INNOVATING MDR-TB TREATMENT IN HIV-POSITIVE PATIENTS

 HIV-positive patients undergoing MDR-TB oral Six Month treatment

Global efforts to control tuberculosis are seriously threatened by multidrug-resistant tuberculosis (MDR-TB) in people who are HIV positive. Numerous research had mixed results regarding the link between HIV infection and MDR-TB.

World Health Organization recently recommended a new standard of care treatment regimen which states that an all-oral treatment regimen for multidrug-resistant tuberculosis (MDR-TB) is efficient and secure in people living with HIV.

HIV-Positive & MDR-TB 

 Dr. Ilaria Motta of Médecins sans Frontières reported at the 24th International AIDS Conference (AIDS 2022) in Montreal on Sunday that an all-oral treatment regimen for multidrug-resistant tuberculosis (MDR-TB) is efficient and secure in people living with HIV. This regimen was recently recommended as a new standard of care by the World Health Organization.

However, conference attendees who are involved in the 1 / 4 / 6 x 24 campaign to encourage public health programmes to invest in enough "staff, stuff, space, systems, and support" to make new shorter regimens for TB treatment accessible to everyone by 2024 claim that many people in the worst-affected countries still lack access to all-oral treatment.

HIV-Positive

MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB)

MDR-TB necessitates a lengthier course of therapy than drug-sensitive TB, particularly in cases when the patient has TB that is resistant to multiple antibiotic classes. In order to achieve a cure for MDR-TB, treatment using previous regimens may continue up to two years and needed the use of medications with severe toxicities as well as injectable treatments. Due to the length and toxicity of treatment, a high failure rate has been shown when patients are unable to endure or adhere to it, frequently resulting in the emergence of extensively drug-resistant (XDR) TB.

MDR-TB

There have been significant attempts over the past 10 years to find treatment plans for MDR-TB and XDR-TB that don't require injectable medications, are less expensive, and limit exposure to harmful pharmaceuticals. 

"TB PRACTECAL" ( NEW WHO COMPARISON STUDY DESIGN)

The World Health Organization standard of care, which consists of a 9–24-month course of treatment combining oral and injectable treatments depending on local guidelines, was given to the control group in the large, randomized comparison study known as TB PRACTECAL. This study compared three 6-month all-oral regimens for the treatment of MDR-TB.

Bedaquiline, pretomanid, and linezolid made up the main components of the experimental treatment in TB PRACTECAL (BPaL). After 16 weeks of treatment, the linezolid dose was decreased from 600 mg to 300 mg in order to lessen toxicity. Bedaquiline, pretomanid, and linezolid were given to one research arm, while moxifloxacin 400 mg or clofazimine 100 mg were given to the other experimental arms along with BPaL.

TB  PRACTECAL

To prevent drug interactions, antiretroviral therapy was altered for participants who were HIV-positive, and they often received integrase inhibitor-based therapy. South Africa, Uzbekistan, and Belarus all hosted the trial.

The ZeNIX trial reported at IAS 2021 that the three-drug BPaL regimen was very effective in treating XDR-TB and MDR-TB in extremely drug-resistant patients. It demonstrated that reducing the amount of time a patient was exposed to linezolid without reducing its effectiveness.

The BPaL plus moxifloxacin treatment had the lowest rate of unfavourable outcomes and the largest positive difference in outcome between an experimental treatment and the standard of care, according to the main findings of TB PRACTECAL, which were presented at the Union World Conference on Lung Health in 2021 and Conference on Retroviruses and Opportunistic Infections in March of this year.

BPaL

The World Health Organization announced recommendations in May stating that the optimal standard of care for treating MDR-TB or rifampicin-resistant TB is the use of BPaL plus moxifloxacin or BPaL.

Ilaria Motta gave a presentation at AIDS 2022 on the treatment outcomes for 153 trial participants (27% of the total study participants), the majority of whom were from South Africa.

Between research arms, the prevalence of HIV was divided equally. Roughly 40% of participants were female, the median CD4 count was around 300, and almost two thirds had smear-positive TB at baseline. Just under 20% of all individuals and almost 10% of HIV-positive participants had fluoroquinolone resistance, a sign of a case that is very difficult to treat with normal medication.

The percentage of individuals in each study arm who had unfavourable results at week 72 following randomization and the percentage who had a significant adverse event or grade 3 adverse event at week 72 were the study's primary outcomes. The following outcomes were considered unfavourable: loss to follow-up, treatment failure, recurrence of MDR-TB, and death.

The BPaL/moxifloxacin arm saw the lowest rate of unfavourable results, with a risk difference of 11.4% between 28% in the experimental arm and 40% in the standard of care arm. In HIV-negative patients, the experimental arm had a 6% unfavourable result while the standard of care arm had a 51% unfavourable outcome. Despite the fact that the percentage of risk difference between HIV-positive and HIV-negative participants was statistically insignificant (p=0.08) due to the small sample size, the study's authors caution that it is difficult to draw a conclusion that the regimen is less effective in HIV-positive individuals.

The risk differences between participants who were HIV-positive and those who were HIV-negative in the other investigational study arms were also not statistically significant, although the researchers again warn that the sample size is too small to draw any firm conclusions.

Compared to BPaL or BPaL/moxifloxacin, the experimental regimen incorporating clofazimine was less well tolerated; 29% of HIV-negative individuals and 40% of HIV-positive individuals reported experiencing a major adverse event of grade 3 or higher. Both HIV-negative and HIV-positive patients experienced Grade 3 or higher, or major adverse events, less frequently in the BPaL/moxifloxacin arm, at 20% and 17%, respectively.

In any trial arm, there was no discernible difference in the incidence of adverse events between participants who were HIV-positive and those who were HIV-negative. The three significant adverse events (grade 3 or higher) that were most frequently reported were neutropenia, anaemia, and hepatic dysfunction.

Campaign 1 / 4 / 6 x 24

Infection with TB can now be treated in as little as one or three months, and the majority of forms of drug-sensitive and drug-resistant TB can be treated in four and six months, respectively (hence the campaign's name, "1 / 4 / 6"). However, very few people have access to these more efficient, shorter regimens.

The 1 / 4 / 6 x 24 campaign was introduced by Treatment Action Group, Partners in Health, and Doctors Without Borders during AIDS 2022. The campaign is requesting:

·      Swift revisions to national and international standards to suggest shorter regimens

·      Creation of shorter treatment regimens in fixed-dose combinations to aid implementation and adherence

·      Creation of novel diagnostics to aid in the detection of TB and MDR-TB

·      Using patent pooling, technology transfer, and licencing, new products and diagnostics can be quickly registered for use in short-course treatments, and access to novel medications and diagnostics is improved.

·      Investment in TB programmes and diagnostics grew as a result of quick research to fill knowledge gaps in the usage and implementation of shorter-course regimens.