Side effects of TB treatment (first-line: HRZE)

By drug

Monitoring and management

• Baseline tests: LFTs, and visual acuity, visual fields, and colour vision before ethambutol.
• Repeat tests:
  • Check LFTs monthly if the baseline is abnormal or the patient has risk factors (alcohol, hepatitis B or C, HIV, pregnancy or postpartum, age).
  • Check visual acuity and colour vision monthly while on ethambutol.
• Stop-drug thresholds (Harrison's): Stop the hepatotoxic drugs if ALT or AST is at least 3 times the upper limit of normal with symptoms or jaundice. Also stop them if it is at least 5 times the upper limit of normal without symptoms.
• Neuropathy prevention: Give pyridoxine 25-50 mg/day to patients at risk, such as those with HIV, diabetes, alcohol use, or malnutrition, and to those on other neurotoxic drugs.
• Ethambutol in young children: It is not routinely used because visual monitoring is difficult.
• Pyrazinamide in pregnancy: WHO and other international bodies recommend it routinely. The US does not, because teratogenicity data are inadequate.

Typical clinical approach (general practice, not from the retrieved text)

• Minor GI upset or itch: Treat symptomatically, give the drugs with food or at bedtime, and continue treatment.
• Drug-induced liver injury: Stop the hepatotoxic drugs, then reintroduce them one at a time once LFTs recover. Follow your local or national protocol for the order and any interim non-hepatotoxic regimen.
• Severe rash or hypersensitivity: Stop all drugs, then reintroduce them sequentially to identify the culprit.
• Visual symptoms: Stop ethambutol immediately and refer to ophthalmology.

Second-line and MDR-TB drugs

Recent evidence (PubMed, last 2 years)

• A systematic review and meta-analysis of adverse events with first-line therapy in children (PMID 40127187).
• A meta-analysis of antituberculosis drug-induced liver injury incidence and risk factors in India (PMID 39225936).
• A systematic review of adverse events with bedaquiline- and pretomanid-based MDR regimens (PMID 42121320).

Step-by-step management of anti-TB drug-induced liver injury (DILI)

Step 1: Monitor, and don't over-react to a mild rise

• About 20% of patients on the standard four-drug regimen get an asymptomatic ALT rise. It is frequently due to isoniazid ("hepatic adaptation") and often resolves despite continued treatment.
• If the ALT rise is modest and the patient has no symptoms, do not change therapy. Increase the frequency of clinical and lab monitoring.
• ALT is preferred over AST because it is more specific.

Step 2: Decide whether to stop

• ALT is more than 5 times the upper limit of normal (ULN), with or without symptoms.
• ALT is more than 3 times the ULN with symptoms (nausea, vomiting, abdominal pain, anorexia, jaundice, unexplained fatigue).

Step 3: Exclude other causes

• Viral hepatitis (A, B, C, E)
• Biliary disease
• Alcohol
• Other hepatotoxic drugs (including herbal products and paracetamol)
• Ischemia

Step 4: Work out the pattern, which hints at the culprit

• Transaminase-predominant injury is more likely isoniazid or pyrazinamide.
• A disproportionate rise in bilirubin and ALP is more suggestive of rifampicin.

Step 5: Follow the patient until recovery

• Check ALT and INR (or PT) serially until they return to baseline.
• Consult a hepatologist if the patient worsens clinically or biochemically. Watch for jaundice with coagulopathy or encephalopathy, which signals acute liver failure.
• Liver failure may need transplant evaluation (general practice, not stated in the text I retrieved).

Step 6: Bridge the treatment gap if needed

• Whether to give a liver-sparing regimen depends on how infectious the patient is, how severe the TB is, and which treatment phase they are in.
• A typical liver-sparing regimen is ethambutol, a fluoroquinolone (such as levofloxacin), and an aminoglycoside. In a UK series, severe TB was covered with ethambutol plus amikacin.
• If the patient is late in treatment or has a low bacillary burden, it is reasonable to hold all TB treatment until liver function normalizes.

Step 7: Reintroduce drugs once ALT is below 2 times ULN

• For patients with pre-existing liver disease, wait until ALT is back near their baseline.
• Most programs reintroduce drugs one at a time, so a recurrence identifies the culprit.

1. Rifampicin first, with or without ethambutol depending on the treatment phase. It is least likely to cause hepatotoxicity.
2. Isoniazid after 3-7 days if ALT has not risen.
3. Pyrazinamide after another 3-7 days. Whether to restart it depends on the treatment phase and the severity of the injury.

Step 8: Adjust the final regimen

• If the hepatitis was severe and rifampicin and isoniazid are tolerated, assume pyrazinamide was responsible and leave it out.
• A prolonged course (several weeks) to normalize also points to pyrazinamide.
• Without pyrazinamide, the total duration may be extended to 9 months, depending on doses taken, disease severity, and bacteriology.
• If isoniazid or rifampicin is the culprit, the regimen is rebuilt around the remaining drugs plus a fluoroquinolone and others. Duration is then usually longer, typically 9 to 18 months depending on which drugs are lost (general practice).

Where guidelines differ

• ATS and BTS favour sequential reintroduction.
• WHO suggests restarting all drugs together, then going sequential only if a second episode occurs.
• Individualize based on how severe the TB and the liver injury are.

Special situations

• Chronic hepatitis B or C, or HIV: ALT elevations during treatment are several times more likely. In HCV, treating the hepatitis has allowed safe reintroduction of anti-TB drugs (Sleisenger and Fordtran's).
• Pre-existing liver disease: Use baseline ALT as the reference, and monitor more often (monthly or more frequently).

Recent literature

• Lim et al., BMJ 2023, on anti-TB DILI.
• Lewis et al., 2024, on diagnosis, prevention, and risk management of TB drug DILI (PMID 39212296).

Detection of leprosy (Hansen disease)

1. Case suspicion

• A skin patch that is pale or reddish, or a plaque or nodule, especially with numbness.
• Nerve pain or tenderness, weakness, or deformity of the hands, feet or eyes.
• Painless ulcers or burns on the hands or feet.
• Contact with a known case.

2. The three cardinal signs

1. A hypopigmented or reddish skin lesion with definite loss of sensation.
   • Test light touch with cotton, wool or a feather.
   • Test pain with the sharp and blunt ends of a toothpick.
   • Test temperature if needed.
   • Early indeterminate lesions and facial lesions can be hard to judge. Facial innervation is dense, so sensory loss may be subtle.
2. A thickened peripheral nerve with sensory loss and/or weakness of the muscles it supplies.
   • Palpate the nerve and compare it with the opposite side.
   • Note tenderness. In multibacillary disease, thickening is often bilateral.
   • Commonly examined nerves: greater auricular, ulnar, radial cutaneous, median, lateral popliteal, posterior tibial, sural.
3. Acid-fast bacilli on a slit-skin smear, or in a skin biopsy or biopsy PCR.

3. Supporting investigations

4. Classification after detection

• Paucibacillary (PB): 1 to 5 skin lesions, with no bacilli demonstrated in a smear or biopsy.
• Multibacillary (MB): more than 5 lesions, or bacilli on smear or biopsy, or nerve involvement in some schemes.

5. Look for complications at the time of detection

• Grade disability in the hands, feet and eyes.
• Screen for reactions (type 1 reversal reaction, type 2 erythema nodosum leprosum) and for "silent neuritis". Silent neuritis is progressive nerve impairment without pain or tenderness.
• Screen household contacts, since contact tracing is part of case detection.

6. Differential diagnoses to consider

• Tinea versicolor
• Vitiligo
• Pityriasis alba
• Post-inflammatory hypopigmentation
• Cutaneous sarcoidosis
• Granuloma annulare
• Cutaneous lymphoma
• Other causes of neuropathy

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