Latest advancements in TB science in spotlight

Bobby Ramakant *

Important game-changing scientific advancements in preventing and treating TB (TB or tuberculosis, is among the deadliest of infectious diseases globally), were in spotlight at the recently concluded International Conference on Retroviruses and other Opportunistic Infections (CROI 2022).

If we look at the pace at which new better tools to prevent, diagnose, or treat TB have come in the past decades, it is a deeply painful realisation because despite scientific advancements, the pace of TB research and investment that has gone into it, is way off mark.

We still use more than a century old diagnostics, drugs that are too toxic, therapies that are too long and may cause post-treatment disabilities, treatment outcomes that can never be accepted as 'gold standard', and half-heartedly made measly investment promises, continue to hold us back in the fight to #endTB. That is why listening to new TB science updates at CROI 2022 was in particular a ray of hope for me.

Latest TB science updates included those regarding two most historically neglected areas: treatment for drug-susceptible TB (common TB when bacteria is not resistant to medicines) and latent TB (TB prevention). “Advancing TB science is vital because it is TB that is robbing us of gains made in advancing HIV treatment science and rollout. TB is the most common opportunistic infections among people living with HIV and a major cause of untimely deaths among them.

In 2020, there were 214,000 deaths from TB among people living with HIV. Even one TB death is a death too many. When TB is preventable, when TB is curable, then how can even one TB death occur in any sane and just society? We have to walk the talk on oft-chanted #EverylifeMatters,” said Shobha Shukla, founder of CNS (Citizen News Service) who was on the panel “CROI 2022: Global Advocates Offer Insights and Directions on the Science and Next Steps Needed.”

Harry Tembo, Zambia Community Advisory Platform, Zambia; Katie Willingham, The Well Project, United States; Richard Jefferys, Treatment Action Group, United States; Shobha Shukla, CNS, India; and Simon Collins, i-Base and EATG, United Kingdom were among the panelists and session was moderated by HIV prevention research stalwart-advocate Jim Pickett.

Latest advancements in drug-susceptible TB

Study 31/A5349 found that a new treatment regimen (combination of medicines) for treating drug-susceptible TB of the lungs in adults and adolescents, can effectively and safely cure TB in 4 months, instead of 6 months (when treated with current standard regimens). This new regimen used in the study had a combination of 4 medicines: Isoniazid, Rifapentine, Moxifloxacin, and Pyrazinamide.

The study concluded that this new regimen of 4 months was non-inferior to the current standard regimen of 6 months. In fact the overall efficacy results for HIV positive sub-group were higher at 85% as compared to 78% cure rate for participants who were living with HIV in the standard of care regimen group. This regimen is the first successful short-course treatment regimen for drug-susceptible TB disease in almost 40 years. WHO has endorsed this regimen for use [CDC guidance is forthcoming], said Shobha Shukla.

New research for treating TB in children

Another study called SHINE which was done in Africa and India, compared outcomes using a treatment regimen for 4 and 6 months respectively to treat smear-negative and non-severe forms of TB of the lungs in children (HIV positive and negative both included). Isoniazid, Rifampicin, Ethambutol and Pyrazinamide were the medicines used in the regimen. Study concluded that the 4-months duration therapy was non-inferior to standard 6-months duration therapy. Only 3% unfavourable outcomes and few toxicity related side-effects were reported in both groups (4 and 6 months duration treatment groups).

New research for better MDR-TB preventive treatments

Many ongoing studies are evaluating 6-months multi drug-resistant TB (MDR-TB) preventive therapies for close contacts of MDR-TB patients. TB CHAMP study is examining Levofloxacin medicine to be used as part of MDR-TB preventive therapy in children below 5 years of age, who are close contacts of adult MDR-TB patients.

PHOENix (Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients) study is comparing Delamanid with Isoniazid for preventing MDR-TB in children, adolescents and adults who are close contacts of 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.

Research ongoing for long-acting injectables for treating TB

Long-acting injectable possible formulations of TB drugs could have several potential benefits, like improved adherence, greater acceptability, and better integration of TB preventive therapy into other treatment programmes, like those for HIV, maternal and child health, said Shobha Shukla.

CROI also shared information on new TB drugs, including long acting injectables, that are in various stages of development: TBAJ-876, a next generation diarylquinoline, is in phase-1 of multiple ascending dose (MAD) study. It has shown improved safety, pharmacokinetics and superior potency. Sutezolid and Delpazolid are new oxazolidinones in phase 2b/2c studies.

DprE1 inhibitors (a novel class of anti-TB agents) are also being developed. OPC-167832, in combination with Bedaquiline and Delamanid, is being evaluated for 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 for shorter treatment regimen.

Existing TB drug Bedaquiline could be a potential suitable candidate for long acting injectable. One single dose of long acting formulation of Bedaquiline was found to maintain drug and metabolite concentration for up to 3 months in mice. Modelling results expect that this would also be observed in the clinic. New diarylquinolines (like TBAJ-876) may be good candidates for long-acting TB preventive therapy.

Treatment of MDR-TB

Until recently, the standard of care MDR-TB treatment regimen was 18-24 months long and gave a cure of around 50% with highly toxic drugs and painful daily injections given for a minimum of the first 6-months of treatment.

TB PRACTECAL study led by MSF is evaluating a 6 months all oral regimens containing Bedaquiline and Pretomanid in combination with Linezolid, Moxifloxacin and Clofazimine. The study design has 4 groups: one group gets the WHO standard of care regimen; second group gets a regimen of Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin; third group gets a regimen of Bedaquiline, Pretomanid, Linezolid, and Clofazimine; and fourth group gets a regimen of Bedaquiline, Pretomanid, and Linezolid.

As of now, a regimen of Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin, with a tapered dose of Linezolid, has been found to be non-inferior (safe and efficacious) 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.

Nix-TB and ZeNix studies have already found an all-oral short-course 6-months treatment regimen of Bedaquiline, Pretomanid and Linezolid, for highly drug-resistant TB patients (MDR-TB, XDR-TB, pre-XDR-TB) to be safe and efficacious with a treatment success rate of 90% even in HIV infected MDR-TB patients. In ZeNix study, Linezolid dosage was reduced from 1200 mg to 600 mg to decrease toxicity, and duration was reduced from six months to two months, without affecting treatment success rate.

Preventing TB cannot be on the backseat

"Globally Directly Observed Treatment Shortcourse (DOTS) has been in use since 1980s. In India it was launched in 1997 as part of the Revised National TB Control Programme (RNTCP) which is now known as National TB Elimination Programme or NTEP. This current standard DOTS therapy (6 months long regimen) for TB treatment is a lifesaving therapy for those who do not have drug-resistance and get cured, but we cannot forget that this is not the gold standard by any means - this therapy remains burdensome to patients and their care providers, and toxic for many. We need better, more effective, less toxic, shorter treatment for drug-sensitive TB too," said Shobha Shukla.

She added: "For MDR-TB and extensively drug-resistant TB (XDR-TB) treatments, governments need to implement scientifically proven, shorter, and patient-centric treatment options with reduced number of drugs and minimal side effects."

"Why is there an unacceptably-long delay in rolling out best of science outcomes to those people who are most in need?" asks firebrand feminist and health rights activist Shobha Shukla.

Shobha said that testing and treating active TB disease is not enough if we want to end TB worldwide, unless we diagnose those with latent TB infection (especially those who are at greater risk) and provide them TB preventive treatments so that their risk of getting active TB disease is as low as possible. Not only we have not addressed latent TB infection adequately - historically - but we have even rolled existing programmes unsatisfactorily.

For example, in India use of Isoniazid preventive therapy (IPT) to reduce risk of active TB disease in children and people living with HIV with latent TB was offered even before rollout of lifesaving antiretroviral therapy (ART) began in 2004. But the ground reality of IPT rollout after almost two decades, is simply unacceptable.