drug–drug
interactions
Associated with weight gain
Raltegravir p.o. Requires twice-daily dosing
Associated with weight gain
Cabotegravir i.m. Can have injection site reactions
NNRTI Rilpivirine p.o. or i.m. Less effective if high pre-therapy HIV viral load and/or low CD4+ T cell counts
Can have injection site reactions when administered i.m.
Efavirenz p.o. Associated with neuropsychiatric adverse effects
Etravirine and p.o. Higher barrier to resistance than other NNRTIs
doravirine
PI Darunavir p.o. Requires use of a pharmacological booster (cobicistat or ritonavir)
Associated with cardiovascular events in some cohorts of people living with HIV
Atazanavir p.o. Recommended to be given with a booster
Symptomatic hyperbilirubinaemia in some people living with HIV
Entry inhibitor Maraviroc p.o. Requires specialized tropism testing before use
Hepatotoxicity and hypersensitivity have been reported
Ibalizumab i.v. Must be given as i.v. infusion
Fostemsavir p.o. Requires twice-daily dosing
Capsid inhibitor Lenacapavir p.o. or i.m. Approved as a long-acting subcutaneous injection administered every 6 months; multiple studies of
this and other formulations are ongoing
HBV, hepatitis B virus; i.m., intramuscular; INSTI, integrase strand transfer inhibitor; i.v., intravenous; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse
transcriptase inhibitor; PI, protease inhibitor; p.o., per os (by mouth); TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

In the setting of HIV drug resistance, a new regimen containing two
fully active antiretroviral drugs (that is, two antiretroviral drugs that the
virus is fully susceptible to) may be sufficient to achieve virological con-
trol if it includes at least one drug with a high barrier to resistance, such as
DTG or boosted darunavir (DRV)191. Furthermore, the NADIA and VISEND
studies demonstrated that switching a failing NNRTI-based regimen to
DTG- or boosted DRV-based regimen while maintaining the same NRTI
backbone results in effective and durable viral suppression, even when
NRTI resistance is present198,199. If no fully active drug with a high barrier
against resistance is available, the new regimen should ideally include
three fully active drugs191. In some cases, an antiretroviral drug from the
same class as those in the failing regimen may retain full or partial activity
depending on their resistance barrier. Treatment of multidrug-resistant
HIV in highly treatment-experienced patients often involves salvage
regimens that include one or more drugs with a different mechanism of
action, such as an entry inhibitor200,201 or a capsid inhibitor202 in addition
to optimization of their background ART regimen.
ART must be administered for life. To ensure the safety and efficacy
of ART across the lifespan, HIV care providers must consider patient
preferences and medical comorbidities (Table 3). Ritonavir and cobi-
cistat are used as pharmacological boosters to increase levels of PIs and
elvitegravir to therapeutic concentrations, but they can have significant
drug interactions203. Regimens with food requirements, increased
pill burden and higher dosing frequencies can contribute to treat-
ment fatigue. Once-daily, single-tablet regimens, on the other hand,
increase adherence and virological suppression204. Long-acting ART

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is also an option for some people living with HIV who have difficulty
with oral regimens or simply prefer injectable treatment. Long-acting
cabotegravir and rilpivirine are now available in some countries as an
ART switch option for some people living with HIV who are virally sup-
pressed on oral ART205,206. However, the uptake of this regimen globally
is likely to be limited by implementation challenges, including the need
to maintain a cold chain for rilpivirine storage and the current practice
of administering the regimen in health-care settings only. Additional
limitations of the regimen include the risk of two-class resistance if
virological failure occurs and a lack of coverage for hepatitis B. The
ongoing phase III clinical trial, LATITUDE/AIDS (Clinical Trials Group
study A5359), is examining the efficacy of this regimen for people living
with HIV with a history of poor adherence to oral ART and poorly con-
trolled HIV infection. A nuclear capsid inhibitor, lenacapavir, which can
be administered every 6 months, was approved in the European Union,
Canada and the USA in the second half of 2022 as adjunctive therapy for
multidrug-resistant HIV202.
Certain clinical scenarios warrant use or avoidance of specific
antiretroviral regimens. Up to 20% of people living with HIV have HBV
co-infection207, and should receive tenofovir-containing ART. For
people living with HIV who are or plan to become pregnant, special
consideration must be taken to select ART that is safe and effective for
both the parent and child. Physiological changes during pregnancy can
affect the pharmacokinetics and efficacy of some antiretroviral medica-
tions, precluding their use during pregnancy208. After initial concerns
about a potential association of DTG with neural tube defects208 were
resolved in follow-up analyses209–212, it is now a first-line antiretroviral
drug worldwide for women who are or plan to be pregnant.
HIV care continuum
The HIV care continuum is an important public health model that
describes the trajectory that individuals move through from HIV screen-
ing and diagnosis to treatment and then viral suppression. This can
be viewed from a prevalence viewpoint considering all people in a
particular demographic whether positive or negative for HIV, or from
a disease-specific viewpoint in which the proportion of individuals
diagnosed, treated and virally suppressed is expressed as a proportion
of all similar people living with HIV. UNAIDS has recommended that
countries and regions aim to test at least 95% of all at-risk people for
HIV, that 95% of those who test positive should be linked to HIV care and
ART and, of those on ART, 95% should be maintained to become virally
undetectable by 2030. These are the so-called 95-95-95 targets. These
data, and certainly denominators, are not always available, particularly
for some age groups and risk groups. In addition, viral load testing is
not available everywhere, particularly in some LMIC settings, and so
the tool, which would enable comparisons across countries, regions
and populations, is not always available for this use213.
HIV treatment-associated comorbidities
Despite virally suppressive ART, people living with HIV experience both
earlier onset and higher rates of chronic non-infectious comorbidities
than the general population, owing in part to subtle adverse effects and/or
residual inflammation and immune activation214. Potential drug-specific
adverse effects can affect renal function, bone density, neuropsychiatric
symptoms, cardiovascular risk and body weight (Table 3).
Renal disease and bone mineral density. The first tenofovir pharma-
ceutical formulation, TDF, causes high serum levels of tenofovir that
correlate with an increased risk of adverse kidney and bone mineral
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density effects. This characteristically affects the proximal renal tubules
and can manifest as Fanconi syndrome215. The high serum levels of
tenofovir associated with TDF use also explain the association of TDF
with bone mineral loss, which has been related to the direct effects of
TDF on bone as well as the proximal renal tubule209. By contrast, the
second tenofovir formulation, TAF, has improved renal and bone safety
profiles213 because the serum levels of tenofovir achieved with it are ~90%
lower than with TDF210. Of note, TDF is relatively weight suppressing
and has been associated with potentially beneficial lipid effects212,216.
Neuropsychiatric effects. EFV is no longer a first-line agent, not only
because options with better virological profiles are now available but
also because of its neuropsychiatric adverse effects217. However, some
people living with HIV who have tolerated and achieved virological
suppression on an EFV-based regimen may remain on this agent, which
was previously widely used. Studies have also shown increased rates
of neuropsychiatric adverse events with some INSTIs, particularly
insomnia and other sleep disturbances with DTG218–221.
Cardiovascular risk. Abacavir has been linked to cardiovascular events,
which deters its use in high-risk individuals222,223. In addition, PIs and EFV
are known to cause dyslipidaemia, and one large observational study
found a link between cumulative exposure to ritonavir-boosted DRV
and increased cardiovascular risk224. Although INSTIs are considered
lipid neutral, a recent study suggested that exposure to INSTIs may be
associated with an early increase in cardiovascular events, although
this has not been confirmed in other studies225.
Excess weight gain. INSTIs, particularly the second-generation INSTIs
(bictegravir and DTG), and TAF have been associated with more weight
gain than other regimens226–229. The weight gain in those who initiate
ART for the first time is likely multifactorial and may include an aspect
of ‘return to health’, making it more difficult to distinguish from the
additional effect of INSTIs and/or TAF on weight. Nevertheless, excess
weight gain has been noted to disproportionately affect some patient
subgroups, particularly Black women, and a few patients do become
newly overweight or morbidly obese230. There is substantial interest in
understanding the full clinical implications of these observations, the
underlying mechanisms and ways to mitigate them. A few studies, spe-
cifically the Do-IT study and the DEFINE study, are evaluating whether
switching to different antiretroviral drugs such as doravirine, TDF or
DRV will promote weight loss in affected individuals231,232.
Treatment as prevention
In addition to reducing morbidity and mortality in people living with
HIV, effective ART also prevents HIV transmission between serodis-
cordant couples, a concept known as ‘treatment as prevention’ (TasP).
TasP was demonstrated in HPTN 052, in which early ART initiation was
associated with a 96% relative reduction in the number of linked HIV-1
transmissions233. The effectiveness of ART in blocking viral transmission
is attributable to sustained suppression of HIV-1 in the genital secretions
of individuals with suppressed plasma HIV-1 RNA234,235. The science that
underpins TasP is often simplified as ‘undetectable equals untransmit-
table’ or U = U. Specifically, individuals on ART with plasma HIV-1 RNA
suppressed below 1,000 copies/ml are very unlikely to transmit HIV-1,
and those below 200 copies/ml cannot transmit HIV-1 (ref. 236) to sexual
partners, although HIV-1 RNA is sometimes present in the genital secre-
tions of such individuals237,238. Unfortunately, awareness of TasP and
U = U is low in some populations, particularly in sub-Saharan Africa,
15
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where most people living with HIV live239. Current knowledge gaps
need to be filled, as knowledge of TasP has a beneficial effect on overall
HIV knowledge, stigma, testing and viral suppression240. Meanwhile,
the realities of TaSP and U = U urge intensification of global action to
achieve the ambitious UNAIDS target of 95-95-95 in all populations as
a pathway to ending AIDS by 2030 (refs. 241,242).
HIV cure
Although continuous ART has major individual and public health
benefits, ART is not curative, and viral rebound occurs after ART
interruption243, with very rare exceptions (post-treatment control-
lers)101. The term ‘HIV cure’ encompasses HIV remission defined as
viral control in the absence of ART, and ‘HIV eradication’ is defined
as elimination of intact, replication-competent virus. HIV reservoirs,
which remain incompletely understood, are the major barrier to cure.
Only a few individuals have achieved HIV eradication. These cases
occurred in the context of cancer treatment that involved stem cell
transplantation using cells from donors with the CCR5Δ32 mutation,
hence natural resistance to HIV infection244. However, stem cell trans-
plantation is not a scalable HIV cure approach; emerging consensus
is that combination approaches targeting different mechanisms of
viral persistence will be needed. Efforts are now underway to develop
target profiles for HIV cure interventions, recognizing that the charac-
teristics of an ideal target drug profile may be beyond the boundaries
of current scientific knowledge245. Some approaches under investiga-
tion include various combinations of newer latency-reversing agents,
bNAbs, toll-like receptor agonists, therapeutic chimeric antigen recep-
tor T cells, vaccines, vaccine adjuvants and gene therapies246. Studies
of the most promising interventions are expected to be demanding for
participants given the likely need for analytical treatment interruption
and invasive procedures to prove HIV cure. Continued community
engagement and education will be crucial to galvanize informed partici-
pation in these challenging studies, which the field must ensure reach
people living with HIV from diverse settings, genders and economic
backgrounds.
Quality of life
Health-related QoL (HRQoL) is an important health aspect in people
living with HIV. Many factors related to their condition can affect physi-
cal, mental, cognitive, emotional and social functioning247,248. Although
HIV research has prioritized prevention, detection, linkage to care and
viral suppression, these many advances have also enabled research
and policy measures to progress towards ensuring good HRQoL for all
people living with HIV249,250. The relationship between HRQoL and the
adverse effects of ART and its associated short- and long-term toxicity
is important to patient care248. However, HRQoL is known to be related
to many other dimensions as well. For example, our understanding
of the scope of the multifaceted aspects affecting the QoL of people
living with HIV has dramatically improved in recent years: access to
health services, socio-demographic status, mental health and stigma
and discrimination have been proved to greatly influence the overall
health and HRQoL of people living with HIV251.
Stigma can take many forms, and its impact on people living with
HIV can manifest as social exclusion, negative attitudes or beliefs,
discrimination or even violence towards individuals or groups252.
HIV-related stigma can have significant psychological and social
impacts on people living with HIV that negatively affect their QoL253,254.
Stigmatized individuals may experience internalized stigma that
yields or exacerbates depression, anxiety, low self-esteem and social
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isolation255,256. In some individuals, stigma can also affect social relation-
ships, leading to feelings of rejection, marginalization and loss of social
support. It can also discourage people from seeking testing, treatment
and care, which can have serious consequences for their health and
well-being257. Public stigma refers to the negative attitudes and beliefs
that exist at the societal level about people living with HIV, for example,
fear, prejudice and stereotypes that may lead to discriminatory poli-
cies and practices that limit opportunities and access to resources, for
example, employment, education, health care and housing258,259.
Thanks to ART, the evolving needs of people living with HIV have
shifted from immediate survival to requiring a broader conception
of HIV care: one that is integrated, multidisciplinary and takes into
consideration, and measures, additional relevant outcomes. Peo-
ple living with HIV are at greater risk than the general population of
multimorbidity260,261, even in settings with good access to ART262,263, and
often report poor QoL264. Common comorbidities among people living
with HIV include cardiovascular disease, HIV-associated neurocogni-
tive disorder, chronic kidney disease, lung disease and osteoporotic
fractures265–267.
This broader conception of HIV care is in line with the new
WHO 2022–2030 HIV Strategy and the UNAIDS targets set for 2026
(refs. 268,269). It is likely to change how HIV health-care services are pro-
vided. To enable this paradigm shift, though, HRQoL must be included
as the standard against which we measure the quality of HIV care268.
Health systems and services must assume a major role in monitoring the
HRQoL of people living with HIV via patient-reported outcome meas-
ures (PROMs) and patient-reported experience measures (PREMs)270,271.
National and regional HIV programmes must incorporate HRQoL in their
strategic goals and quantitative targets272. Improving population-level
HRQoL by monitoring and implementing people-centred measures,
as reflected by patient-reported outcomes, is not only feasible and
effective273,274 but necessary if we are to develop coherent public health
policies that align with the future of HIV care delivery.
Aiming for better levels of HRQoL can confer a positive impact on
both individuals and health systems275, resulting in the best possible
long-term outcomes for people living with HIV.
Outlook
The global response to the HIV epidemic has been inspiring and unique
with a multisectoral and inclusive approach. Engagement of civil soci-
ety, activism and advocacy around the world, an emphasis on equity
and human rights, galvanization and investment in scientific innova-
tion, and the foundation of global collaboration and problem solving
has been unprecedented276. The most profound advance has been the
discovery and evolution of ART, coupled with the global expansion of
treatment services, which has led to the reversal of the earlier escalat-
ing AIDS mortality globally. In South Africa, for example, expansion
of HIV treatment services caused average life expectancy in the entire
population to increase from 52 years to 61 years in less than a decade
from 2000 (ref. 277).
The AIDS epidemic is, however, not on track to end28. The UNAIDS
2020 targets for treatment and prevention were missed in almost every
country and were further exacerbated by the COVID-19 pandemic.
Although ART has transformed the HIV response by averting deaths,
improving QoL and preventing new HIV infections, HIV treatment
alone will not end the epidemic. Maintaining expanding treatment pro-
grammes, especially in LMICs, is not sustainable. The UNAIDS universal
test, treat and suppress (95-95-95) campaign aims to ensure that 95% of all
people at risk of HIV exposure should be tested for HIV, that 95% of
16
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those diagnosed positive should be linked to antiviral treatment and
that 95% of those should be virally suppressed. The concept was that if
these milestones could be reached, then secondary prevention benefits
would accrue, leading ultimately to epidemic control. This will require
ongoing mobilization of both international and domestic funding with
deployment and scale-up of all the efficacious prevention interventions
now at our disposal including oral and longer-acting PrEP options.
The lingering social barriers to accessing available biomedical
interventions, such as stigma, gender-based disadvantages and
discrimination, and oppressive laws, will need to be systematically
eliminated. A renewed commitment to end HIV in children is long over-
due, with 130,000 new HIV infections occurring in children in the past
year5. This will require a multipronged approach to address integrated
care for women of reproductive potential to ensure access to effective
contraception, PrEP, antenatal and postnatal testing, and treatment
before conception, during pregnancy and postnatally. As 40 million
individuals around the world continue to require uninterrupted and
lifelong effective ART the adoption of differentiated service delivery
models that consider individual preferences, population diversity and
health system needs are urgent. Opportunities to integrate HIV care
with that of other important comorbidities, such as tuberculosis,
malaria, viral hepatitis, non-communicable diseases and cancer screen-
ing and treatment, will contribute to long-term treatment success
and well-being249,276. Finally, to realize the end of the HIV epidemic a
global resolve to continue the development of an effective, affordable
preventive vaccine and a functional cure for HIV remain a priority. As
the largest population of young people transition from childhood to
adulthood, we risk the loss of HIV epidemic control unless real inroads
are made in reducing new HIV infections. Many of the lessons gained in
the HIV response have implications for future pandemics, including the
recent COVID-19 pandemic. Yet, there is evidence that the global com-
mitment to HIV and the HIV response is waning. This is deeply troubling
as the reduction of world attention and action on HIV is occurring at a
time when it is evident that lessons learned during the HIV epidemic
could point a way towards sustainable health for all by 2030 (ref. 276).
Published online: xx xx xxxx
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Acknowledgements
J.V.L. acknowledges support to ISGlobal from the grant CEX2018-000806-S funded by
MCIN/AEI/10.13039/501100011033, and support from the Generalitat de Catalunya through
the CERCA programme. J.V.L. acknowledges input from G. Brown, D. Barger and P. Carrieri.
R. L. Redondo and C. Reis Vieira developed Fig. 6. C. Williamson (University of Cape Town)
reviewed the text. S.R.L. receives funding from the National Institutes for Allergy and
Infectious Diseases. UM1 AI164560-01 Delaney AIDS Research Enterprise (DARE) Collaboratory
and the National Health and Medical Research Council (NHMRC) of Australia including an
NHMRC programme grant (to S.R.L.) and practitioner fellowship (to S.R.L.).
Author contributions
Introduction (L.-G.B.); Epidemiology (L.-G.B. and C.B.); Mechanisms/pathophysiology (L.-G.B.,
N.M. and S.R.L.); Diagnosis, screening and prevention (L.-G.B. and S.D.-M.); Management
(L.-G.B., B.T. and M.C.M.); Quality of life (L.-G.B. and J.V.L.); Outlook (L.-G.B.); Overview of the
Primer (L.-G.B.).
Competing interests
The authors declare no competing interests.
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