For the treatment of drug-resistant tuberculosis (DR-TB), different treatment strategies are offered, out of which decentralized treatment strategies may play an important role. This article gives you a short description of Decentralized treatment strategies for drug-resistant tuberculosis care in Khyber Pakhtunkhwa.
Tuberculosis (TB) is a potentially dangerous infectious disease that mostly affects the lungs and can lead to death. The causative agent is Mycobacterium tuberculosis (MTB). The history of tuberculosis goes back 150 million years. It has a strange relationship with mankind. Romantic disease, wasting disease, and the Kings’ Evil are all names associated with TB due to different superstitions. In ancient times, it caused the deaths of musicians, and artists, thus the name “Romantic Disease.” Tuberculosis is also known as our national enemy, as the founder of Pakistan, Quaid-e-Azam Muhammad Ali Jinnah, also died from a Mycobacterium tuberculosis infection.
MTB is suspended in the air in the form of a very minute droplet which when inhaled by another individual could infect him or her. Coughing, sneezing, laughing, and talking loudly launch loads of bacteria in the form of droplets into the air which remain suspended there. These bacteria could only be killed by UV rays when suspended in the air. When in the respiratory system in the majority of cases it enters the Lung parenchyma and remains there in a dormant form. The bacteria are engulfed by the macrophages and remain in non-activated form. In non-activated form, it does not cause any harm however, when activated it infects the Lung parenchyma and the symptoms of the disease begin to appear. This is known as Pulmonary TB (PTB).
Symptoms of Tuberculosis (TB)
Symptoms of Pulmonary TB include chronic persistent cough for two or more two weeks, chest pain with breathing or coughing, unintentional weight loss, fatigue, fever, night sweats, chills, and loss of appetite. Tuberculosis can potentially infect other organs via bloodstream transmissions, such as the kidneys, spine, or brain. This is known as Extra-pulmonary TB. When TB affects organs other than your lungs, the signs and symptoms differ. For example, tuberculosis of the spine may cause back pain, while tuberculosis of the kidneys may result in blood in your urine.
Due to the emergence of HIV, the virus that causes AIDS, the prevalence of tuberculosis began to rise in the year 1985. HIV impairs a person’s immune system, making it incapable of fighting TB bacteria. However, it remains a source of concern. Diabetes mellitus (DM), which also lowers the immune system of the person, is another significant agent for the rising rate of TB. The immune system of such a person is now unable to combat TB. TB-HIV and TB-DM co-infections lead to poor outcomes and slow recovery.
Better tuberculosis control programs were developed with the aid of WHO, the Global Fund, and NTPs of many areas of the world, and tuberculosis began to decline again in 1993 as a result of these stronger control programs.
Read more: Symptoms of Tuberculosis
Drug-Resistant Tuberculosis (DR-TB)
TB has made a strong comeback in the form of drug-resistant TB (DR-TB) in recent years. Many tuberculosis strains are resistant to the medications most commonly used to treat the disease called the first-line drugs of Anti-tuberculosis Therapy. Because of the rise in drug-resistant forms, tuberculosis remains a major killer today. Some tuberculosis germs have evolved the ability to persist despite medicines over time. This is due to incorrect medicine dosages or treatment tactics, as people do not take their medications as prescribed or do not complete the course of treatment.
Drug-resistant strains of tuberculosis emerge when an antibiotic fails to kill all of the bacteria it targets causing a selection pressure. The surviving bacteria become resistant to that drug and often other antibiotics as well. Some TB bacteria have evolved resistance to routinely used medications such as isoniazid and rifampin, resulting in Multidrug-resistant TB (MDR-TB), the most common form of DR-TB. Some TB strains have also developed resistance to drugs less typically used in TB treatment, such as fluoroquinolone antibiotics and injectable therapies such as amikacin and capreomycin. These drugs are frequently used to treat infections that are resistant to more widely used antibiotics.
For more than two decades, the rise of drug-resistant strains has posed a threat to global efforts to eliminate tuberculosis (TB). Inadequate real-time surveillance, limited deployment of x-ray-based screening and rapid molecular confirmatory tests, and inefficient referral mechanisms for detecting, treating, and managing patients have all fueled the DR-TB epidemic. As a result, there is an increasing access gap in diagnosing and treating rifampicin-resistant (RR) and multidrug-resistant tuberculosis (MDR-TB).
Multidrug-resistant tuberculosis poses a huge challenge to tuberculosis control programs and is significantly more difficult to treat than drug-susceptible tuberculosis. It necessitates the use of less effective second-line medications with more unpleasant side effects when compared to drug-sensitive TB. It has a lengthy treatment period of 11 to 24 months and a low treatment success rate. As a result, it is critical to identify and treat MDR-TB patients. Inadequate MDR-TB treatment may impair patients’ outcomes, increasing the chance of widespread drug resistance. Multidrug resistance strains can spread quickly within vulnerable populations if not treated properly. Because typical short-course chemotherapy for MDR-TB has been linked to unacceptably high rates of failure and relapse, new therapeutic techniques in developing countries are required.
Global TB Perspective
Globally, TB is recognized as the leading cause of death from an infectious disease. Over the past years, the global incidence of TB has fallen, but the cumulative reduction in the TB incidence rate from 2015 to 2020 was 11%, just over halfway to the 2020 milestone. Globally in 2020, TB treatment coverage (the number of people notified and treated divided by the estimated incidence was 59% (range 53-66%). The latest data show treatment success rates of 86% for TB and 77% for TB patients living with HIV.
Global TB targets
The global TB targets in the Sustainable Development Goals (SDG), the End TB Strategy, and the United Nations high-level meeting on TB are important reference points when discussing the implications of the global targets with national stakeholders. With the targets and milestones in mind, you may ask what progress has been made so far. You will learn that the global targets for 2020 were not met and that we are not on track to meet most of those for 2022. This situation is further exacerbated by the COVID-19 pandemic, which has reversed years of progress in providing essential TB services and reducing the burden of TB disease and has resulted in a fall in global spending on TB diagnosis, treatment, and prevention. Urgent action is needed to mitigate and reverse these impacts.
Global TB Progress
Data for the period 2018–2020 also shows that the achievement of most of the global targets set for 2022 at the United Nations High-level Meeting is also off-track. Half of the targeted 40 million people diagnosed, treated, and officially reported TB has been reached. For children, the combined total is 41% of the targeted 3.5 million. The target for the detection and treatment of people with multidrug-resistant or rifampicin-resistant TB appears to be even further out of reach. Of the targeted 1.5 million people, only 32% have been reached during 2018 – 2020. For children, only 11% of the targeted 115 thousand were treated.
Global commitments for Drug-resistant TB
Drug-resistant TB is a major contributor to antimicrobial resistance worldwide, and the incidence continues to be a public health crisis. Globally, the burden of multidrug-resistant and rifampicin-resistant TB remains stable. For more than a decade, the prevalence has remained at about 3-4% among new TB cases and 18-21% among previously treated cases. In 2020, 150 thousand people were enrolled in treatment, and only about 1 in 3 of those were in need. Of people enrolled in treatment in 2018, only 59% were treated successfully.
In the United Nations High-Level Meeting on TB, Members States recognized multidrug-resistant and rifampicin-resistant TB as public health threats and committed to starting 1.5 million people, including 115 000 children, on treatment for these diseases by 2022. With 2022 approaching, what progress has been made toward these targets? Globally, the annual number of people reported to have been provided with treatment for TB disease has grown from about 6 million in 2015 to 7.1 million in 2019. However, a substantial drop to 5.8 million in 2020 was reported. The number of people reported to have been provided with treatment for multidrug-resistant or rifampicin-resistant TB annually has also grown, from a global total of almost 123 000 in 2015 to 177 000 in 2019. But this positive trend was reversed in 2020, with a 15% reduction to 150 000.
As mentioned earlier, the total number of people treated for multidrug-resistant or rifampicin-resistant TB from 2018 to 2020 is only 32% of the way towards the 5-year target of 1.5 million. The number of children treated for multi-drug resistant or rifampicin-resistant TB was around 12 000, which is only 11% of the 5-year target of 115 000. There is still a long way to go to achieve the targets agreed upon at the United Nations High-Level Meeting.
Tuberculosis in Pakistan
Pakistan is ranked fifth among the world’s 30 high-TB-burden countries. These high TB burden nations accounted for 86% of all estimated incident cases worldwide, with India (26%), China (8.5%), Indonesia (8.4%), the Philippines (6.0%), Pakistan (5.8%), Nigeria (4.6%), Bangladesh (3.6%), and South Africa (3.3%).
Pakistan with a population of 221 million has an estimated number of 573 000 (GTB 2021) cases while in 2021 the country was able to notify 339 256 cases. Among the missing cases, many may be found in rural areas and in the unregulated private sector where efforts need to be made to strengthen notifications.
Drug-Resistant Tuberculosis in Pakistan
10 countries (China, the Democratic Republic of the Congo, India, Indonesia, Nigeria, Pakistan, Philippines, Russian Federation, South Africa, and Viet Nam) account for about 70% of the global gap between the estimated global incidence of MDR/RR-TB each year and the number of people enrolled in treatment in 2020.
Pakistan ranks fifth among high DR-TB burden countries in the world with an estimated 25000 RR/MDR-TB cases among estimated TB cases, 4.2% among new cases, and 7.3% among previously treated cases.10 In the drug resistance survey in 2012-13, the prevalence of RR was estimated at 4.2% in new and 18.1% among previously treated cases. Estimates for previously treated patients were recently reduced to 7.3% based on routine surveillance. The number of DR-TB cases estimated from all notified TB cases is around 25,000, while in 2021 the National TB Control Program put 2872 patients on second-line treatment. In terms of the total number of DR-TB cases diagnosed, the most populated provinces are the ones with the highest burden of DR-TB cases notified.
For the year 2019, Punjab accounted for 48% of total DR-TB cases, while Sindh province accounted for 38%. Therefore, these 2 provinces alone cope with more than 85% of the country’s cases and their improvement is crucial for the overall country’s development. The other provinces KP and Baluchistan accounted respectively for 10% and 3% of the reported cases.
History of Programmatic Management of DR-TB in Pakistan
In 2009, Pakistan was approved through the GLC mechanism to start treatment for 400 MDR-TB patients. Programmatic management of drug-resistant TB (PMDT) was piloted in three hospitals in 2010 through the Global Fund. Initially, the conventional long-term regimen (LTR) of two years was used, and with subsequent changes in the WHO and national guidelines, the changes were implemented at all treatment sites accordingly.
New drugs like bedaquiline (Bbq) regimen were first introduced in 6 PMDT sites in 2016 and expanded to all sites in 2018. Short Term Regimen (STR) was also introduced in 2018. In 2019, Pakistan updated its National DR-TB Guidelines in line with WHO guidelines. The all-oral Short Term Regimen (STR) was introduced in February 2020 after its endorsement by the WHO and Strategic Technical Working Group (STAG) in Pakistan.
A major challenge is a slow increase in the detection and enrolment of RR patients, despite rapid Xpert expansion. The centralized model of the PMDT Site is based on a dedicated PMDT Team provided through Global Fund. Treatment and management of RR-TB are expensive, prolonged, and associated with multiple adverse effects. These factors have contributed to poor patient adherence further increasing the prevalence of DR-TB. The treatment success is low although the declining trend has stopped. The main challenges are the high death rate / LTFU and the
failures. Deaths are most likely caused by patients presenting too late for TB diagnosis due to lack of access and health facilities are not alert enough to detect presumptive TB and ensure lab investigation. LTFU is probably linked to the long distance to PMDT sites which usually covers 3–4 districts.
DR-TB in Khyber Pakhtunkhwa
Khyber Pakhtunkhwa (KP) is a province of Pakistan with an estimated 30.5 million people, with adjacent FATA areas having 5.3 million people. The capital of KP is Peshawar, where all the main offices are located. The main office of the TB control program is also situated in Peshawar. A total of five PMDT units and 239 BMUs are working here in this province to provide healthcare facilities to the people of the province. Thousands of trained, experienced, and well-qualified human resources are working in these PMDTs and BMUs to give good care to TB/DR-TB throughout the province, led by the manager of the Provincial TB Control Program (PTP), Dr. Muddasser Shahzad, Dr. Faisal Younis (the provincial MDR manager), Dr. Ahmed Ismail (the provincial TB advisor), and Dr. Abdul Raheem (the provincial program officer).
Approaches and Findings
In the current centralized PMDT approach, care for DR-TB patients is provided by highly trained staff. Specific rooms are allocated by the relevant hospital administration, which was renovated through the Global Fund keeping in mind the required infection control measures. This model could, however, only guarantee the establishment of PMDT sites in 26 districts out of 154 districts throughout Pakistan, or 17% of the districts. Each PMDT site is attached to 4-5 districts from where the patient has to travel to get DR-TB services. The baseline and follow-up tests, including sputum microscopy, blood tests, radiology, etc., were provided through the hospital, whereas the sputum culture and drug susceptibility testing were provided through specialized laboratories (National and Provincial Reference Laboratories), where sputum samples were transported through courier service.
Gap analysis done in 2019 at the national and provincial levels revealed that diagnosis and registration were high in districts where PMDT sites were established, whereas districts without established PMDT sites had a much lower DR-TB detection rate. This finding indicates that the availability of DR-TB management services sensitized doctors and paramedics in the districts regarding DR-TB and contributed to increased detection and early treatment starts.
Decentralized treatment strategies for drug-resistant tuberculosis
A gross calculation for a country with 221 million (M) inhabitants, means that there is 1 DR-TB treatment site for every 7 million people on average. Some sites cover even 15 million people’s catchment areas; in some sites, patients need to travel more than 500 km to reach their respective PMDT sites. For rural and even urban areas, finding the appropriate site for care is challenging. This affects the country’s figures, being in position 28 of the 30 World HBCs in terms of access to treatment. It is not surprising that only 14 percent of the estimated DR-TB patients are diagnosed and enrolled. The high direct and indirect costs of traveling such distances can be overwhelming for many poor patients. At the same time, long travels on public transport by smear-positive patients and the needed daily stays in order cities expose many others in the community to DR-TB while increasing the risk of COVID-19. Arriving late is not the fault of the patient. The system is extraordinarily tough for vulnerable people, and this partially explains the low diagnosis and enrollment rates. Even if money is not a barrier, if the patient is feeling too weak or too sick, he or she will not attend the facility (getting even worse) or, if able to attend the enrolment visit, may lose opportunities for monthly drug refills. There are ongoing plans for decentralization and service expansion in all provinces monitored, but the process is in the seed stage. For decentralization, the 4 provinces monitored are selecting for the new PMDT sites 2 clerical people (a coordinator and data manager, supported by the local physician) with funds from the Global Fund for 2-3 years.
The patients in the centralized PMDT model have to travel long distances to different districts each month for follow-up. This increases travel fatigue, travel costs, and the loss of daily wages, not only for the patient but also for the accompanying treatment supporter. Seeking care from untrained physicians may amplify the pattern of resistance. The travel cost also includes food costs, a night’s stay, and other miscellaneous costs. Finally, undetected and untreated patients may also spread the infection to other exposed contacts around them. The social support currently given in this scenario is minimal and does not even cover one-way travel for one person. Each patient is provided with PKR 4000/month for social protection and travel costs, while each treatment supporter is provided with PKR 1000/month as travel costs. All payments are done through the Easy Paisa system. With PMDT sites in different districts, the patients fail to report the side effects timely, leading to sequelae. ADR management is therefore either delayed or not done. The inability of the PMDT site to manage the side effects also leads to mistrust among patients regarding the treatment and ultimately a low follow-up rate. Long-distance travel in local transport also increases the risk of spreading infection. The buses, trains, or other means of transport are closed environments, putting the other travelers at high risk of acquiring DR-TB infection.
At each PMDT site, management of Drug Resistant TB is done according to specified protocols and guidelines by trained staff. PMDT not only entails the clinical aspect of DR-TB management but also includes programmatic and administrative aspects. The management of DR-TB patients is, therefore, not only done at the health facility level but is also overseen by national, provincial, and district-level teams.
Their roles and responsibilities at the central level are revised, especially focusing more on capacity building and the provision of technical expertise at the provincial level. The revised roles and responsibilities at the central level include the establishment of norms and procedures for DR-TB, development of national policy for adoption at the provincial level, development of training curricula and provincial capacity building, provision of technical expertise about difficult-to-manage DR-TB cases, monitoring, and evaluation of programmatic components with the provision of feedback, advocacy for improved community DR-TB care, provision of quality based diagnosis services, and establishment of liaison with other vertical programs like HIV for improved DR-TB diagnosis and effective coordinated treatment.
In this system, each provincial team plays its role. A role at the provincial level is also very important, which includes different responsibilities linked with different parts of the provincial team. This team includes the main TB control team (already discussed above) and provincial reference laboratories (PRL), which further link to the national reference lab (NRL) for any assistance. These both teams have different varieties of duties like establishment of different procedures for the control of DR-TB, plan & assess needs for different procedure, monitoring of programme, and evaluate the programme, advocate for community care, integration with DS-TB, ensure un-interrupted supply of diagnostic logistics (drugs, Xpert kits, R&R Tools etc.), capacity building and monitoring of staff and trained staff for giving good quality treatment and managing patients, provide Human resource, coordinate operational research on community care, organize and regularly supervise DS-TB and DR-TB diagnosis and treatment, coordinate with the central level, other institutions, e.g., NGOs and patient support systems, develop a specimen transport system in collaboration with the district teams, integrate DR-TB with other services, e.g., HIV and maternal services, make linkages between PMDT Sites with culture labs & between peripheral labs with Peripheral Lab, provide DST services in collaboration with the National Reference Lab and ensure free of cost and un-interrupted treatment for the patients. District Level.
The roles and responsibilities at the district level (District Health Management Team), which includes the Chief Executive Officer, District Health Officer (Preventive Services), District TB Coordinator, District Laboratory Supervisor, etc., include supervision of the DR-TB management sites in the districts, ensuring all DR-TB detected patients are enrolled at the relevant PMDT Sites, development of linkages between PMDT Sites and Gene Xpert labs, development of a specimen transport system within the district, advocacy within the district, coordination with provincial teams, identifying hot spots in the district, the rectification of administrative issues in collaboration with health facility administrations, assisting in patient retrievals, and contact screening.
Conclusion
Upscaling the present centralized PMDT sites and linking them with different decentralized DR-TB sites and equipping them fully with modern diagnostic tools for tuberculosis will have a very positive impact on DR-TB case finding, detection, and enrollment, and patients will be able to get proper treatments without bearing catastrophic costs which will lead to a reduction in LTFU patients and improve the TSR of these patients.
Recommendation
Decentralization of DR-TB care is the best possible way for each district to achieve 100% DR-TB treatment coverage. The decentralized site will comprise staff from the hospital. The patient will then be referred back to his/her district where the patient will receive monthly treatment. In cases of difficult-to-manage conditions or requirements for expertise, the patient will be referred back to the central PMDT site; hence, the decentralized sites will act as satellite sites of the central PMDT site. Once the satellite staff is trained to treat the patient successfully, the satellite site may become a completely decentralized site.
This may be helpful for patients in timely diagnosis, and timely treatment and lower the transmission level and achieve successful outcomes. In addition, virtual decentralization could be a good idea where access to internet services is possible.
Decentralized treatment strategies for drug-resistant tuberculosis care in Khyber Pakhtunkhwa
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