Medical Focus - GPH - Vol 3 No 2 250521

Volume 3 No 2 - 2021
HIV, TB and Mental Health newsletter for healthcare professionals
across the continent
Sponsored by:
EM-59824

Editorial
In this issue
3 Editorial
Prof S. Kolade Ernest
4
7
10
13
Outlook of paediatric
tuberculosis in the
Covid-19 pre-vaccine era
Dr Ray Ezekiel Onoja
Prof S. Kolade Ernest
Overview of Long-COVID
or PASC and when is it
COVID and when is it not
Dr Murray Dryden
Managing schizophrenia
with long-acting
injectables (LAIs) with
emphasis on the secondgeneration
antipsychotics
(SGAs)
Dr Frans Korb
The role of NNRTIs in the
InSTI era
Dr Bronwyn Bosch
Disclaimer: This information is intended for educational
purposes only and does not replace
independent professional judgment. The views
expressed by the editor or authors in this newsletter
do not necessarily reflect those of the
sponsors or publishers. Johnson and Johnson and
publishers do not endorse or approve and assume
no responsibility for the content, accuracy
or completeness of the information published in
the articles. Product information or data shared
in the publication are for scientific evaluation
only. Product information discussed may also not
be approved in the label by the MOH. No content
of this publication may be reproduced in any way
without the express prior permission from the
author and publishers. Anyone in breach of this
copyright will be held personally liable.
Sponsor:
Johnson & Johnson
Production Editors: Ann Lake, Helen Gonçalves
Design:
Jane Gouveia
Enquiries: lakeann@mweb.co.za
Telephone: 011 802 8847
Guest Editor: Professor S. Kolade Ernest MBBS(Ibadan), FWACP(Paed), Cert. HP & Mgt.,
FSM, MNIM, FRCPCH (UK)
Professor of Paediatrics and Child Health, University of Ilorin, Nigeria
Honorary Consultant Paediatrician, University of Ilorin Teaching Hospital
Expert in Paediatric Infectious Disease including HIV and Community Child Health
edical Focus: A Guide to Patient Health is a Global
Public Health response of Johnson and Johnson,
published in order to build expertise in the African
region particularly for those who care for HIV, TB and
mental health patients. Again, in this issue, Volume 3 Number 2,
highlights of key clinical developments and challenges are made
for better understanding of these major diseases. Johnson and
Johnson Global Public Health and the publisher were able to assemble prominent
experts who contributed from their wealth of experiences to this edition.
I am so excited about this volume and almost cannot wait to put it in the hands
and inbox of the regular and new readership of the Medical Focus Newsletter. It is
my good pleasure to provide this editorial.
Dr Ray Ezekiel Onoja and Professor Kolade Ernest both paediatric co-workers,
presented an outlook of paediatric tuberculosis in the COVID-19 pre-vaccine era.
Very insightful article that forms the ‘leftist position’ of a global event which can
be compared with situations in the near future when COVID-19 vaccine coverage
would have become standard of care and a high herd immunity achieved globally.
Dr Murray Dryden's contributions on Long-COVID or post-acute sequelae of SARS-
CoV-2 infection (PASC) is timely so that many healthcare providers would find it
highly resourceful both for definition of terms and what presently is generally
acceptable on this new disease. He rightly argued that the cause of PASC is unknown
but might be heavily related to the inflammation and cellular injury that
occur during the acute infections. He also submitted a good guide in the diagnosis
and management of PASC that would possibly motivate you to make this edition a
pocket book as more patients may be getting to that stage of PASC.
Psychiatrist and clinical psychologist, Dr Frans Korb reviews the centrality of
second generation antipsychotic medications when managing schizophrenia with
long-acting injectables. The contribution also included other benefits of longacting
injectables and provided a useful table of the agents with accompanying
notes.
With about 90% of global HIV cases living in low and middle income countries, discussions
around HIV would always be of pertinent interest to all of us in Africa. Dr
Bronwyn Bosch, a research clinician and safety physician with Wits Reproductive
Health and HIV Institute in Johannesburg reviews the role of non-nucleoside reverse
transcriptase inhibitors (NNRTIs) in an era of integrase-strand inhibitors (InSTIs). Remember,
even though NNRTIs have been very useful over the years, the unacceptable
challenge of emerging drug resistance would make them the less preferred
choice where InSTIs with more tolerable treatment-related side effects, are readily
available. The conclusion is very insightful and a good guiding encouragement.
I have no doubt that the discussions in this issue will be very useful asset to the
readership of this newsletter. I’m also very hopeful that this issue will motivate
others so we can have widening readership across Africa and beyond. Please enjoy
this edition.
3 Vol 3 No 2 - 2021

Outlook of paediatric tuberculosis in the
Covid-19 pre-vaccine era
Dr Ray Ezekiel Onoja
Department of Paediatrics & Child Health, University of Ilorin Teaching Hospital, Ilorin, Nigeria
Professor S. Kolade Ernest MBBS(Ibadan), FWACP(Paed), Cert. HP & Mgt., FSM, MNIM, FRCPCH (UK)
Department of Paediatrics & Child Health, University of Ilorin Teaching Hospital, Ilorin, Nigeria
he COVID-19 pandemic caused by the novel
coronavirus (SARS-CoV-2), commenced in Wuhan,
China in late 2019 with rapid global spread, sparing
no continent, with the first African case being
reported in Egypt in February 2020. By the 20th of February
2021, more than 111 million cases globally had been reported
with almost 2.5 million deaths. 1
Nigeria who has been battling other infectious diseases like
tuberculosis, HIV and malaria for decades without significant
eradication success, has also been affected with the pandemic.
Nigeria had reported 150,908 cases and 1,813 deaths as at
20th February 2021. The impact of this pandemic is far reaching
and the consequence of both the disease and measures
put in place to control the disease are beginning to emerge. 2
The burden of TB/HIV and multidrug-resistant TB is high in
Nigeria. The country is ranked seventh among the thirty high
TB burden countries and second in Africa. It is estimated that
407,000 HIV negative people in Nigeria have TB each year. 3
In addition there are an estimated 63,000 HIV positive people
that get TB each year. An estimated 115,000 HIV negative people
die from TB in Nigeria each year and an estimated 39,000
HIV positive people also die from the disease.
TB incidence is anticipated to increase in high burden HIV/
TB countries including sub-Saharan African countries with increasing
COVID-19 burden. 4
In a retrospective cohort study 5 involving a review of medical
records of children (0-14 years) with TB in 3 states in Nigeria,
it was discovered that of 724 childhood TB cases registered
during the review period, 220 (30.4%) were aged 0-4 years.
Fifty-eight percent had pulmonary TB. New TB infection in
98.5%, and human immunodeficiency virus (HIV) coinfection
was found in 108 (14.7%). About 28% (201) were bacteriologically
diagnosed. The proportion of TB treatment success was
83.0%. Treatment success was significantly higher in children
aged 5-14 years than those 0-4 years (85.3% vs 77.7%, P = .01).
Factors associated with poor outcomes in patients aged 0-4
years were male sex, HIV-positive status, and clinical method
of diagnosis. The arrival of COVID-19 would possibly be a ‘double
burden’ that must be continuously evaluated to see what
difference vaccines would make.
COVID-19 and TB co-infection
COVID-19 is a highly contagious acute viral disease, whereas
TB is a chronic bacterial disease. Both COVID-19 and TB affect
the respiratory system, primarily the lungs, and have similar
symptoms such as cough, fever and breathing difficulty, although
the severity and duration of the symptoms may vary.
While the route of transmission for COVID-19 and TB may be
similar and require close contact with infected people, the efficiency
in transmission is better in COVID-19 compared to TB.
For COVID-19, the source of infection can be both symptomatic
and asymptomatic patients, while for TB the main source
of infection is symptomatic patients with productive cough. 6,7
Coinfection of TB and SARS CoV-2 is of particular concern due
to several reasons: 8,9
• Concern #1:
Diagnosis of TB is likely to be missed due to non-specific
clinical features in both (TB & COVID-19) and lack of radiological
findings specific to TB.
• Concern #2:
COVID 19 or use of immune-modulators in moderate-severe
COVID-19 may lead to reactivation of latent TB in high
endemic areas.
• Concern #3:
Co-existing active TB disease may predispose to severe
COVID 19 illness from basic immunology considerations.
• Concern #4:
Possibility of drug-drug interactions (e.g. rifampicin and
remdisivir) due to simultaneous use of anti-TB medications
and available COVID 19 therapeutic options.
Disease outcomes
Some studies have described the outcome of COVID-19 in
people and children with current or active TB disease. TB disease
was either diagnosed before contracting COVID-19 or
was diagnosed at the time of COVID-19 diagnosis, due to some
overlapping symptoms in people with COVID-19 and or TB. 5,6
Most of these studies reported that current TB disease was
associated with severe COVID-19 that required hospitalisation
and oxygen supplementation or ventilation. However, most of
the patients recovered from COVID-19 and were discharged
from hospital. Some studies reported increased mortality in
people with COVID-19 and active TB, and concluded that TB
was associated with prolonged recovery from COVID-19 and
or mortality. All studies with data on COVID-19 in people with
previous TB reported that previous TB was associated with severe
COVID-19, though most of the patients recovered after
prolonged stay in hospital. In the future, lung lesions associated
with COVID-19 may increase the risk of PTB, which induces
a true vicious circle of HIV-TB-COVID-19 co-infection. Generally,
children with TB and COVID-19 have mild COVID-19 disease.
Reasons for this require critical evaluation in the future.
4
Vol 3 No 2 - 2021

The potential impact of COVID-19 pandemic on
tuberculosis 10,11
COVID-19 could impact TB control in several ways, including
increasing transmission of TB in the household, delaying the
diagnosis and treatment of TB, increasing poor treatment
outcomes and risks of developing drug-resistant TB.
Impact on Transmission
Lockdown was one of the measures used by countries to
prevent the spread of COVID-19. This measure may facilitate
household transmission of TB as over-crowding was prevalent
in developing countries during the lockdown.
A study conducted in Brazil showed that intensity of household
exposure increased the risk of TB infection and disease
among household members. Post lockdown periods still
present the same risk to under-5 year old children because
they depend on adults to walk away from such overcrowded
homes with heightened transmission.
Impact on treatment and diagnostic services
Overwhelming of health care systems by COVID-19 cases is
likely to impact on TB treatment and diagnostic services in
several ways:
• Diversion of resources (including human and financial)
away from routine services, to manage the pandemic
• Limited oversight and accountability of TB programmes
• Reduced number of health care personnel either due to
isolation or due to the illness
• Stigma and fear of COVID-19 infection at health care facilities,
discouraging people from visiting TB services
• Screening services for TB have experienced competition,
e.g. gene expert cartridges for TB being used for COVID-19;
sputum specimens being prioritised for COVID-19 testing
delaying diagnosis of TB
• Inappropriate use of BCG in response to the unproven theory
that BCG may protect against COVID-19
All of these seven factors will contribute to delays in the
diagnosis and commencement of treatment. Late diagnosis
and inappropriate treatment of TB can also increase the
risk of poor treatment outcomes and development of drugresistant
TB. Misdiagnosis and under-detection of TB are
ongoing problems for TB programmes. It was estimated that
3 million TB cases were undetected in 2018. This number
is likely to increase due to our current diversion of health
facility toward the containment of COVID-19 pandemic.
Impact on prevention and control of tuberculosis
Prevention and control strategies for TB have already been
compromised due to the COVID-19 pandemic. Many fora for
exchanging TB research and information, such as seminars,
workshops and annual conferences, have not been conducted
in 2020. For instance, the World Tuberculosis Day, which is
celebrated on March 24 each year, to build public awareness
about the prevention and control of TB and to raise funding
to support TB control efforts, has been cancelled in several
countries.
Vaccination programmes, including the BCG vaccination that
has been given to prevent childhood TB, have been negatively
affected by COVID-19.
Furthermore, TB preventive therapy, which is often given to
high-risk groups to prevent the progression of latent TB to active
TB has also been affected by COVID-19. The worldwide
pandemic of COVID-19 may affect the global strategy of ending
TB by 2035 in several ways.
Many of the factors affecting diagnostic and testing services
also affect prevention and control programmes. Shortages of
resources, either directly due to diversion towards pandemic
management or indirectly due to broader economic consequences
of the pandemic and stretched national budgets, are
likely to impact on routine public health programmes.
The COVID pandemic has left a devastating effect on the poor,
through job losses, rising prices, and disruptions to services
such as education and health care. As a result of this, more
people have fallen into extreme poverty. This will have a longterm
impact on the burden of TB because poverty is widely
recognised as an important risk factor for being infected and
developing active TB.
Strategies to mitigate the effect 8,9,13
• Apply infection prevention and control measures (e.g.
cough etiquette, personal protective equipment)
• Separate or isolate people with presumed or demonstrated
infectious TB
• Provide TB preventive treatment for high-risk groups and
initiate TB treatment early
• Maintain supports to essential TB services during and after
the COVID-19 pandemic
• Provide information to patients about COVID-19 and TB so
they can protect themselves and continue their TB treatment
• Decentralise TB treatment to community health workers
and increase access to TB treatment for home-based TB
care
• Provide adequate supply of TB medication to patients for
safe storage at home
• Design mechanisms to deliver medicines and to collect
specimens for follow-up testing at home
• Integrate TB and COVID-19 services for infection control,
contact tracing, community-based care, surveillance and
monitoring
• Train health professionals and recruit additional staff to
work on TB programmes
• Use virtual care and digital health technologies (e.g., video
observed therapy) for adherence support, early initiation
of treatment, remote monitoring of TB patients, counselling,
and follow-up consultations
• Design strategies to deliver BCG and TB preventive therapy
at home
• Create community awareness of the importance of TB services
• Conduct research to identify the impact of COVID-19 on
reactivation of TB and to design interventions mitigating
this problem
5 Vol 3 No 2 - 2021

What to expect as COVID-19 vaccine coverage
widens
As global and regional COVID-19 Vaccine coverage increases,
one expect that less and less infections would happen and
then the burden on our health system would lessen so that
more resources can be available for the TB programmes.
Take home messages
• The burden of HIV/TB infection is high in developing countries
• Nigeria has the 7th largest burden of TB, with over 400 000
infections among HIV negative people yearly while over
60 000 HIV positive people are infected yearly
• TB and COVID share some common symptoms, methods
should be put in place to ensure that both are identified
early and treated appropriately
• People with previous TB infection is associated with severe
COVID infection. Conversely, the lesions associated with
COVID may increase the risk of TB
• Due to the pandemic and lockdown measures and the
consequent disruption in TB services, service providers
must develop innovative means of sustaining services
Conclusion
Unlike most acute infections, TB takes a rigorous sometimes
tortuous path to treat. Resources to treat TB diseases have
been inadequate so that the arrival of COVID-19 only heralded
global TB programme failure. But we must not give in to
accepting failure but to do all we can to navigate the trouble
waters created by COVID-19 pandemic, TB-co-infection and
the challenges of multidrug resistant TB.
References
1. Gray DM, Davies M-A, Githinji L, Levin M, Mapani M,
Nowalaza Z et al. COVID-19 and Pediatric Lung Disease:
A South African Tertiary Center Experience. Front Pediatr
2021; 8: 836.
2. Kumar R, Bhattacharya B, Meena V, Soneja M, Wig N.
COVID-19 and TB co-infection - ‘Finishing touch’’ in perfect
recipe to ‘severity• or •death’. J Infect 2020; 81: e39–e40.
3. Khurana AK, Aggarwal D. The (in)significance of TB and
COVID-19 co-infection. Eur. Respir. J. 2020; 56.
4. Stochino C, Villa S, Zucchi P, Parravicini P, Gori A, Raviglione
MC. Clinical characteristics of COVID-19 and active tuberculosis
co-infection in an Italian reference hospital. Eur.
Respir. J. 2020; 56.
5. Chidubem L Ogbudebe, Victor Adepoju, Christy
Ekerete-Udofia, Ebere Abu, Ginika Egesemba, Nkem
Chukwueme, Mustapha Gidado Childhood Tuberculosis
in Nigeria: Disease Presentation and Treatment
Outcomes PMID: 29511357 PMCID: PMC5826094 DOI:
10.1177/1178632918757490
6. Finn McQuaid C, McCreesh N, Read JM, Sumner T, Houben
RMGJ, White RG et al. The potential impact of
COVID-19-related disruption on tuberculosis burden. Eur.
Respir. J. 2020; 56.
7. Gao Y, Liu M, Chen Y, Shi S, Geng J, Tian J. Association between
tuberculosis and COVID-19 severity and mortality:
A rapid systematic review and meta-analysis. J. Med. Virol.
2021; 93: 194–196.
8. Mousquer GT, Peres A, Fiegenbaum M. Pathology of TB/
COVID-19 Co-Infection: The phantom menace. Tuberculosis.
2021; 126: 102020.
9. Ata, F., et al., A 28-Year-Old Man from India with SARS-
Cov-2 and Pulmonary Tuberculosis CoInfection with Central
Nervous System Involvement. Am J Case Rep, 2020. 4.
10. Boulle, A., et al., Risk factors for COVID-19 death in a population
cohort study from the Western Cape Province,
South Africa. Clin Infect Dis, 2020. 5.
11. Can Sarinoglu, R., et al., Tuberculosis and COVID-19: An
overlapping situation during pandemic. J Infect Dev Ctries,
2020. 14(7): 721-725.
12. Chen, T., et al., Clinical Characteristics and Outcomes of
Older Patients with Coronavirus Disease 2019 (COVID-19)
in Wuhan, China: A Single-Centered, Retrospective Study. J
Gerontol A Biol Sci Med Sci, 2020. 75(9): 1788-1795.
13. Faqihi, F., et al., COVID-19 in a patient with active tuberculosis:
A rare case-report. Respir Med Case Rep, 2020. 31:
101-146.
6
Vol 3 No 2 - 2021

Overview of Long-COVID or PASC and when is it
COVID and when is it not
Dr Murray Dryden MBChB
National Institute for Communicable Diseases Division of National Health Laboratory Services
South Africa
Definitions
• The COVID Symptom Study identified six clusters of symptoms
suggests that roughly 10% of patients are at risk. 4,5 • Currently there is no laboratory test identified that can
There is currently no universally accepted definition of Long-
COVID. However, the National Institute for Health and Care
Excellence (NICE) in the UK have put forward the following
definitions: 1
(persistent cough, hoarse voice, headache, diar-
rhoea, skipping meals, and shortness of breath) in the first
week of acute COVID that may increase one’s risk two to
three times for developing longer term symptoms. 6
• Acute COVID-19
• Predicting who is likely to develop PASC is currently not
––
Signs and symptoms of COVID-19 for up to 4 weeks following
from symptom onset.
possible. However, there are certain groups of people who
appear to be particularly predisposed.
• Ongoing symptomatic COVID-19
––
Pre-existing diagnosis of depression is associated with
––
Signs and symptoms of COVID-19 from 4 weeks up to severe post-COVID fatigue. 7
12 weeks.
––
It is twice as common in women as in men and a slight
• Post-COVID-19 syndrome
increase in people who are overweight but not statistically
––
Signs and symptoms that develop during or after an
significant. 8
infection consistent with COVID-19, continue for more
than 12 weeks and are not explained by an alternative
diagnosis.
––
There seems to be different symptom clusters in different
ages, so it could be that there is a different type
in younger people compared with the over 65s but a
• Long-COVID
more reliable link can only be established as more data
––
Described signs and symptoms that continue or develop
is collected. 8
after acute COVID-19. It includes both ongoing
symptomatic COVID-19 (from 4 to 12 weeks) and post
• Severity of acute COVID-19 has not shown to be a reliable
predictor of those who will and who will not develop PASC.
COVID-19 syndrome (12 weeks or more).
Presentation
NIH Director Francis Collins has proposed post-acute sequelae
of SARS-CoV-2 infection (PASC) to be used as the formal
clinical name for Long COVID.
Patients may present with a remarkably wide range of persistent
or recurrent symptoms following acute SARS- CoV-2
infection, including the following: 1,9,10
• Most Common
Aetiology
––
Severe fatigue
The aetiology of PASC is still undefined. Currently available ––
Shortness of breath/breathlessness
research suggests that it may be as result of the inflammation
––
Persistent cough
and injury that occurs during the acute infectious phase ––
Chest pain or heaviness
of SARS-CoV-2 infection 2 in a variety of organ systems including
––
Joint pain or swelling
the brain, heart and the lungs to name a few, but ulti-
• Other Symptoms
mately the injury may be wide spread throughout all organ ––
Cognitive impairment – “brain fog”
systems in the body. 3
––
Muscle pain
––
Headache
The injuries are not as a result of ongoing SARS-COV-2 infection
––
Intermittent fever
but rather the injury to the body that occurred during ––
Palpitations
the acute infectious period.
––
Anosmia and/or ageusia
––
Reduced exercise capacity
Patients who may be diagnosed are not infectious and cannot
––
Vertigo and tinnitus
be spread PASC (or occur in someone who had not been ––
Peripheral neuropathy
infected by SARS-COV-2 whether they were formally diagnosed
––
Metallic or bitter taste
or not.)
––
Skin rash
Who is at risk?
The syndrome is often accompanied by anxiety and depression,
associated with the protracted and unpredictable
Preliminary research seems to suggest that PASC may develop
in both patients who experienced mild and severe disease course of the symptoms.
with no immediately recognisable correlation.
• In those who became ill with SARS-COV-2, preliminary data Diagnosis
7 Vol 3 No 2 - 2021

be used to diagnose someone with PASC.
• Although patients may potentially be diagnosed retrospectively
with acute SARS-CoV-2 infection by means of
antibody testing, the presence of antibodies does not
confirm the diagnosis of PASC.
• A thorough history and examination is recommended to
exclude other causes or to make a differential diagnosis
linked to PASC.
• Diagnosis is primarily clinical and on the basis of exclusion
of other potential causes.
Patients who were formally diagnosed with COVID-19 by
means of a positive SARS-CoV-2 PCR or/and antigen test with
persistent symptoms beyond 4 weeks of acute illness, should
be considered a PASC diagnosis.
• Patients who present with COVID-like illness but without
a confirmed SARS-CoV-2 PCR or antigen test may be considered,
provided any other potential causes have been
excluded.
• It is important to consider that other undiagnosed clinical
conditions may better explain the persistence of COVIDlike
symptoms and as such sufficient investigation is necessary
before settling on PASC as the final diagnosis.
Management
Patients need to be reassured that they are not alone and
preliminary research suggests resolution of most symptoms,
if not all, will occur with time. 5 The pathophysiology of PASC
is currently poorly understood and an accurate timeline of
this has yet to be established.
Current recommendations with regard to the management
of PASC illness are patient specific, symptomatic management
by a primary care physician: 11
• Addressing immediately life threatening conditions are of
paramount importance and urgent escalation along appropriate
referral pathways is crucial.
• For non-threatening conditions, the mainstay of management
includes advice on self-management strategies,
caregiver support and education, peer-to-peer support
groups, stress management, stigma mitigation and lifestyle
modification.
• As a consequence of multiorgan system involvement, a
multidisciplinary and holistic approach is necessary when
developing a management plan for these patients. 12 This
multidisciplinary team should include occupational therapists,
rehabilitation medicine specialists, physiotherapists
and mental health care practitioners.
General management principles include the following: 5
• Fatigue is considered the most difficult symptom to manage.
––
Careful pacing and goal setting approaches have proven
useful in other similar conditions.
––
Beginning with low intensity exercises and gradual
step wise increase specifically tailored to individual
patients will most likely result in optimal outcomes.
• Pain, aches and fevers should be treated with simple analgesia
and anti-inflammatories as required.
• Anosmia is particularly concerning to patients and requires
reassurance that this will return with time.
––
Additional measures in those who fail to improve may
involve olfactory training in an effort to enhance recovery.
• Chronic cough or shortness of breath may benefit from
breathing control exercises and respiratory physiotherapy.
––
Although in cases where the symptoms are debilitating
with poor return to previous function, referral to
specialist level would be recommended
• Athletes and patients in physically demanding occupations
who have been formally diagnosed with
COVID-myocarditis should avoid significant cardiovascular
strain and/or exercise for a reasonable amount of rest
and have a repeated echocardiogram and ECG assessed
by a specialist cardiologist before return to previous levels
of activity.
In addition to the general physical limitations that occur as a
result of PASC, the psychological aspect of the disease process
should not be overlooked.
• Patients showing signs of post-traumatic stress disorders
(typically occurring in those who developed severe disease
requiring ICU) and depression should be appropriately
referred to psychologists and/or psychiatrists.
• The impact of the ongoing fatigue may result in loss of
income in some patients and referral to social workers
and social relief funds are recommended.
• The formation of support groups in settings where the
aforementioned resources are not available may prove
vital in ensuring the mental wellbeing of those affected
as well as reduce the stigma which may arise as a result
of the current lack of understanding within communities.
Improved mineral and vitamin intake in theory may provide
clinical benefit but there is insufficient evidence to definitively
say the use supplements to reduce the risk of acute
SARS-CoV-2 infection or improve PASC symptoms. 1
A recent article in the JAMA has found that the use of high
dose zinc and vitamin C either separately or in combination
did not significantly decrease the duration of symptoms in
acute COVID-19. 13
When to consider COVID-related disease and
what else to look out for
Any patients who were formally diagnosed with COVID-19 by
means of a positive SARS-CoV-2 PCR or/and antigen test with
persistent symptoms beyond 4 weeks of acute illness, should
be considered a PASC diagnosis.
In addition patients who present with COVID-like illness but
without a confirmed SARS-CoV-2 PCR or antigen test can still
be considered under the same umbrella, provided any other
potential causes have been excluded. However, it is vital to
ensure that situational bias in the mists of global pandemic
does not result in underdiagnosis and/or misdiagnosis.
Although it is important to not ignore the significance of
PASC and how it may have serious implications for both patients
and the health care system, the incidence is currently
8
Vol 3 No 2 - 2021

still predicted to around ±10% of those who were confirmed
to have had COVID-19.
All health care workers need to ensure that they continue to
take a full clinical history, perform an accurate physical examination
and order appropriate investigations as necessary
before settling on any specific diagnosis – there is significant
overlap of symptoms between COVID and other communicable
and non-communicable diseases.
Patients with chronic/newly diagnosed medical conditions
should be optimised in order to limit their contribution to
ongoing symptoms that may be considered under the diagnosis
of PASC.
• All health care workers and health care systems have a
responsibility to ensure that patients taking chronic medication
have access to their medications even during periods
of lockdown and quarantine.
• Distribution of chronic medications in a more decentralised
programme to ensure and improve access while
limiting travel to health care facilities during this time
needs to be investigated further.
• Post viral fatigue is a poorly understood but a viable alternative
to PASC in patients who become infected with
Influenza or other non-SARS-CoV-2 coronaviruses.
• Patients who present with symptoms in keeping with
COVID-19 but have also travelled into an area where
malaria is potentially endemic should be investigated for
both COVID-19 AND malaria.
––
Malaria can certainly present with a headache, fever,
coughing and fatigue – remarkable considering it has
a completely different pathophysiology compared to
typically respiratory pathologies – and early diagnosis
and treatment are absolutely essential to avoid fatal
outcomes.
––
History of travel into malaria endemic areas is an
immediate risk factor but patients who live outside
of these areas and have not travelled should not be
ruled out purely based on clinical history without at
least a rapid malaria test within the African context.
• Within the South African context, the HIV status of any
patient who presents to a health care facility has to be
established at initial point of care. Thousands of dollars
have been spent to help identify patients with HIV and
start them on treatment as soon as possible; however we
are still seeing new infections every single day.
––
The pathophysiology of HIV significantly impairs the
body’s ability to fight infection and undiagnosed, immunocomprised
patients are particularly susceptible
to a host of infectious, of which respiratory infections
tend to play a significant role in their initial presentation.
––
Pneumocystis jiroveci (PJP) pneumonia is the most
common opportunistic infection in patients with HIV,
typically presenting with shortness of breath, fever,
dry/non-productive cough as well has a hypoxaemia
and the diagnosis is further supported by radiological
findings of a ground glass appearance. 14
––
All of these symptoms are in keeping with the clinical
findings one may expect for someone with acute
COVID-19 but an incorrect diagnosis as a result of
situational bias may prove fatal for a condition with
known treatments.
• Similarly patients who develop tuberculosis also may be
misdiagnosed as COVID-19 due to overlapping presenting
symptoms of cough, fever and fatigue. 15
• It is important to note that although these infections typical
presented as opportunistic infections in patients with
underlying HIV, they can and do occur in those who are
HIV negative due to other underlying immune-suppressive
states.
In patients where symptoms persistent or have worsening
symptoms, escalation of care to specialist level should be
considered, particularly in patients who continue to exhibit
significant cardiovascular, pulmonary and neurological system
involvement.
• Patients who have been diagnosed with COVID-19 are at
risk for the development chronic myocarditis, thromboembolic
disease and cerebrovascular disease; however,
more clinical research is necessary before definitive predictive
factors can be identified.
• Patients who present with typically unusual symptoms
for PASC such as weight loss or a previous medical history
or family history suggestive of cancer must be investigated
for neoplastic disease processes.
• It is imperative that all patients be thoroughly investigated
by means of a good clinical history, physical examination
and appropriate laboratory tests before a final diagnosis
of PASC is made.
Take Home Message
• PASC is an evolving condition of considerable concern
that requires significant investment into further clinical
research to better understand the epidemiology, pathophysiology,
disease course, outcomes and potential
means of management.
• Although we are still managing our way through a global
pandemic, we need to remember that COVID is not the
only problem patients may present with.
• Common, endemic communicable and non-communicable
diseases should remain high on the list of differential
diagnoses with PASC primarily a diagnosis of exclusion.
• General considerations to consider include the optimisation
of underlying comorbidities (chronic or newly diagnosed)
including HIV, tuberculosis, anaemia, diabetes
mellitus and mental health issues in order to limit their
contribution to ongoing symptoms.
References
1. National Institute for Health and Care Excellence (NICE). National
Institute for Health and Care Excellence (NICE). [Online].: National
Institute for Health and Care Excellence (NICE); 2020 [cited 2021
January. Available from: https://www.nice.org.uk/guidance/ng188/
chapter/Common-symptoms-of-ongoing-symptomatic-COVID-19-andpost-COVID-19-syndrome.
2. Mahase E. Long covid could be four different syndromes, review suggests.
BMJ. 2020; 370.
3. Wade D. Rehabilitation after COVID-19: an evidence-based approach.
Clinical Medicine. 2020; 20(4).
References 4-15 available on request.
9 Vol 3 No 2 - 2021

Managing schizophrenia with long-acting Injectables (LAIs) with
emphasis on the second-generation antipsychotics (SGAs)
Dr Frans Korb
Psychiatrist and Clinical Psychologist
Blairgowrie, Johannesburg, South Africa
chizophrenia is essentially a life-long disease that
usually starts in young adulthood with a prodrome in
adolescence and a lifetime prevalence ranging
between 1 to 1.5 %. The disease comprises a group of
disorders with heterogeneous aetiology and a strong
biological basis. Both the DSM-5 and ICD-10 classification
systems provide criteria for diagnosis which is usually
characterised by debilitating psychotic symptoms affecting
daily functioning in all aspects of life. Typically, ‘positive’
symptoms include fixed, false beliefs (delusions) and
perceptions without cause (hallucinations). The ‘negative’
symptoms are more difficult to treat and are issues like
apathy, lack of drive, disorganised behaviour and thought.
Catatonic symptoms such as mannerisms and bizarre
posturing might also be present.
Schizophrenia is a chronic disease that runs a course of psychotic
episodes with relapses and periods of reasonable
functioning in-between. Each relapse of the psychosis is
usually followed by a further deterioration in the patients’
baseline functioning. Relapses most often require hospitalisation.
Antipsychotics remain the mainstay of treatment for
schizophrenia.
Classification of antipsychotics
All currently available antipsychotics have in common blocking
dopamine in the brain to a greater or lesser extent. Traditionally
they can be classified according to their biochemical
structure and their antipsychotic effect (high-potency versus
low-potency drugs). In later years, the antipsychotic group of
drugs have been divided into the typical, or first-generation
antipsychotics (FGAs) and atypical, or second-generation
antipsychotics (SGAs) groups primarily referring to their potential
of producing movement disorders. The mode of administration
(tablet vs oral dispersible vs immediate release
vs long-acting injectable) has also been important areas of
development and research.
Management of schizophrenia
The APA Practice Guideline for the Treatment of Schizophrenia
1 proposes three phases of management. In the Acute
Phase issues such as: Prevent harm to self and others, control
of disturbed behaviour, reduce severity of psychosis, address
precipitating factors, effect rapid return to best level of functioning,
develop alliance with patient and family, and formulate
a treatment plan and facilitate aftercare are implemented.
The goals of the second Stabilisation Phase are aspects including:
Reduce stress on the patient, minimise likelihood of
relapse, enhance adaptation to life in community, facilitate
continued symptom reduction and consolidation of remission,
and promote recovery. Thirdly the Stable Phase has as
its goal to sustain symptom remission or control, ensure the
patient is maintaining or improving level of functioning and
quality of life, treat exacerbation of symptoms or relapses
and monitor for adverse treatment effects. 1
In the Acute Phase oral SGAs antipsychotics are usually the
treatment of choice because of their generally lower risk
of extrapyramidal side effects as compared with the FGAs.
Traditionally the long-acting injectable antipsychotics (LAIs)
was regarded as the most suitable choice in the Stable/
Maintenance Phase of treatment. When planning long-term
management, a balance between efficacy, side-effects and
adherence for the individual should be considered. 2
Newer data and guidelines regard LAIs antipsychotic agents
and in particular the SGAs to be an important consideration
for treatment in all three phases of schizophrenia management.
LAIs should not only be reserved for individuals with
multiple episodes of schizophrenia but should include first-episode
psychosis and treatment-refractory schizophrenia. 1,2,3
Adherence and rehospitalisation
It is well documented that schizophrenia is a chronic illness
with a high risk of relapse that is frequently associated with
treatment discontinuation. Adherence to anti-psychotic
medication is most often a big challenge in the management
of schizophrenia. The Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) study was initiated by the NIMH.
A total of 1493 patients with schizophrenia were recruited
at 57 U.S. sites. The results indicated that, overall, 74% of
patients receiving oral antipsychotics discontinued the study
medication before 18 months. Inefficacy or intolerable side
effects were cited as the most common reasons. 4
Several studies mainly from medical insurance companies examined
the ‘revolving door’ phenomenon amongst patients
with serious mental illness including schizophrenia. They
found that non-adherence with medication was one of the
most important factors related to frequency of hospitalisation.
5 The use of LAIs is particularly relevant for those people
whose adherence to oral treatment is poor. Improvement in
adherence can reduce relapse rates and rehospitalisation.
The use of LAIs is a convenient option for patients to overcome
the need of taking medications every day to maintain
remission. 2
10
Vol 3 No 2 - 2021

Improved adherence is one of the major advantages of LAIs.
Improved adherence in turn will result in the potential of a
decreased risk of mortality, reduced risk of hospitalisation,
and decreased rates of treatment discontinuation, including
discontinuation due to inefficacy. 1 An update on antipsychotic
treatment again indicated that LAI antipsychotics enhance patient
compliance to continued treatment and reduce the risk
of rehospitalisation by 20–30% compared with oral agents. 6,7
The challenge for treating physicians is thus to identify patients
with low awareness of their disease and prescribe treatment
that is easy to adhere to. This could improve and control
their symptomatology and decrease recurrence of psychotic
episodes and improve the overall quality of their life.
Other benefits LAIs
The American Psychiatric Association Practice Guideline for
the Treatment of Patients with Schizophrenia (currently under
review and update) provides a summary of the LAIs. 1 Table
1 provides an overview of available long-acting injectable
antipsychotic agents. 2 Leslie Citrome after a review of the
evidence base, offers guidance on the appropriate selection
among the long-acting injectable formulations of both first
and second-generation antipsychotics. 8
The management of schizophrenic patients with LAIs ensure
that patients will receive their medication continuously and
eliminate the possibility of missing doses. Healthcare workers
would immediately be aware of a failed visit or missed
injection and then arrange the necessary follow-up. Patients
have reported a subjective sense of better symptom control
and a greater convenience because of the need to take fewer
medications daily. This further resulted in reduced conflict
with family and care workers because of less medication-related
reminders. On the negative side some patients
objected to the discomfort associated with receiving regular
injections (both frequency of administration and injection
volume). 1 Furthermore, LAIs can reduce the risk of accidental
or deliberate overdose in high-risk individuals. 2
Further barriers in the use of LAIs include clinician lack of
knowledge, negative attitude about LAIs, stigma, social support,
patient autonomy, control over medication dosing, fear
of needles, access, resource, and cost issues. 9,10
Due to the different pharmacokinetics of the LAIs patients
will experience medication side-effects for longer periods of
time after discontinuation of the medication. Side-effects of
LAIs are essentially the same as the oral preparations. The
‘silent’ side-effect of metabolic dysregulation with all antipsychotics
should always be kept in mind. 11 In the largest
meta-analysis published to date comparing the efficacy and
tolerability of 32 oral antipsychotics for the acute treatment
of adults with multi-episode schizophrenia it was found in
conclusion that there are some efficacy differences between
antipsychotics, but most of them are gradual rather than discrete.
Differences in side-effects between antipsychotics are
more marked. 12
Table 1. Long-acting injectable antipsychotic agents
Agent
Usual Dose Usual Interval
Range Between Injections
Notes
Typical/First Generation Antipsychotics
Give second dose after 4–10 days then space out to every
Flupenthixol 20–40 mg 2–4 weeks 2–4 weeks. Higher doses (up to 100 mg) have been used for
treatment resistance
Zuclopenthixol 200–400 mg 2–4 weeks
Short-acting form (zuclopenthixol acetate) lasting 2–3 days is
also available as second-line treatment of acute behavioural
disturbance in schizophrenia
Haloperidol* 25–200 mg 4 weeks
Initiate at a lower dose (maximum 100 mg) and adjust the dose
upward as required. There is limited clinical experience with
doses greater than 300 mg per month
Fluphenazine* 12.5–100 mg 2–4 weeks
An oral dose of 20 mg of fluphenazine hydrochloride is equivalent
to fluphenazine decanoate 25 mg (1 ml) every 3 weeks
Atypical/Second Generation Antipsychotics
Risperidone 25–50 mg 2 weeks
Supplement with oral antipsychotic for at least 3 weeks during
initiation
Paliperidone 25–150 mg 4 weeks
Initiation (loading) dose is required. Formulation with a duration
of action of 3 months is available
Olanzapine* 300–400 mg 2–4 weeks
Post-injection delirium/sedation syndrome can occur in about 1%
of recipients, so appropriate monitoring is required
Aripiprazole 300–400 mg 4 weeks Supplement with oral antipsychotic for 2 weeks during initiation
With LAIs it may take 2-4 months to achieve the desired steady-state plasma concentrations.
* Not available in South Africa
Adapted From: Galletly C, Castle D, Dark F, et al Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management
of schizophrenia and related disorders. Australian and New Zealand Journal of Psychiatry 2016, Vol. 50(5) 1-117
11 Vol 3 No 2 - 2021

The introduction of LAIs should always be done in combination
with adequate psychoeducation and shared decision
making. 1
FGA LAIs versus SGA LAIs
The long-acting injectable first-generation antipsychotics
(LAI FGAs) was first developed in the 1960s. More recently
the long-acting injectable second-generation antipsychotics
(LAI SGAs) has been an important advance in the management
of schizophrenia.
In general, it has been reported that patients with schizophrenia
have a 15–20 year shorter life expectancy than the
general population. It has also been suggested that the side
effects of antipsychotic medications be considered as contributing
to this excess mortality. To this effect Heidi Taipale
and co-workers 13 conducted a large nationwide register-based
data analysis to study all-cause mortality among
all patients aged 16–64 years with schizophrenia in Sweden
(N=29,823 schizophrenic patients). Their results indicated
that LAI use is associated with an approximately 30% lower
risk of death compared with oral agents. Furthermore, SGA
LAIs are associated with the lowest mortality.
With the introduction of more SGA LAIs there has been an
increased focus on the potential benefit of these drugs. A
recent published study focussing on antipsychotic adherence,
discontinuation and rehospitalisation in schizophrenia
included a sample of 3,428 patients receiving oral antipsychotics
and 340 patients receiving LAI antipsychotics after
discharge from hospitalisation. Slightly over half (n = 183) of
LAI users used an SGA LAI. Both FGA and SGA LAI users had
lower odds of nonadherence compared with patients receiving
oral antipsychotics. Similarly, compared with those receiving
oral antipsychotics, LAI initiators also had lower odds
of rehospitalisation. However, when examined separately,
only patients receiving SGA LAIs and not FGA LAIs had a statistically
significant reduction in odds of rehospitalisation.
Among individual LAIs, odds of rehospitalisation only among
initiators of paliperidone palmitate were statistically different
from those among users of oral antipsychotics. 14 One
of the main reasons for non-adherence remains emergent
side-effects on medication. In their published review, Park
et al concludes that the second-generation depot drugs are
better tolerated and have fewer adverse neurological side
effects. 15
A small study evaluated the clinical and psychosocial outcomes
among recent and long-term diagnosed schizophrenia
outpatients treated with LAI-SGA during a follow-up period
of 12 months. As with all antipsychotics the positive symptoms
improved. They also found that the greatest improvements
were among those patients who started LAI-SGA within
5 years of diagnosis. These improvements were on the
PANSS negative and depressive factors, as well as in global
functioning, severity, and intensity of suicidal ideation. Their
preliminary findings support the hypothesis that LAI-SGA
may influence the course of the illness if administered at the
early phase of the illness. 16
Prikryl et al argues for the use of SGA LAIs in the management
of first-episode schizophrenia. In general, approximately
80% of patients with the first-episode schizophrenia
reach symptomatic remission after antipsychotic therapy.
However, within two years most of them relapse, mainly due
to low levels of insight into the illness and nonadherence to
their oral medication. Prescribing LAI SGAs can significantly
reduce the risk of relapse and thus improve not only the social
and working potential of patients with schizophrenia but
also their quality of life. 17 This may have a significant influence
in the longer-term course of the illness.
Pharmacoeconomic data comparing SGA LAIs with oral atypical
antipsychotics regarding reducing dosing frequency, delivery/monitoring
by healthcare provider and improved adherence
found a reduction in healthcare resource utilisation.
SGA LAIs, particularly paliperidone-LAI, were associated with
lower medical costs that successfully offset more than one
half of the higher pharmacy costs relative to oral atypical antipsychotics.
18,19
Conclusion
General consensus indicates that the use of LAIs remains
underutilised. A survey amongst 202 psychiatrists in France
confirmed that most psychiatrists used second-generation antipsychotics
(SGAs), and preferentially an oral formulation, in
the treatment of schizophrenia. They summarised their findings
in that personal experience, government regulatory approval,
and guidelines for the treatment of schizophrenia were
the main factors guiding clinicians’ decision-making regarding
the type and formulation of antipsychotic prescribed. 20
Guidelines for the use and management of long-acting injectable
antipsychotics in serious mental illness were published
in BMC Psychiatry. The authors concluded that using
an evidence-based clinical approach, psychiatrists, through
shared decision-making, should be systematically offering
to most patients that require long-term antipsychotic treatment
a LAI antipsychotic as a first-line treatment. 21
Currently available LAI formulations are predominantly once
monthly injectables. The first 3-monthly injection formulation
of paliperidone palmitate has recently been approved. 6
Pharmacokinetic data indicated stable plasma drug concentrations
over a 3-month period enabling only four injections
per year. This new addition in the management of schizophrenia
adds a valuable new treatment option. 19,22
References
1. American Psychiatric Association. Practice Guideline for the Treatment
of Patients with Schizophrenia (Second Edition). Washington, DC:
American Psychiatric Association, 2010 (Updated Draft Version 2019)
2. Galletly C, Castle D, Dark F, et al. Royal Australian and New Zealand
College of Psychiatrists Clinical Practice Guidelines for the Management
of Schizophrenia and Related Disorders. Australian and New
Zealand Journal of Psychiatry. 2016; 50(5): 1-117
3. Kane JM & Garcia-Ribera C. Clinical Guideline Recommendations for
Antipsychotic Long-Acting Injections. British Journal of Psychiatry.
2009; 195: s63–s67. (doi: 10.1192/bjp.195.52.s63)
References 4-23 available on request.
12
Vol 3 No 2 - 2021

The role of NNRTIs in the InSTI era
Dr Bronwyn Bosch MBChB (UCT)
Research Clinician/Safety Physician
Ezintsha, Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand
Johannesburg, South Africa
ow- to middle-income countries (LMICs) such as our
own are home to around 90% of the global HIV burden
of disease. Despite good progress in aims to achieve
the UNAIDS 90-90-90 targets, factors such as pretreatment
drug resistance, poor treatment adherence and
side effects related to currently available antiretroviral
therapy (ART) regimens pose a threat to continued progress
in this regard, 1 not forgetting the extensive service disruptions
owing to the Covid-19 pandemic. In addition, older ART
regimens comprising high pill burdens, significant side effects
and low barriers to resistance have typically been available in
these settings, contributing to less sustainable regimens. 1 In
recent years, integrase-strand inhibitors such as dolutegravir
have been added as a formidable opponent in first-line ART
regimens in South Africa. With increased use and more
clinical trial data becoming available, however, concerns
around associated weight gain and long-term implications
thereof have raised questions around its suitability for all.
Non-nucleoside reverse transcriptase inhibitors
For much of the HIV pandemic, non-nucleoside reverse
transcriptase inhibitors (NNRTIs) have served as the
cornerstone of combination antiretroviral therapy largely
due to their virologic efficacy, with most first-line regimens
containing either efavirenz (EFV), nevirapine (NVP), or
more recently rilpivirine (RPV) along with two nucleoside
/nucleotide reverse transcriptase inhibitors (NRTIs).
Additionally, NVP has and continues to play a crucial role in
preventing mother-to-child HIV transmission 2 – a particularly
key entry point into HIV care for many women in South Africa.
NNRTIs prevent HIV-1 replication through direct binding
to the reverse transcriptase enzyme, thereby inhibiting its
activity and halting transcription of viral single-stranded RNA
into DNA. 18 Whilst highly effective against HIV-1 infection,
NNRTIs do not show activity against HIV-2 infection and
are not recommended in the treatment thereof. Whilst
predominantly found in West Africa, the prevalence of HIV-2
infection in South Africa is poorly known and not routinely
tested for.
Another significant limitation with older NNRTIs including
EFV, NVP and RPV, is the low genetic barrier to resistance,
requiring only a single mutation to impair clinical efficacy. This
in a country with high rates of non-adherence to treatment,
poses a significant threat to available future options for ART.
Coupled with a high level of cross-resistance within the NNRTI
class, resistant mutations often render multiple drugs useless
in both second and third line ART regimens. 4 Additionally,
transmitted NNRTI resistance is emerging as a major
concern in first-line strategies, particularly in LMICs. Pretreatment
drug resistance (PDR), largely driven by the use
of the NNRTIs EFV and NVP, has continued to increase with
the implementation of combined antiretroviral therapy
(cART), resulting in increased treatment switches 5 and
resultant higher treatment costs. The rates of PDR currently
exceed 10% in most LMICs warranting a change in first-line
antiretrovirals to more robust drug classes as per WHO
recommendations. 1 If not enforced, it has been estimated
that PDR will contribute to over 16% of total deaths, 9% of
new infections and 8% of total cART costs by 2030. 1,6
In South Africa, pre-treatment drug resistance is estimated
to be around 14% and largely driven by NNRTI resistance.
The efficacy of second generation NNRTIs rilpivirine (RPV)
and etravirine (ETR), despite higher genetic barriers to
resistance, are often compromised through NNRTI class
cross-resistance. 7 These resistance mutations are retained in
roughly two-thirds of patients, despite second-line therapy,
and have been elicited in genotyping in more than 65% of
people living with HIV (PLWH) failing second-line ART. 8,9 This
in a country where genotyping is reserved for those failing
second-line therapies, hampers early detection of drug
resistance mutations. Preventing and managing emergent
HIV drug resistance is a key component of the HIV response
and is essential in maintaining first-line, cost effective
therapies for as long as possible.
InSTIs
In response to the above, newer agents for first-line ART
regimens are constantly being evaluated. One such addition
is dolutegravir (DTG), an integrase-strand inhibitor (InSTI),
which was added to the South African ART guidelines in 2019
after being proven non-inferior to multiple different agents
in both first- and second-line ART regimens, including the
local ADVANCE clinical trial comparing 2 DTG regimens to
the previous standard of care (EFV/TDF/FTC). Dolutegravir’s
strength lies in its high genetic barrier to resistance, coupled
with rapid viral load suppression, availability in a fixed dose
combination (alongside TDF/3TC) and overall good tolerability,
with resultant seamless integration into public health care
programmes worldwide. It is estimated that since its rollout in
South Africa in 2019, over 1 million PLWH have been switched
to a dolutegravir-based first-line ART regimen.
However, no drug is without risk. Two particular adverse
effects of concern related to dolutegravir use include
associated weight gain and the potential for neural tube
defects (NTDs) with use in early pregnancy. Whilst the most
13 Vol 3 No 2 - 2021

recent data from the Botswana Tsepamo cohort shows no
statistically significant difference in the prevalence of NTDs in
infants born to women on DTG as compared to those on non-
DTG regimens, 10 weight gain remains a significant concern.
InSTI-related weight gain was first reported in mid-2018, and
initially thought to be a drug class side effect. As evidence
emerged, dolutegravir appeared to cause larger amounts of
weight gain as compared to its class counterparts. From the
available data, women (particularly those of African descent)
are at increased risk, as are those with lower CD4 counts
and higher viral loads at ART initiation. 11 The mechanisms
responsible for such weight gain are still poorly understood,
making it difficult to profile those at greatest risk thereof,
with no clear management strategies identifiable. This in a
country with high levels of obesity raises concerns around
the long-term metabolic implications of its use, reminding
us that more options to suit particular patient profiles are
required. Doravirine is one such option.
Newer therapies
Doravirine, a novel, potent NNRTI is currently recommended
for use in high-income countries in the hope of restoring
NNRTI use in ART through minimisation of drug toxicity. 12
It is currently indicated for use in treating adult ART-naïve
PLWH, as well offering an option for switch in those stable
on ART with suppressed viral loads. The safety of doravirine
in pregnant or lactating women and children under the age
of 18 years old has not yet been established, nor has its use
in treatment-experienced patients or those with a history of
virologic failure.
Whilst inhibiting HIV-1 replication in a manner similar to its
class counterparts, doravirine’s strength lies in exhibited
efficacy against prevalent NNRTI-associated and transmitted
drug-resistant mutants. 13,14 Two pivotal clinical trials, DRIVE-
AHEAD and DRIVE-FORWARD, have shown doravirine to
be non-inferior to both efavirenz- and ritonavir-boosted
darunavir-based regimens respectively. 15,16 Additionally,
DRIVE-AHEAD findings showed similar viral suppression rates
in participants starting at both high (>100 000 copies/mL) and
low baseline viral loads, eliminating viral load restrictions such
as those seen with the use of rilpivirine. 15,17 As noted above,
resistance to NNRTIs poses a huge threat to the efficacy of the
drug class as a whole, allowing a potential role for doravirine
in combating this in a cost effective manner.
Doravirine appears to be well tolerated, with neurological and
psychiatric side effects similar to those seen with efavirenz
but occurring much less commonly, and no life-threatening
side effects requiring discontinuation yet noted. 17 Dosing is
daily and can be taken without regard to food, allowing for
ART continuation despite food insecurities. As such, weight
gain has not yet been highlighted as an associated concern,
and improvements in LDL-cholesterol profiles as compared
to EFV have been noted. 17
Whilst low potential for drug-drug interactions has been
recorded, doravirine’s use with rifampicin is not recommended
due to significantly reduced plasma concentrations – this
a concern when considering ART programmes in a country
with high co-infection rates of tuberculosis and consideration
of complexities surrounding addition of doravirine to a fixeddose
combination regimen and resultant cost and adherence
implications. 19,20 This said, it does not appear to impair drug
concentrations of implantable contraceptives such as seen
with EFV use, widening options for long acting, reliable
contraceptive choices in women of child bearing potential.
Resistance to doravirine is associated with selection of one or
more resistance mutations, however this has not yet been fully
characterised. Clinical studies thus far show that emergent
resistance to doravirine is often accompanied by resistance
mutations affecting nonnucleoside reverse transcriptase
inhibitors (NNRTIs), and generally resulting in cross-resistance
to efavirenz and rilpivirine. In light of the ever increasing
NNRTI-resistance strains seen worldwide, but particularly in
South Africa, these patterns suggest that doravirine would
not be suitable for second-line therapy, but no studies to date
have evaluated the effects of doravirine resistance on virologic
outcomes of second-line antiretroviral regimens or the effects
of baseline resistance mutations on doravirine efficacy. 18
Conclusion
InSTIs, whilst well tolerated and sturdy additions to ART
programmes owing to their high genetic barrier to resistance,
continue to raise concerns around associated weight gain and
the long-term metabolic consequences thereof. Additionally,
many healthcare practitioners and patients alike are still
hesitant with the use of dolutegravir in women of child
bearing potential, despite the now negligible associated risk
of neural tube defects. Newer NNRTIs such as doravirine
offer hope of an alternative in these instances, particularly
in patients with certain commonly acquired HIV-1 drug
mutations not targeted by rilpivirine or efavirenz and for
those experiencing intolerable side effects on other agents.
With the introduction of newer ARVs such as doravirine, the
number of convenient and efficacious treatment options
available to PLWH are increased, allowing for the tailoring
of regimens to specific patients in hopes of increasing
adherence and sustained regimen durability.
References
1. Ndashimye E, Arts EJ. The urgent need for more potent antiretroviral
therapy in low-income countries to achieve UNAIDS 90-90-90 and
complete eradication of AIDS by 2030. Infect Dis Poverty [Internet]. 2019
Dec 2;8(1):63. Available from: https://idpjournal.biomedcentral.com/
articles/10.1186/s40249-019-0573-1
2. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, et
al. Intrapartum and neonatal single-dose nevirapine compared with
zidovudine for prevention of mother-to-child transmission of HIV-1 in
Kampala, Uganda: HIVNET 012 randomised trial. Lancet [Internet]. 1999
Sep;354(9181):795–802. Available from: https://linkinghub.elsevier.
com/retrieve/pii/S0140673699800087
3. Sluis-Cremer N, Tachedjian G. Mechanisms of inhibition of HIV replication
by non-nucleoside reverse transcriptase inhibitors. Virus Res [Internet].
2008 Jun;134(1–2):147–56. Available from: https://linkinghub.elsevier.
com/retrieve/pii/S0168170208000075
4. Sluis-Cremer N. The Emerging Profile of Cross-Resistance among the
Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors. Viruses [Internet].
2014 Jul 31;6(8):2960–73. Available from: http://www.mdpi.com/1999-
4915/6/8/2960
5. Boender TS, Hoenderboom BM, Sigaloff KCE, Hamers RL, Wellington M,
Shamu T, et al. Pretreatment HIV Drug Resistance Increases Regimen
14
Vol 3 No 2 - 2021

Switches in Sub-Saharan Africa. Clin Infect Dis [Internet]. 2015 Aug
3;civ656. Available from: https://academic.oup.com/cid/article-lookup/
doi/10.1093/cid/civ656
6. Phillips AN, Stover J, Cambiano V, Nakagawa F, Jordan MR, Pillay D, et
al. Impact of HIV Drug Resistance on HIV/AIDS-Associated Mortality, New
Infections, and Antiretroviral Therapy Program Costs in Sub–Saharan
Africa. J Infect Dis [Internet]. 2017 May 1;215(9):1362–5. Available from:
http://academic.oup.com/jid/article/215/9/1362/3002848/Impact-of-
HIV-Drug-Resistance-on-HIVAIDSAssociated
7. Brenner B, Turner D, Oliveira M, Moisi D, Detorio M, Carobene M, et al.
A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers
cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS
[Internet]. 2003 Jan;17(1):F1–5. Available from: http://journals.lww.
com/00002030-200301030-00001
8. Ndashimye E, Avino M, Kyeyune F, Nankya I, Gibson RM, Nabulime
E, et al. Absence of HIV-1 Drug Resistance Mutations Supports the
Use of Dolutegravir in Uganda. AIDS Res Hum Retroviruses [Internet].
2018 May;34(5):404–14. Available from: http://www.liebertpub.com/
doi/10.1089/aid.2017.0205
9. Steegen K, Bronze M, Papathanasopoulos MA, van Zyl G, Goedhals D, Van
Vuuren C, et al. Prevalence of Antiretroviral Drug Resistance in Patients
Who Are Not Responding to Protease Inhibitor–Based Treatment: Results
From the First National Survey in South Africa. J Infect Dis [Internet]. 2016
Dec 15;214(12):1826–30. Available from: https://academic.oup.com/jid/
article-lookup/doi/10.1093/infdis/jiw491
10. Zash, R; Holmes, L; Diseko, M; Jacobson, D; Mayondi G et al. Update on
neural tube defects with antiretroviral exposure in the Tsepamo study,
Botswana. 2020;
11. Venter WDF, Sokhela S, Simmons B, Moorhouse M, Fairlie L, Mashabane
N, et al. Dolutegravir with emtricitabine and tenofovir alafenamide
or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and
tenofovir disoproxil fumarate for initial treatment of HIV-1 infection
(ADVANCE): week 96 results from a randomised, phase 3, n. Lancet HIV.
2020 Oct;7(10):e666–76.
12. Talwani R, Temesgen Z. Doravirine: a new non-nucleoside reverse
transcriptase inhibitor for the treatment of HIV infection. Drugs of
Today [Internet]. 2020;56(2):113. Available from: http://journals.
prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_
JournalId=4&p_RefId=3109966&p_IsPs=N
13. Feng M, Sachs NA, Xu M, Grobler J, Blair W, Hazuda DJ, et al. Doravirine
Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-
Associated Mutants at Clinically Relevant Concentrations. Antimicrob
Agents Chemother [Internet]. 2016 Apr;60(4):2241–7. Available from:
https://aac.asm.org/content/60/4/2241
14. Anderson MS, Gilmartin J, Cilissen C, De Lepeleire I, van Bortel L,
Dockendorf MF, et al. Safety, tolerability and pharmacokinetics of
doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor,
after single and multiple doses in healthy subjects. Antivir Ther [Internet].
2014;20(4):397–405. Available from: http://www.intmedpress.com/
journals/avt/abstract.cfm?id=2920&pid=48
15. Fletcher C V. Overview of antiretroviral agents used to treat HIV [Internet].
UpToDate. 2020 [cited 2021 Feb 19]. Available from: https://www.uptodate.
com/contents/overview-of-antiretroviral-agents-used-to-treat-hiv?se
arch=doravirine&source=search_result&selectedTitle=1~13&usage_
type=default&display_rank=1#H1842892952
References 15-20 available on request.
As a healthcare professional (HCP), you can effortlessly complete all your CPD compliance
requirements on the SAMA accredited, Medical Practice Consulting (MPC) Online Education
System, without having to leave the comfort of your own home or practice.
The MPC System provides a comprehensive CPD compliance solution that offers accredited
CPD events, journals and courses, as well as industry leading CPD management services such
as automatic issuing and secure storage of all your CPD certificates within the MPC CPD
Manager.
What sets the MPC CPD Manager apart is its unique functionality that enables HCPs to electronically
submit your CPD activity records directly to the HPCSA at the click of the button
when audited.
All this functionality is available at no cost on MPC.
Register today on www.mpconsulting.co.za.
Healthcare professionals can acquire CPD points with this newsletter by completing an online
multiple-choice questionnaire on www.mpconsulting.co.za.
All queries should be directed at support@mpconsulting.co.za | 012 111 7001.
15 Vol 3 No 2 - 2021

S4