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Impact of long-acting therapies on the global
HIV epidemic

Nomathemba C. Chandiwanaa, Celicia M. Serenataa,M, Andrew Owenb,

Steve Rannardc, Carmen P�erez Casasd, Cherise Scottd, Andrew Hille,

Polly Claydenf and Charles Flexnerg

Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure
prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens
may improve dosing convenience, tolerability and cost compared with current daily-
based oral therapy. They can also circumvent stigma associated with oral therapy for
both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple
challenges remain, many specific to low-income and middle-income countries (LMICs),
where the epidemic is most concentrated and HIV prevention and treatment options are
limited. To optimize the use of long-acting formulations, key outstanding questions
must be addressed. Uncertain costing, scale-up manufacturing, complex delivery
systems and implementation challenges are potential barriers when considering the
scalability of long-acting ARVs for global use.

Copyright � 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

AIDS 2021, 35 (Suppl 2):S137–S143

Keywords: access and barriers, long-acting antiretrovirals, low-income and
middle-income countries, treatment optimization

Introduction

Current oral antiretroviral regimens are extremelyeffective
at suppressing HIV with minimal toxicity. Wherever fixed-
dose combinations are available, they offer the simplicity of
once-daily single-tablet dosing and have enabled vast scale-
up of antiretroviral therapy (ART) in low-income and
middle-income countries (LMICs) during the last 15 years
[1]. However, these gains might be threatened in the
absence of sustained viral suppression [2]. Among the most
common reasons for lackof adherence are forgetting, being
away from home, and a change in daily routine [3].
Depression, pill fatigue, alcohol and substanceuse, secrecy/
stigma, and health service-related barriers (e.g. distance to
clinic, stockouts) are also reported [4].

Long-acting (LA) antiretrovirals with infrequent dosing,
for example, weekly oral or long-acting parenterally
administered agents, may be useful in circumstances
where daily oral therapies are not feasible, difficult to
administer, and/or when adherence may be inadequate
[5,6]. Limitations of such approaches to drug delivery
include the management of toxicities, given that exposure
to these agents is not easily reversed; and prevention of
drug resistance, when these drugs are discontinued, and
drug concentrations are slowly reduced below targets
over time. New agents with long-acting anti-HIV-1
activity and older antiretrovirals in modified delivery
systems are being tested in both treatment of chronic
infection and PrEP for people at high risk of infection
[7–9].

aEzintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, bDepartment of Molecular and
Clinical Pharmacology, cDepartment of Chemistry, Centre of Excellence in Long-acting Therapeutics (CELT), University of
Liverpool, Liverpool, United Kingdom, dUnitaid, Geneva, Switzerland, eDepartment of Translational Medicine, Liverpool
University, Liverpool, fHIV i-Base, London, United Kingdom, and gDivisions of Clinical Pharmacology and Infectious Diseases,
School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

Correspondence to Nomathemba C. Chandiwana, Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Building
C, 32 Princess of Wales Terrace, Johannesburg 2193, South Africa.

Tel: +27 76 164 3215; e-mail: nchandiwana@ezintsha.org
�

Celicia M. Serenata deceased.

Received: 9 September 2021; accepted: 29 September 2021.

DOI:10.1097/QAD.0000000000003102

ISSN 0269-9370 Copyright Q 2021 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the
terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and
share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. S137

http://dx.doi.org/10.1097/QAD.0000000000003102


These approaches appear to be especially attractive for
people complaining of pill fatigue, including adolescents,
women during pregnancy and the postpartum period,
and for those experiencing HIV-associated stigma [3,10].
However, in higher income countries, disparities in
access are barriers to uptake of long-acting ARTand PrEP
for women and black MSM [11–14]. Due to high
tuberculosis (TB) and hepatitis B (HBV) burdens, as well
as cold chain requirements, currently available long-
acting formulations, are not ideal for LMICs. Other
barriers to the optimal implementation of long-acting
antiretrovirals in LMICs, include the increased frequency
of the injection appointments, provider concerns of
identifying appropriate candidates for LA ART and
operational challenges of the availability of single use
needles [15,16]. As these formulations, are shown to be
safe, well tolerated, more user-friendly, and economically
viable, they are likely to gain broader appeal.

Current pipeline of long-acting antiretroviral
therapy for treatment and prevention
Current clinical and experimental long-acting technolo-
gies can be classified as oral, parenteral, transdermal or
implantable approaches (Fig. 1). Parenteral (intramuscular
or subcutaneous) and implantable technologies have
already proven clinically successful for other indications,
while other approaches may be less invasive but are at earlier
stages of development [9,17,18]. For HIV prevention, the

pipeline is advancing quickly, with a diversity of long-
acting options being developed [19], including the recently
reported results of long-acting cabotegravir in preventing
HIVamong MSM and in cisgender women, and the recent
approval of a monthly vaginal ring of dapivirine [20,21]. In
the HIV treatment pipeline, a number of initiatives are
looking into long-acting products, with multiple candi-
dates at different stages of development (Table 1), and other
products in a diverse number of platforms entering this
dynamic pipeline that hold promise to radically change the
way ART is taken [22–24].

The first long-acting injectable combination (cabote-
gravir with rilpivirine) shown to be noninferior to daily
oral ART, with high patient satisfaction in research to date
has recently approved been approved for use in North
America and Europe [25–28]. This is an important
landmark in ART development but its use may be limited
in LMICs as long-acting rilpivirine requires cold chain
preservation, two separate vials for injection every
8 weeks, occurrence of drug resistance, and there is
interaction with anti-TB therapy [29,30]. New classes of
antiretrovirals can now be formulated in long-acting
forms, including capsid inhibitors, and nucleoside reverse
transcriptase translocation inhibitors, such as islatravir
[31,32]. In terms of biotherapeutic research, HIV broadly
neutralizing antibodies (bnAbs) are becoming attractive
strategies for treatment and prevention.

S138 AIDS 2021, Vol 35 (Suppl 2)

Fig. 1. Schematic of long-acting drug delivery technologies in clinical and preclinical development.



The first monoclonal antibody (ibalizumab) was approved
in March 2018 for treatment-experienced patients with
multidrug-resistant HIV [33]. A rapidly growing number
of HIV bnAbs are in development now, including
combinations of different bnAbs and second-generation
products, which might bring about important advantages
for LMICs scaled use [5,34].

Perspectives/experience of long-acting
antiretrovirals in low-income and middle-income
countries
Long-acting formulations offer a promising new avenue
for simplifying HIV treatment but most options are not
adapted to the needs of LMICs (for example, several
products now in clinical trials are infusions, or intrave-
nous injectables) or are at very early stages of develop-
ment. Long-acting antiretrovirals for either treatment or
PrEP have primarily been studied in mostly men from
higher income countries, which is not representative of
the global HIV epidemic [8,35,36]. This leaves a large
knowledge gap in the safety, efficacy, acceptability, and
cost of long-acting antiretroviral options used in diverse
populations in LMICs.

Several studies suggest that long-acting ART could be a
preferred and cost-effective option compared with oral
antiretrovirals in LMICs. In 2013, when long-acting
ARTwas still in very early stages of development, a 400-
patient survey found surprisingly high levels of
enthusiasm for long-acting injectables for treatment.
More than 80% of respondents indicated they would
consider switching from oral to parenteral ART if the
injection frequency were once per month; interest was
less with more frequent injections [37]. Since then,
several other surveys have confirmed these findings,
including in female sex workers, adolescents, and

people from predominantly minority communities
[8,38,39]. Participants in phase 2 and 3 clinical trials
of long-acting ART therapy have reported very high
levels of acceptance but these results are not easily
generalizable as they only included those who had
agreed to participate [7,8,36,40]. In the HPTN 076
trial, despite nearly two-thirds of women reporting pain
or tenderness at the injection site but despite this, long-
acting rilpivirine was an acceptable option for longer
term HIV protection, particularly among the African
women included in the study [41].

The experience with long-acting injectable contracep-
tion, as well as extended release implants, seems to
indicate a strong preference for these formulations over
daily tablets [17]. However, injectable contraception is
not without its pitfalls. For example, the risk of
‘breakthrough’ pregnancies, when women delay/miss a
follow-up visit. For long-acting ARVs, the equivalent
could be recurrent viraemia with risk for transmission and
developing resistance.

Nevertheless, there is great enthusiasm for this mode of
delivery to be available, including in LMICs [42].
Communities, donors, and policy makers see this as
strategy to address stigma (no visible tablets to carry
around) and suboptimal adherence [43]. Though
providers were more reticent about its broader imple-
mentation [15,35], which will likely be the case in LMICs
as well, especially given concerns of drug resistance from
missed doses. In addition, when many countries have
moved to multimonth dispensing, and the most common
first-line regimen now comes packaged in 3-month
supplies, any injectable ART that would require monthly
visits with a healthcare worker is unlikely to be attractive
to many countries, especially if at a higher cost.

Long-acting ARVs Chandiwana et al. S139

Table 1. Long-acting antiretroviral therapy formulations already in clinical evaluation or commercialized.

Agent Class/type Manufacturer/sponsor Status

Treatment
Cabotegravir LA and
rilpivirine LA injections

Integrase inhibitor þ
nonnucleoside reverse
transcriptase inhibitor
(NNRTI)

ViiV Healthcare, Janssen Approved (Canada, March
2020, EMA Dec 2020, FDA
Jan 2021)

Ibalizumab Monoclonal antibody TaiMed Biologics Approved FDA (Mar,2018) &
EU approval (Sep-2019)

Islatravir (MK-8591) NRTI Merck Phase 3
Elsulfavirine (VM-1500A) NNRTI Viriom Phase 2/3; approved in Russia.
Rovafovir etalafenamide
(formerly known as GS-9131)

Nucleoside reverse
transcriptase inhibitor (NRTI)

Gilead Sciences Phase 2

Leronlimab (PRO 140) Monoclonal antibody CytoDyn Phase 3
UB-421 Monoclonal antibody United BioPharma Phase 1
VRC01 Monoclonal antibody NIAID Vaccine Research

Center
Phase 1

VRC01LS Monoclonal antibody NIAID Vaccine Research
Center

Phase 1

Lenacapavir (formerly known
as GS-6207) Gilead

Capsid inhibitor Gilead Sciences Phase 2

Albuvirtide Fusion inhibitor Frontier Biotechnologies Co.,
Ltd

Approved (China, June 2018)



Although there are good networks working on initiatives
relating to long-acting formulations, such as the Long-
Acting/Extended Release Antiretroviral Research
Resource Program, or LEAP, these do not include
researchers from LMICs [23]. So complimentary studies
will be needed in these settings to inform operational
issues, efficacy, feasibility, and cost-effectiveness. For
example, cabotegravir/rilpivirine long-acting formula-
tions need to be studied in African and Asian populations
to confirm its efficacy in the HIV sub-types prevalent in
these settings. The use of long-acting injectable
formulations in LMICs will also require a review of
manufacturing capacity.

A 2018 WHO review of LAI ART candidates acknowl-
edged both the advantages and disadvantages of long-
acting formulations [44]. Issues around service delivery
platforms, especially if long-acting formulations require
more frequent healthcare visits can be overcome in using
innovative delivery models, for example, providing
ART/PrEP through private pharmacies and other
nonpublic sector facilities [45,46]. These differentiated
delivery models, could be considered for long-acting
ART. Planning for implementation of long-acting
formulations should build on experience gained from
the expansive scale-up of HIV interventions/family
planning innovations, such as prevention of vertical
transmission, voluntary medical male circumcision, and
more recently, oral PrEP programmes as well as self-
injection of contraception [47].

Long-acting drugs and formulations for other
infectious diseases in low-income and middle-
income countries
If long-acting/extended release formulations for HIVare
successful, this is likely to stimulate and facilitate the
development, availability and adoption of similar for-
mulations for other infectious diseases in LMICs. Similar
to the HIVepidemic, global responses to TB, malaria and
hepatitis C, diseases for which global goals for elimination
have been established for 2030, face a range of serious
challenges, including the lack of a highly efficacious
vaccine, complex protocols for chemoprophylaxis,
increasing burden on health services and supply systems,
pervasive stigma and discrimination, poor drug quality,
and emergence of resistance [48].

Long-acting products are in various stages of develop-
ment for these diseases. For TB, a long-acting formula-
tion of bedaquiline, a key component of MDR-TB
regimens, showed antimicrobial activity for up to
12 weeks after a single dose in a mouse model of TB
[49]. Long-acting antimalarials are being assessed for
prevention and could even be used in place of a vaccine
for regional eradication. New compounds and repurpos-
ing existing drugs as long-acting formulations are being
explored. Formulations, analogous to that of rilpivirine
and cabotegravir LA, could be used for prevention of

malaria in humans to protect most vulnerable populations
in endemic areas. [50,51]. Likewise, the potential for
repurposing ivermectin as a long-acting malaria vector-
control tool (and for other vector-borne neglected
tropical diseases) is being investigated [52,53]. For control
of hepatitis virus infections, the tenofovir alafenamide
implants could be used in chronic hepatitis B virus (HBV)
infection, although other long-acting antiretroviral
formulations lack activity against HBV [54]. A test-and
cure strategy for hepatitis C virus (HCV) may be possible
if there were a two-drug injectable combination that
could deliver effective antiviral concentrations for 8 to
12 weeks [55].

Cost of scale-up of long-acting antiretroviral
therapy in low-income and middle-income
countries
The economic argument for the use of long-acting
antiretrovirals will be a primary concern. Long-acting
products, although they mayadd some costs comparative to
standard of care in the short-term, can bring substantial cost
savings in the long-term to help alleviate burdens from
existing and new health threats [23,56]. Their benefits
enable national programmes and individuals to untap the
maximum potential of available therapies leading to
reduced transmission of target pathogens, improved clinical
outcomes, and greater impact in disease burden, eventually
reducing the total funding needs. A robust economic
understanding will require a thorough interrogation of the
costs associated with manufacturing and sourcing the
product (manufacturing processes, selling prices, storage,
and logistic costs), as well as with the economic impact of
the intervention on wider healthcare provision.

Importantly, not all long-acting technologies are the
same, and each have very different manufacturing
considerations. Even particle dispersions for injection
can be manufactured using different processes that are
likely to differ considerably in terms of manufacturing
cost [57–59], with ‘syringeability’ and drug/excipient
ratios also dictating the ultimate drug concentration
within an acceptable administration volume. Scale-up of
manufacturing will require investment in capability to
meet the needs of new technologies and/or additional
demand in LMIC markets and the need for prodrug
derivatization for compatibility with some approaches
may also increase complexity and cost [57,58,60]. For
parenterals and implantables, sterility is also of pivotal
importance and selection of an appropriate manufactur-
ing technology should consider the need for premanu-
facturing or postmanufacturing sterilization, which may
also impact cost. Ultimately, there should be an effort to
decrease the cost of goods manufactured, with careful
thought on selection of technology and platform during
product development. And also, efforts must be
undertaken now to enabling a market where scaled
production by different manufacturers can render LA
market viable. There are precedents, notably in HIV

S140 AIDS 2021, Vol 35 (Suppl 2)



treatment and prevention, of large-scale manufacturing
with limited margins serving high-volume markets.
Notwithstanding the differences between such oral
antiretroviral market, and the production of long-acting
formulations that might require advanced manufacturing
approaches to control drug release and perhaps complex
platform for delivery (implants, patches, etc.), efforts to
develop a sustainable market are warranted.

Likewise, for long-acting formulation based on biologic
components (monoclonal antibodies), and given the
particularity of these products, a clear strategy would be
required to address the conditions for a future healthy
market in LMICs that can deliver equitable access to
populations most in need as early as possible [23]. For
example, joint efforts by the International AIDS Vaccine
Initiative (IAVI), Scripps Research and the US National
Institutes of Health to accelerate affordable and sustain-
able global access when bnAbs are shown to be efficacious
for HIV prevention and possibly for treatment [61].
Timely interventions are warranted to address affordabil-
ity, scaled-up production by generic manufacturers,
intellectual property, regulatory pathways for similar
biotherapeutics, adaptability or ease of use, and simplified
delivery supporting their scaled use.

In addition, many remaining challenges are pathogen-
specific and use-case-specific, with cost implications
being very different for prevention of malaria with a
single agent for a single season, compared with a life-time
commitment to a fully suppressive antiretroviral drug
combination. A holistic approach to consideration of the
wider healthcare implications is also required and many of
the potential cost, equity, and/or healthcare benefits are
not easy to directly quantify. For example, long-acting
treatment of schizophrenia may represent a more relevant
example than contraception, given the measurable
benefits and cost-savings from long-acting injectable
antipsychotics with reduction in mortality, rehospitaliza-
tion, relapse, and caregiver burden (31%) [62–65].

As demonstrated by long-acting contraception, it is
possible to see high uptake and impact in LMICs [17,66].
To supply the market in LMICs for modern contracep-
tion methods, generic products of long-acting formula-
tions were included in the WHO Prequalification
Programme and are currently supplied by the United
Nations Population Fund (UNFPA). Market shaping
interventions (enabling the increase in supplier-base and
diversity of products) have led to significantly decreased
prices and increased uptake in LMICs. Using similar
pathways and interventions for emerging long-acting
products for infectious diseases, especially when current
standards of care are not adequate, may ensure their
maximal impact.

In conclusion, long-acting antiretroviral agents have great
potential to improve the way we both treat and prevent

HIV. The two-drug combination of long-acting
injectable cabotegravir and rilpivirine is likely to be
approved in sub-Saharan Africa by the end of 2022, with a
wider number of investigational long-acting antiretroviral
formulations in clinical development that could be better
adapted for use in LMICs. However, challenges include
managing side effects, drug–drug interactions, use in
pregnancy, and long-lasting drug concentrations after
discontinuation of the formulations that could lead to the
development of drug resistance. In addition, affordability,
acceptability, and ability to deliver at scale must be
anticipated. These products are likely to revolutionize the
treatment and prevention of HIV, and this approach to
drug delivery holds great promise for other infectious
diseases as well.

Acknowledgements

We dedicate this work to our deceased co-author,
colleague and friend, Celicia Serenata, a wonderful human
being who lived her life improving the lives of others.

Funding for this AIDS journal supplement was provided
by the US Agency for International Development
(USAID) through the OPTIMIZE Cooperative Agree-
ment AID-OAA-A-15-00069 to Ezintsha, University of
the Witwatersrand. The content of this supplement is
solely the responsibility of the authors and does not
necessarily represent the official views of USAID, or any
other agency.

Conflicts of interest
NC has received research funding from ViiV Healthcare,
Merck, Janssen and Gilead, and speaker fees from Janssen.

A.O. and S.R. thank Unitaid for co-funding creation of
CELT and for project LONGEVITY. A.O. and S.R. are
Directors of Tandem Nano Ltd and co-inventors, with
C.F., of patents relating to drug delivery for infectious
diseases. A.O. has received research funding from ViiV
Healthcare, Merck, Janssen and consultancy from Gilead,
ViiV Healthcare and Merck. C.F. has served as a paid
consultant to Merck, Mylan Pharmaceuticals, and ViiV
Healthcare; is a paid Data Safety and Monitoring Board
member for Algernon Pharmaceuticals; and has served as
an expert witness in a legal case involving Gilead Sciences.

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