|DR PRJ GANGADHARAM AWARD ORATION
|Year : 2020 | Volume
| Issue : 1 | Page : 15-18
Drug resistance in tuberculosis: A clinician's view
Kamal Kishor Chopra
Director, State Tuberculosis Training and Demonstration Centre and New Delhi TB Centre, New Delhi, India
|Date of Submission||08-Jan-2020|
|Date of Acceptance||24-Feb-2020|
|Date of Web Publication||14-Apr-2020|
Dr. Kamal Kishor Chopra
New Delhi Tuberculosis Centre, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chopra KK. Drug resistance in tuberculosis: A clinician's view. J Mahatma Gandhi Inst Med Sci 2020;25:15-8
| Introduction|| |
At the outset, I am grateful to the Kasturba Health Society and this prestigious institute – A shining example of providing community-oriented quality medical education to several generations and excellent and affordable health care besides many significant contributions in community-based research. I will remain indebted to Mrs. Shakuntla Gangadharam for instituting this aware and I am particularly thankful to Dr. Mrs. Pratiba Narang with whom I have a long professional and personal association for inviting me to be present here today. For me, it is a privilege to deliver an oration in honor of Dr. P.R.J. Gangadharam whose many contributions in control clinical trials, monitoring of drug compliance, and scientific basis of intermittent therapy among many others laid the very foundation of tuberculosis (TB)-control strategies.
The emergence of Mycobacterium tuberculosis strains resistant to at least, isoniazid (INH) and rifampicin (RIF), the two most potent drugs of first-line anti-TB therapy, is termed multidrug-resistant (DR) TB (MDR-TB). This is a cause of concern to TB control programs worldwide. When MDR-TB strains become resistant to the major second-line drugs (SLDs), one of fluoroquinolones and one of the three injectable drugs (amikacin, kanamycin, and capreomycin), it is defined as extensively DR TB (XDR-TB).,
MDR-TB is a manmade, costly, and deadly problem. Rapid diagnosis of MDR-TB is essential for the prompt initiation of effective second-line therapy to improve treatment outcome and limit transmission of the disease.
| Global Burden|| |
Globally, in 2017, there were an estimated 558,000 incident cases of MDR/RIF-resistant (RR)-TB. Worldwide, 3.5% of new cases and 18% of previously treated cases had MDR/RR-TB. The countries with the largest numbers of MDR/RR-TB cases (47% of the global total) were China, India, and the Russian Federation. There were about 230,000 deaths from MDR/RR-TB in 2017, similar to the best estimate for 2016 that was published in the 2017 edition of the WHO global TB report.
| Indian Scenario|| |
India has the second-highest MDR-TB burden in the world after China. The WHO estimated incidence of RIF TB and MDR-TB in India is estimated to be around 135,000. This translates to around 10 patients/100,000 population annually. The results of the first national anti-TB drug resistance survey in India (2014–2016) showed that MDR-TB is 6.19% among all TB patients, with 2.84% among new and 11.60% among previously treated TB patients.
| Causes of Increase in Drug-Resistant Tuberculosis|| |
Suboptimal TB control practices (e.g., poor DOT, inadequate infection control measures, and treatment without drug susceptibilities or culture) is the major cause in MDR-TB. From a microbiological perspective, the resistance is caused by a genetic mutation that makes a drug ineffective against the mutant bacilli. An inadequate or poorly administered treatment regimen allows DR mutants to become the dominant strain in a patient infected with TB.
| Programmatic Management of Drug-Resistant Tuberculosis Services in India|| |
After successfully establishing the DOTS services across the country in 2006, the Revised National TB Control Program (RNTCP) rolled out the programmatic management of DR TB (PMDT) services in 2007. There was an exponential scale up during 2011–12 to achieve complete population coverage in March 2013. PMDT prioritizes diagnosis and management of M/XDR-TB cases and mono and poly first-line drug (FLD)-resistant cases without M/XDR-TB treated with FLD regimes. Early implementing states used phenotypic drug susceptibility testing (DST) for the diagnosis of DR-TB. Since 2012, all patients undergo rapid molecular DST (mostly line probe assay [LPA]) for the diagnosis. Criteria for MDR-TB are as follows:
- All notified TB patients (public and private)
- Follow-up positive on microscopy including treatment failures on standard first-line treatment and all oral H mono/poly regimen
- Any clinical nonresponder including pediatric (if specimen available)
- People Living With HIV/AIDS (PLHIV)
- Smear-ve/NA with X-ray suggestive of TB including pediatric TB, vulnerable groups as defined in TOG-2016
- DR TB contacts, nucleic acid amplification testing is offered upfront for the diagnosis of TB among these presumptive TB patients.
| Tuberculosis Diagnostics|| |
The care of patients with TB starts with a quality assured diagnosis. Arguably, the most important component of health systems is the laboratory services. An unprecedented effort to improve and expand TB laboratory capacity is underway, spearheaded by the WHO and the Stop TB Partnership and Global Laboratory Initiative and its network of international collaborators. For an increased output, a given laboratory can conduct DST on many more patients by molecular and liquid than solid culture method. The rapid diagnosis reduces patient loss, mortality, and operational complexity of the current system. The infrastructure requires flexible capacity, with molecular, solid, and liquid capacity for testing. Thus, for DST at a certified laboratory, wherever available molecular DST (e.g., LPA) is a preferred diagnostic method because of the rapid and highly accurate RIF results, followed in preference by a liquid C-DST and then solid C-DST. Similarly, for follow-up cultures, wherever available, the liquid culture will be preferred over solid culture. However, this will be liquid cultures for at least the crucial months of follow-up (initial phase (IP) – 3, 4, 5, and 6 and continuation phase – 18, 21, and 24), and over and beyond this, it will be determined by the workload of individual laboratories.
| Nonmultidrug-Resistant Tuberculosis Cases in India|| |
Currently, there is no policy for the management of non-MDR cases in India. New smear-positive cases remaining positive after 2 or 3 months of therapy are continued on the same regimen. Furthermore, smear-positive retreatment cases at baseline are initiated on retreatment regimen, i.e., Cat II. If they remain positive after 3 or 4 months of treatment, the same schedule is continued and DST is repeated for patients failing to first-line category treatment.
To know the prevalence of non-MDR-TB cases, data of about 7000 cases treated under programmatic conditions were reviewed to find out the prevalence of resistance to individual drug and treatment outcomes of such patients taking either Cat I or Cat II treatment. Data revealed H mono resistance to the tune of 34% (17% among Cat I and 83% among Cat II patients). Among these cases, the failure rate was around 49%. Worse than this on repeat DST, there was an implication of resistance up to 40% against RIF among these patients.
Clinical implications include treating mono- and poly-resistant cases with first-line regimen are associated with a high risk of unfavorable outcomes including failure to treatment. This risk increases with the number of drugs against which the bacilli are resistant. A significant risk of amplification of resistance to RIF was observed in mono- and poly-resistant patients treated with FLD.
On the other hand, in a study conducted in NDTB Centre (unpublished data) among 1200 MDR suspects, 12% were found to be pan sensitive on DST. Patients got Cat I or CAT II treatment based on the previous history of anti-TB treatment. Their treatment outcome was correlated. Only 60% of cases responded to treatment. More than 14% of cases failed to treatment, may be due to in vitro, in vivo variation in susceptibility of organisms. Some of them may have taken irregular treatment.
Baseline second-line DST among confirmed MDR cases also found 22% strains resistant to ofloxacin and 2% to both ofloxacin and kanamycin. The impact on treatment outcome and implication of resistance to other drugs are yet to be seen.
| Effect of Drug Resistance on Treatment Outcome With first-Line Drugs|| |
The effect of drug resistance on the outcome of TB treatment using standard regimens depends on the type and number of drugs to which the strain is resistant versus the potency of the treatment regimen.
Modern first-line short-course treatment regimens for TB use R for the full 6-month duration. R resistance leads to increased rates of failure or relapse, depending on sensitivity to other drugs in the regimen (H, Z, E, and sometimes S). Using only FLDs, MDR-TB has <50% chance of relapse-free cure, barely better than the natural course of untreated TB. H mono resistance has little impact on the treatment outcome. Influence of E mono resistance is not known because it is a very rare and less reliable DST. The influence of Z monoresistance is also unclear; however, initial Z resistance would be expected to lead to increased relapse. Resistance to H with E or S increases risk of failure and relapse to approximately 10% of patients using R-throughout regimen, 40% without R regimen in CP. Resistance to H + E + S leads to failure to any First line (FL) regimen in approximately one-third to half of patients due to the acquisition of R resistance with the strain developing into true MDR-TB. Due to the poor growth of some MDR-TB strains, concomitant R resistance may be missed by conventional DST. It is the probable cause of more failures among retreatment patients with initial H-resistant, R-susceptible disease.
| Amplification of Drug Resistance|| |
Except for MDR-TB and combined resistance to H, S, and E, majority of patients with initial drug resistance will be cured using standard FLD regimen. The risk of amplification of resistance with the development of MDR-TB in failure cases is a real problem. Due to the poor growth of some MDR-TB strains, concomitant R resistance may be missed by conventional DST. This can be a possible explanation for studies reporting significantly more failures among retreatment cases with initially H-resistant, R-susceptible disease compared with the same initial resistance but treated with less powerful 6-month R-throughout regimens. It is therefore reasonable to assume that some patients who carry H- or R-resistant strains, but not both, will fail or relapse with an unmodified FLD regimen. The revised FLD regimen should be used with repeat rapid R DST in case of delayed conversion or even a switch to the MDR regimen at any time in first-line retreatment, with correlating clinical conditions. The alternative recommendation in some guidelines is replacing H by fluoroquinolones (FQ), but this would create pre-XDR strains out of MDR strains that are difficult to grow and may be misclassified as H + E, H + S or H + E + S resistant.
| Effect of Drug Resistance on Treatment Outcome With Second-Line Drugs|| |
Very little data are available regarding the impact of initial second-line resistance on standard MDR-TB treatment regimens. FQ resistance seems to be most important and only about 10% of those with initial FQ resistance have failed or relapsed from the regimen for “new” MDR-TB patients. Thioamide resistance has a minimal impact on the outcome of the regimen. Resistance to thioamides in strains from patients never exposed to these drugs will often be caused by cross-resistance with H due to inhA mutation. The remaining SLDs (p-aminosalicylic acid and cycloserine) have little activity and are vulnerable as these are companion drugs only. Resistance to these drugs will only matter when there is already some resistance to FQ or other companion drugs and possibly with weaker regimens.
| Effect of Drug Resistance on Treatment Monitoring Parameters|| |
There is confusion regarding the meaning of positive smears at the end of the intensive phase. Sputum smear conversion depends mainly on the extent of the disease and bacillary load at the start of the treatment and much less on the regularity of drug intake and drug resistance. Only MDR-TB clearly delays smear conversion during standard first-line treatment, even with the most powerful IP Cat II treatment – prolonged excretion of dead bacilli. In principle, culture is a better parameter for treatment monitoring. However, with referred sputum samples, results of these often paucibacillary specimens become less reliable and delays would reduce their usefulness. With solid media and drug-susceptible extensive disease, culture conversion often precedes smear conversion. With serious drug resistance, culture may never convert, contrary to the smear, or may revert to positive sooner than a smear.
| Are Drug-Resistant Strains as Transmissible as Drug-Susceptible Strains?|| |
A case–control study by Snider et al. demonstrated that contacts of patients with DR and drug-susceptible cases of TB had an equal prevalence of positive tuberculin skin test. In contrast, animal studies have shown that INH-resistant strains caused significantly less disease in guinea pigs than drug-susceptible strains.
| Are Drug-Resistant Strains Likely to Progress to Active Disease Once Infection Is Established?|| |
In San Francisco, Burgos et al. found that strains that were resistant to INH either alone or in combination with other drugs were less likely to result in secondary cases than were drug-susceptible strains. In this setting, INH-resistant and MDR-TB cases were not likely to produce new, incident DR TB cases. This presumed effect on pathogenicity may be related to mutations in the katG gene. In addition to these data, other molecular epidemiological studies observed that cases of TB caused by DR strains were less likely to be in clusters. The implication is that DR strains were less likely to be transmitted and/or to cause active TB.
Factors affecting DR strains to progress to active disease are:
- Pathogen related
- Undefined virulence factors
- Variability in virulence between genotypes
- Size of the infecting inoculum.
- Presence of immunosuppression
- Ethnic susceptibility to various strains.
In clinical practice, often ST patterns and clinical responses do not correlate. The reasons for discordant DST results are:
- Bacterial population (isolate vs. subculture)
- Differential growth kinetics
- Different inoculation methods (size and clumps)
- Different methods or media
- Transcription and labeling errors
- Minimum inhibitory concentration-critical concentration.
| Management of Multidrug-Resistant Cases|| |
Management decisions of a resistant case depend on finding the probable cause if prior poor adherence is recognized and may be addressed and DOT ordered. If the risk of drug resistance is due to nonadherence and treatment failure is identified, drug susceptibility tests should be ordered and the regimen should be changed as per the history of drug intake. The clinical response should be correlated with the report of MDR and treatment should be changed after report of drug resistance despite a good initial response. Common errors in the management of MDR-TB cases:
- When initiating or revising therapy, always attempt to employ at least three previously unused drugs to which there is in vitro susceptibility. Common errors done are:
- Used three drugs that were part of previously failed treatment are prescribed
- Ethambutol and Pyrazinamide (PZA) are used alone for the continuation phase.
The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs, for example, ciprofloxacin resistance should have alerted providers to ofloxacin resistance because of cross-resistanceBactericidal drugs with proven efficacy should be used. Many times, clofazamine (a weak drug with unknown efficacy) is added in regimenTwelve months of injectable therapy following culture conversion are generally recommended and exact duration is determined by the extent of disease and drug resistance. Many times, streptomycin stopped after month 6Two years of total treatment after conversion of cultures to negative are usually recommended. Occasionally, patients with limited disease are declared cured after 18 months or sometimes treatment stopped at 13 months.
| Should We Treat or Follow Contacts to Multidrug-Resistant/extensively Drug Resistant?|| |
The answer is….yes. Guidelines for MDR and drug resistance are recommended following the contact for at least 2 years. However, data to support strategies for managing contacts are very sparse.
| Clinical Implications of Resistance among Tuberculosis Cases|| |
DST results must be available as soon as possible to guide treatment choices. Testing algorithms including molecular tests for rif-R may speed decisions. Laboratory tests do not replace clinical judgment. Clinicians need data to interpret results based on performance parameters of the test and potential impact of the prevalence of resistance on predictive value. Relying on clinical and X-ray manifestations has many limitations for the diagnosis of DR-TB as no symptoms or radiological findings differentiating susceptible from resistant TB. Prognosis and response cannot be decisively assessed through radiological examination because lesion regression may require 3–9 month. For follow-up patients, no specific symptoms or radiological findings suggesting failure due to drug resistance are there, it is only the lack of improvement compared with clinical and X-ray manifestations which suggests resistance. Lack of improvement must be seen merely as arousing suspicion of Dr-TB and supporting a request for DST. The diagnosis of DR-TB based only on clinical and radiological criteria should never be accepted, even if there is no improvement after several months of treatment.
| Challenges for Tuberculosis Control Programs|| |
Insufficient public sector MDR and XDR TB diagnosis and treatment services is one of the main challenges as the country scaled up basic TB services via RNTCP DOTS through 2006, MDR-TB services began pilot testing only in 2007. There is a poor quality of TB and MDR-TB laboratory diagnosis in the private sector. TB is often diagnosed with serology, which frequently misdiagnoses TB. The use of TB serological testing has been recommended against by RNTCP, WHO, and some expert groups from India, but such tests are widely available and widely used in the private sector. There is also a lack of information about patients diagnosed with TB and MDR-TB in the private sector. Patients properly diagnosed with TB and MDR-TB in private laboratories are not notified to public health authorities.
There is irrational use and sale of anti-TB drugs and diagnostics outside the program. First-line TB drugs were sold to the extent of 65%–117% of the estimated annual incident cases in India in private markets. Among SLDs, fluoroquinolones are widely available with a significant volume used for TB in India.
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Conflicts of interest
There are no conflicts of interest.
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