Leprosy Mailing List – January 10, 2020
Ref.: (LML) (LML) Dapsone allergy and MB treatment
From: Joel Almeida, London and Mumbai
Dear Pieter & colleagues,
Dr. Shen Jianping (LML 6 Jan 2020) wrote:
"28 % of new leprosy patients, most were MB patients, are treated with only two drugs, rifampicin and clofazimine for one year. We do not know if there is a risk for treatment failure. A paper from Yunnan province, China, reported that the BI declined very slowly among patients with 1301 gene-locus positivity, and treated with only two drugs."
There is indeed likely to be a risk of treatment failure with 1 year of anti-microbial treatment among those LL patients in Yunnan who have only monthly rifampicin and unsupervised ingestion of daily clofazimine at about 1 mg/kg/day. This risk is greater among "slow responders" who tend to be diagnosed with a high BI at all sites, dense AFB globi in macrophages, negative lepromin response and relatively high T-reg cell frequency. In multi-patient families/households with "slow responders", the risk of treatment failure is likely to be greater still. That is because even recessive genes contributing to increased risk can combine in homozygous offspring. Such patients with genetically-linked reduction in specific immunity tend to remain susceptible to HD bacilli. This multiplied risk might well occur even in Yunnan where new patients are more markedly clustered than in many other places. Further, sources of infection/re-infection are likely to be even higher in zones where BCG vaccination coverage has not yet reached 100% in all age groups, or BCG re-vaccination is not given to household contacts.
It is worth noting that the risk of recurrence (by treatment failure/relapse or re-infection) among LL patients tends to be under-estimated:
a) if inexpert clinical examination is relied on for diagnosis of recurrence. Expert clinicians compared to even well-trained but inexpert staff diagnose recurrence as much as 3 times (300%) more frequently/promptly. Delayed recognition of recurrence is accompanied by the risk of transmission as well as of nerve damage, pain and permanent disfigurement.
b) if follow-up of patients released from treatment is discontinued within 5 years, since most clinically diagnosed recurrences occur in years 6 and later after release from treatment.
c) if years 0-5 after RFT (lower-risk years) are included in the denominator, thus disguising the risk in years 6 and later.
d) if patients without LL anergy are included in the denominator, thus disguising the risk in patients with anergy.
Implications for action
The treatment recommendation of the US HD program is probably more reliably effective than other recommendations, especially for countries that have a reputation for being global leaders in public health. This involves daily anti-microbial treatment of LL or BL HD for minimum 24 months, if necessary replacing dapsone with minocycline or a fluoroquinolone. The benefits of reliable cure and near-zero transmission are so great that the necessary investment might be considered a good bargain.
The occasional new diagnosis of HD in a child in Yunnan suggests that sources of infection have not entirely been stopped. For the purpose of ensuring consistent cure and more rapidly reaching near-zero transmission, the following may be considered:
= = = = =
Serological examination of contacts (to exclude disease) for every known current or past MB patient, and also serology for the current/past MB patients themselves.
1. If serologically positive, then full expert clinical examination and full diagnostic panel of tests for HD. Including slit skin smear, skin biopsy histopathology, nerve conduction.
If HD confirmed, treatment according to the recommendations of the US HD program.
a) MB regimen or
b) PB regimen
(replacing dapsone when necessary rather than merely omitting it)
Also,
c) regular monitoring and treatment of any complications / drug adverse effects.
d) In prefectures where any child patients were diagnosed within the past 5 years, all LL patients could be given post-MDT chemoprophylaxis (monthly rifampicin + moxifloxacin + minocycline) to protect them against re-infection.
2. In the remaining contacts/former patients, presumed now to be free from disease -
vaccination with BCG (or MIP vaccine) plus multi-drug chemoprophylaxis (eg., rifampicin + moxifloxacin + minocycline one dose). Multi-drug combinations, unlike single drug use, reduce the risk of selecting drug-resistant mutants.
Further, all newly diagnosed patients and all patients with recurrent HD could be monitored for drug resistance, especially rifampicin resistance. That is because some highly bacillated patients given only rifampicin + unsupervised clofazimine may show an increased frequency of drug-resistant mutant bacilli.
= = = = =
This approach has a high likelihood of not only protecting all diagnosed HD patients, including those with HLA-B*1301, but also accelerating the decline of HD new patients in Yunnan from 10%/year to 20+% per year. This will match or exceed the success of Weifang/Shandong in rapidly achieving near-zero transmission.
Hope that helps. LML's many experts might wish to make further suggestions. It will be interesting to follow what happens in Yunnan. Near-zero transmission might be achieved relatively rapidly, even before GDP per capita expands to affluent levels. A lot of useful work has already been done. Best wishes to Dr. Shen and other great colleagues in China.
Joel Almeida
P.S. An early analysis of bacillary sub-populations during treatment of HD is given in:
Almeida, JG. A Quantitative Basis for Sustainable Anti-Mycobacterium leprae Chemotherapy in Leprosy Control Programs. Int J Lepr (1992) 60(2):255-268. This offers only part of the picture. Long-term (eg., 20 year-plus) follow-up of LL patients can give definitive answers, especially because recurrence can be difficult to diagnose promptly in LL patients.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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