Resisting drug resistance for a #TBFreeTomorrow

Picture this: You have been experiencing symptoms like cough and fever so you had yourself tested for COVID-19, but the results came out negative. Relieved, you decide to wait for the symptoms to get resolved on their own. Weeks passed but your symptoms remain. You try to go see a doctor again but the hospitals accessible to you are full and you don’t know where else to go. So you went home to wait and just hope for things to get better–they didn’t. 

Your symptoms worsened and now you have to be hospitalized. The results of your test bring more bad news–you tested positive for Tuberculosis (TB). You start agonizing over the implications of this diagnosis to your life and that of your family members. 

Up until your hospitalization, you were living in the same house with your family members and TB is a highly communicable disease. This means that their long period of close contact with you has also put them at a high risk for contracting TB. Aside from the obvious health threat, your entire household is also potentially facing the threat of loss of income if the working members also tested positive. 

The other scenario is that you received the diagnosis and confirmation that you have TB. You started the treatment but for various reasons you couldn’t continue with the prescribed 6-8 months treatment regimen. Your symptoms have significantly improved at that point, so you tried to go on with your life sans completed treatment. Eventually your symptoms are back and you’re forced to go back to the doctor. This confirms your fear–your TB is back and even worse, it’s now drug-resistant. 

These two imagined scenarios are not that far off from the current reality of many Filipinos.  

The disruption in the essential TB services such as consultation, testing, and treatment due to limited mobility and other pandemic restrictions have resulted in the drastic drop in the number of TB cases notified in the country. 

Making sense of the gap 

Almost three years since the first case of COVID-19 was confirmed, we’ve seen leaps of progress and advancements in the dialogues and global actions surrounding COVID-19 but the opposite can be said about other infectious diseases– TB case in point. 

TB, caused by the bacteria Mycobacterium tuberculosis, is a communicable disease that is the leading cause of death from a single infectious agent next only to COVID-19 and the number one cause of death for people with HIV. In 2020 alone, the World Health Organization (WHO) reported that 1.5 million people died from TB, and 214,000 of which are people with HIV. 

The pandemic has severely impacted the essential TB-related services and vital resources were diverted away from TB which resulted in infections going undetected, untreated, and unmanaged.

Recent data on relevant health indicators and TB statistics show massive reversal of significant milestones and progress in the TB elimination efforts, particularly in the Philippines which has the highest TB incidence in Asia.

If we are to mitigate and reverse these impacts, restoring access and provision of essential TB-related services must be given immediate priority. The National TB Control Program, under the Department of Health (DOH), is committed to achieving a TB-Free Philippines by the end of 2035. 

Case notification or the process of reporting diagnosed TB cases is an essential activity of the program in finding and treating identified TB patients and helping prevent the further spread of TB.

The Philippines’ TB incidence is estimated to be at 539 cases per 100,000 FIlipinos according to the WHO Global TB Report in 2021 and the target is to bring this down to 55 cases per 100,000 by 2035. Approximately 268,816 TB cases were notified to DOH by the end of 2020, a 35% decrease from the 2019 data. 

Estimated incidence is the computed estimated number of new and relapse TB patients in a year. TB notification is the reported number of patients that are diagnosed and reported. The gap between these two numbers are the missing TB cases,” explains Dr. Ramon Basilio, Head of the National Tuberculosis Reference Laboratory (NTRL), elaborating on the significance of these health indicators.   

Considering that the Philippine Statistics Authority’s tally of the country’s total population as of May 2020 is over 109 million, a large chunk of the TB cases in the Philippines are currently unaccounted for.

“We must find all the missing TB cases, in order to decrease TB incidence. Some of the missing TB cases are unreported to DOH. But worse are the undiagnosed and untreated who may unknowingly spread TB or succumb to the disease,” says Dr. Basilio.   

Under different circumstances, the decrease in the number of notified cases would mean less people are being infected with TB. But with the current situation, the implication of the decrease in TB notification while the estimated TB incidence has increased is that people are presumably going around undiagnosed and unknowingly spreading the infection to others.

Simply put, we don’t know for sure how many people are currently infected with TB. Case finding declined because of the lockdowns and the shift of priorities and resources to address the pandemic. NTRL, in particular, was tapped to become one of the three COVID-19 testing streams for Research Institute for Tropical Medicine (RITM) at the height of the pandemic. 

We need to find the missing TB cases in order to address the TB problem in the country. Not finding these cases can contribute to an increase in the prevalence of TB in the communities. Drug resistance or MDR-TB can also increase. MDR-TB is treatable but takes longer and uses more drugs in the regimen. Not acting on this also puts a strain on the health system and catastrophic costs to patients,” says Dr. Basilio, also zeroing in on the looming threat of increasing incidence of multidrug-resistant TB.  

NTRL, under RITM, is the laboratory arm of the National TB Control Program committed to providing quality TB laboratory diagnostics, research, training and leading the establishment of the TB laboratory network in the Philippines. 

The rising threat of Multidrug-resistant TB

Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. 

Individuals with infectious TB are treated with a full course of the correct dosage of anti-TB medicines that includes isoniazid, rifampicin, pyrazinamide, and ethambutol. The treatment course takes 6 to 8 months and WHO is now recommending patient-centered approaches to ensure treatment adherence. 

Inappropriate or incorrect use of antimicrobial drugs, or use of ineffective formulations of drugs, and premature treatment interruption can cause drug resistance that eventually can be transmitted. In some cases even more severe drug-resistant TB may develop–the Extensively drug-resistant TB (XDR-TB), a form of multidrug-resistant TB that responds to even fewer available medicines (WHO, 2018).

This means that the drugs used to treat TB are rendered useless and can no longer kill the bacteria.

Thus, monitoring the spread of anti-TB drug resistance has become a crucial component of the global fight to stop TB. In response to this, NTRL has been conducting a series of periodic nationwide surveillance activities to measure the prevalence of drug-resistance in bacteriologically confirmed TB cases. 

The latest Philippine TB Drug Resistance Survey conducted in 2018 reported the prevalence of Rifampicin-resistant TB (RR-TB) at 1.8% on new cases and at 16.60% on previously treated patients in the country. These findings underscore the necessity of establishing a dedicated surveillance system for monitoring of drug-resistant tuberculosis (DR-TB) in the country. 

With the development of new molecular platforms, early detection of drug-resistant TB is now possible and as the National Reference Laboratory, it is NTRL’s role to ensure that the country’s TB laboratory catches up to the continuing evolution and improvement of TB diagnostics.

Improving access to quality TB diagnostics 

GeneXpert is the platform or machine that is used most commonly now for TB testing in the country. It is a multi-disease platform wherein one can perform a variety of tests for a specific disease or pathogen depending on the cartridge to be used.  

The Xpert MTB/Rif cartridge was used initially for the diagnosis of TB, but has now transitioned to the use of Xpert MTB/RIF Ultra Assay (Xpert Ultra) after the Philippine Private Sector Diagnostic Consortium (PPSDC), composed of different private laboratories nationwide, first introduced the test in 2020.

Xpert Ultra can provide results for Rifampicin resistance, which will determine the appropriate treatment regimen for patients.  It is used first for all presumptive TB cases. If the case turns out to be Mycobacterium tuberculosis (MTB) positive and Rifampicin susceptible via Xpert Ultra, they are treated using first line drugs. If they are MTB positive and Rifampicin resistant, they are then tested for additional resistances to the other drugs through line probe assay (LPA) or Xpert MTB/XDR.

WHO recently included the Xpert MTB/XDR assay into its roster of endorsed rapid diagnostic tools. It uses the same GeneXpert machine but requires a different cartridge. 

Prior to the use of Xpert MTB/XDR in the network, specimens were sent to NTRL for LPA testing to provide the results on drug resistance. LPA testing takes longer with more complicated procedures and requires certain specifications built in the laboratory. On the other hand, Xpert MTB/XDR testing provides these results quicker, in a platform that is already familiar to the TB laboratory staff and is easier to scale up.

The Xpert MTB/XDR test, developed by Cepheid in USA, is the first low complexity NAAT that detects presence of Mycobacterium tuberculosis (MTB), and resistance to Isoniazid (INH), Ethionamide (ETH), Fluoroquinolones (FQ), and second-line injectable (SLI) drugs. These additional resistances are needed to further refine the treatment among rifampicin-resistant patients. 

It has low complexity which allows for scaling up in peripheral laboratories, and it can give a result in less than 90 minutes. This has the potential to significantly improve the access to rapid anti-TB drug susceptibility testing (DST) in the Philippines. 

DOH in partnership with NTRL and other international development partners, started the preparation for wide implementation of Xpert Ultra in all rapid TB diagnostic laboratories within the national TB laboratory network during the first half of 2021, following DOH Interim Guidelines No. 2020-0375. This entailed the upgrading of software versions of all GeneXpert machines nationwide to make them compatible for the Xpert Ultra.

In Photo: One of the demonstration activities of Xpert Ultra processing performed by NTRL staff in Region 9 Training Center last April 2022. Photo courtesy of NTRL Learning and Development Section

Xpert Ultra was piloted in Regions IX and X in the second half of 2021 and prior to the implementation, NTRL conducted online capacity building activities for the trainers in Zamboanga Peninsula and Northern Mindanao Centers for Health Development (CHD). This is so they can conduct the capacity building of implementers (laboratory staff) within their regions and after the training, the labs can transition to the use of Xpert Ultra once their stock of old/regular cartridges are consumed.

NTRL is adhering to the Philippine Strategic TB Elimination Plan (PhilSTEP) of DOH. We developed a subplan for the TB laboratory network called TB Laboratory Network Strategic Plan (LNSP). The LNSP highlights the important objectives and strategies of the PhilSTEP that are related to the lab network. LNSP hinges on 4 objectives and these are centered on improving accessibility to TB diagnostics, sustaining TB laboratories, improving the quality of testing, and improving the use of data and research for policy,” says Dr. Basilio.

NTRL has been tasked with developing and implementing the training and competency assessment program for the laboratory personnel who will be performing the Xpert MTB/XDR assay.

This 2022, the Disease Prevention and Control Bureau will be rolling out the Xpert Ultra implementation to the rest of the country. NTRL, in line with LNSP, will be conducting online capacity-building activities for the different CHDs in each region. NTRL is also leading the integration of the use of Xpert MTB/XDR assay into the TB diagnostic algorithm as an alternative to Line Probe Assay (LPA); oversees the validation and introduction of the Xpert XDR platform; and provide panel testing for TB molecular rapid diagnostic laboratories in collaboration with Vietnam NTRL. 

Currently, five laboratories already have the capacity to implement the use of Xpert MTB/XDR and our short-term expansion plan is to increase that total to 15,” says Dr. Basilio on the laboratory network expansion.

The wider use of the MTB/XDR cartridge will provide quicker results for the drug resistances. 

“Our desired outcome is quality, quick, accessible and affordable–if not free, TB diagnostic testing and treatment monitoring testing. UHC hopes to come in to make all these sustainable,” ends Dr. Basilio.     

By Reina Manongsong, Communication and Engagement Office