(This article is dedicated to all those who lost their lives to the world’s most deadly infectious disease – TB – and to those who defeated it)
Is it not
shocking that an ancient disease that has been with humans since long before
the recorded history, and is preventable and treatable, still kills around 1.5
million people every year? Molecular analysis of causative microbe of
tuberculosis (TB) suggests that the first infections of humans occurred as much
as 70,000 years ago. But the actual cause of TB was known only 140 years ago,
when on March 24, 1882, Dr Robert Koch announced his discovery of Mycobacterium
– the microbe that causes TB. Even today, TB remains the leading infectious
cause of death globally. 1.8 billion people (nearly 25% of the world’s
population), harbour Mycobacterium tuberculosis. Every year nearly 10 million
people contract the disease and around 1.5 million die from it.
Same disease, but many names
In the past,
this debilitating disease has been known by many names- like consumption,
phthisis, white plague, king’s evil, etc, till in 1834, a German physician
Johann Schonlein coined the term ‘tuberculosis’. Many eminent personalities
have succumbed to it- King Edward VI of England, King Louis XIII of France,
poet John Keats, music composer Frédéric Chopin, writers like Emilie Bronte,
Jane Austen, Moliere, Chekhov, Maxim Gorky, Khalil Gibran and George Orwell,
educator Louis Braille, USA’s longest-serving first lady Eleanor Roosevelt,
India’s first female doctor Anandi Gopal Joshi- to name just a few.
Drug
resistance is among the challenges threatening to reverse the gains made in the
fight against TB
In the
decades following Koch’s discovery, the BCG (Bacillus Calmette-Guerin) vaccine,
antibiotic streptomycin, and other anti-TB drugs were developed. While the BCG
vaccine, made 100 years ago in 1921 does protect children from severe forms of
TB, especially TB meningitis, it has little or no effect in preventing TB in
adults. In 1944 streptomycin, the first antibiotic against TB was discovered by
Selman Wakman. It literally brought patients with TB meningitis (for which
there had been no cure at that time) ‘back to life’. But very soon it also led
to the emergence of streptomycin-resistant TB bacilli. In the following years,
many other anti-TB drugs were developed and combinations of antibiotics were
used to treat patients. But resistance to many anti-TB drugs has emerged and
drug-resistant forms of TB are now a major problem globally.
Treatment of drug-sensitive TB
When TB
bacteria responds to the anti-TB medicines and has not developed resistance to
them, then it is referred to as drug-sensitive TB. And when TB bacteria has
developed resistance against anti-TB medicine(s) then the disease is referred
to as drug-resistant TB.
The current
short-course of 6 months drug-sensitive TB treatment consists of Isoniazid (H),
Rifampin (R), Pyrazinamide (Z), and Ethambutol (E), has been in use since the
1980s. We seem to have got stuck for quite a long time with this ‘one size fits
all’ regimen (of 2 months of intensive-phase treatment with HRZE and 4 months
of continuation phase with HR). However, in the last 18 months or so, there has
been a lot of progress for the treatment of drug-sensitive TB, as shared by Dr
Susan Dorman at Conference on Retroviruses and Opportunistic Infections (CROI
2022).
Dr Susan
Dorman is an infectious disease expert at the Medical University of South
Carolina. We now have a 4-months treatment for drug-sensitive TB of the lungs
for adults and adolescents. This is Isoniazid (H), Rifapentine (P),
Moxifloxacin (M), and Pyrazinamide (Z) regimen (2HPZM/ 2HPM).
Dr Dorman
said that we also have a 4-months Isoniazid (H), Rifampicin (R), Ethambutol
(E), and Pyrazinamide (Z) regimen (2HRZE/2HR) for children with non-severe
drug-sensitive TB of the lungs.
“But these
shorter regimens are certainly not the end. We need to shift to a more
individualised approach to TB treatment, optimise existing TB drugs and
repurposed antibiotics, use novel drugs/ regimens and understand how
host-directed therapies can improve TB treatment, and reduce patients’ burden
through better adherence and monitoring strategies,” said Dr Dorman, while
highlighting the recent advancements in these areas.
The
TRUNCATE-TB study aims to examine 4 different optimised regimens for an
ultra-short treatment (2 months duration) of drug-sensitive TB of the lungs.
These 4 regimens are of:
– Isoniazid,
Pyrazinamide, Ethambutol, Linezolid and Rifampin
– Isoniazid,
Pyrazinamide, Ethambutol, Clofazimine and Rifampin
– Isoniazid,
Pyrazinamide, Linezolid, Rifapentine, Levofloxacin; and
– Isoniazid,
Pyrazinamide, Ethambutol, Linezolid, Bedaquiline.
There are
other ongoing studies examining various host-directed therapies that augment
human host immune responses and thereby shorten therapy and reduce risk of
relapse or subsequent lung damage. One such study being done by Aurum Institute
in South Africa is examining the use of immune modulators like CC-11050,
Everolimus, Auranofin, Ergocalciferol along with standard TB treatment to
mitigate destructive inflammatory responses in HIV negative adults with
drug-sensitive TB of the lungs. CC-11050 and Everolimus have been found to
improve lung function outcomes at day-180 relative to the control group.
Treatment of multi-drug resistant TB (MDR-TB)
Dr David
Moore, Professor of infectious diseases at the London School of Hygiene and
Tropical Medicine shared at CROI 2022 the recent advancements made in the
treatment of MDR-TB treatment. Until recently, the standard MDR-TB treatment
that gave a cure of 50%, was a minimum of 18-months duration with highly toxic
drugs and painful daily injections given for a minimum of the first 6-months of
treatment.
Now we have
an all-oral short-course 6-months treatment regimen for MDR-TB. This regimen is
of Bedaquiline, Pretomanid and Linezolid (BPaL). Nix-TB and ZeNix studies by TB
Alliance have assessed the safety and efficacy of the BPaL regimen in
participants with pulmonary extensively drug-resistant TB (XDR-TB) or treatment
intolerant/non-responsive MDR-TB, and shown favourable treatment outcomes in
90% of the patients, paving the way for shorter and more efficacious treatment
regimens for MDR/ XDR-TB.
TB PRACTECAL
study led by MSF is evaluating 6-months treatment regimens containing
Bedaquiline (B) and Pretomanid (Pa) in combination with existing and
re-purposed anti-TB drugs – Linezolid (L), Moxifloxacin (M) and Clofazimine
(C).
The study design has 4 arms:
– the
control arm is the WHO standard of care regimen;
– BPaLM arm;
– BPaLC arm;
and
– BPaL arm.
As of now,
BPaLM regimen has been found to be non-inferior to the standard of care (9-24
months) treatment of rifampicin-resistant TB of the lungs. Outcomes of other
regimens are expected to be reported soon, shared Dr Moore who is also a member
of the TB PRACTECAL Trial Steering Committee.
TB Preventive Treatment (TPT) for MDR-TB
A person
with latent TB (or latent drug-resistant TB) infection does not have symptoms
and cannot spread TB bacteria to others. But in some of them, the latent TB
infection will progress to active TB disease in their life. All cases of active
TB come from this pool of people with latent TB infection. That is why it is
important to correctly diagnose those with latent TB infection and provide TB
preventive treatment to them so that their risk of progressing to active TB
disease is decimated.
Many ongoing
studies are evaluating 6-months MDR-TB preventive therapies for close contacts
of MDR-TB patients:
TB CHAMP
study is examining Levofloxacin as MDR-TB preventive therapy in children under
the age of 5 years who are close contacts of adults diagnosed with MDR-TB.
PHOENix
(Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant
Tuberculosis Patients) is a multi-country study comparing Delamanid with
Isoniazid for preventing MDR-TB in children, adolescents and adults who are
close contacts with persons with MDR-TB.
V-QUIN study
in Vietnam is examining the efficacy of Levofloxacin for treating latent MDR-TB
in all household contacts of patients with bacteriologically-confirmed
Rifampicin-resistant TB.
New drugs,
including long-acting injectables:
At CROI
2022, Dr Eric Nuermberger of Johns Hopkins University School of Medicine shared
that there are 15 new anti-TB drugs in different stages of development, 9 of
which target 6 novel mechanisms of action, and 6 are the next generation drugs,
most of which target a pathway that has already been validated by other
effective TB drugs.
TBAJ-876, a
next-generation diarylquinoline, which is in phase-1 of multiple ascending dose
(MAD) study has shown improved safety, improved pharmacokinetics and superior
potency. Sutezolid and Delpazolid are new oxazolidinones in phase 2b/2c
studies.
DprE1
inhibitors that represent a novel class of anti-TB agents are also being
developed. OPC-167832, in combination with Bedaquiline and Delamanid, is being
evaluated for the safety and efficacy of a 4-months regimen for drug-sensitive
TB. GSK3036656, a novel translational inhibitor, has been found to be safe and
well-tolerated after single and multiple doses in its First-Time-in-Human
Study. It is a promising anti-TB agent for further clinical development with a
novel mechanism of action and with a shorter duration of treatment.
Long-acting
injectable formulations of TB drugs have several potential benefits for TB
therapy by way of improved adherence, greater acceptability, and better
integration of TB preventive therapy into other treatment programmes, like
those for HIV, maternal and child health. There are existing TB drugs that
could be potentially suitable candidates for long-acting injectable
formulations, said Dr Nuermberger.
One single
dose of a long-acting formulation of Bedaquiline was found to maintain drug and
metabolite concentration for up to 3 months in mice. Early modelling results
support the idea that this would also be observed in the clinic. New
diarylquinolines (like TBAJ-876) may be good candidates for long-acting based
TB preventive therapy. In fact, the University of Liverpool University’s
LONGEVITY project is developing long-acting injectable formulations of existing
oral drugs for TB prevention.
Indeed, as
the theme of World TB Day 2022 says, we must ’Invest to End TB. Save Lives’ and
ensure equitable access to TB prevention and care in line with achieving
Universal Health Coverage.
Shobha
Shukla
(Shobha
Shukla is the award-winning founding Managing Editor and Executive Director of
CNS (Citizen News Service) and is a feminist, health and development justice
advocate. She is a former senior Physics faculty of the prestigious Loreto
Convent College and current Coordinator of the Asia Pacific Regional Media
Alliance for Health and Development (APCAT Media).
