Chapter 6. Safety, management of adverse reactions and other drug-related issues in TB preventive treatment

Safety, management of adverse reactions

WHO has for long recommended the use of TPT for populations at risk of TB, particularly People with HIV and child household contacts of TB patients. However programmatic scale-up of TPT has remained limited in most high TB and HIV burden countries due to other competing priorities. Concerns about the efficacy and safety of TPT and interactions with other medicines, particularly ARVs, may also be barriers to programmatic scale-up. Other frequently raised questions are about the potential for TPT to increase TB drug-resistance in the community and the durability of TPT to protect against disease or mortality. This chapter discusses available evidence around some of these important issues to facilitate TPT uptake and programmatic scale-up.

Drug safety and adverse drug reactions

Overall, the occurrence of serious adverse events leading to death or requiring withdrawal of TPT is rare. However, it is critical to identify any sign of drug toxicity early on and manage it vigorously, particularly among people who are usually healthy. Apart from harming the individual such eventualities can also damage the reputation of the programme and result in suspension of further TPT on a large scale due to loss of public confidence. As with any preventive action, the health care provider must weigh the risks and benefits of TPT for every individual. Obtaining a detailed and accurate medical history (inclusive of medicines being taken and known past adverse drug reactions) and keeping up-to-date information at every contact with the person on TPT, can help identify persons who require close monitoring and the most appropriate course of action if an adverse event emerges. Individuals receiving TPT should also be monitored regularly through scheduled visits (monthly if feasible, or as required for individual care or national programmes).

Table 6.1 summarizes known adverse events associated with currently used TPT drugs. As a part of initial counselling, the health worker should explain the rationale for TPT, importance of completing the course and re-emphasize the risk associated with TB disease. The person on TPT should also be educated about the likely adverse events and urged to contact the health care provider if they develop events suggestive of drug toxicity in between visits (such as loss of appetite, persistent fatigue or weakness, abdominal discomfort, nausea, vomiting, dark-coloured urine, pale stools, rash or itching, yellowing skin or eyes, tingling or numbness in hands or feet). If a health worker cannot be consulted at the onset of such symptoms, the person on TPT should immediately stop treatment. People treated with rifamycins should be warned in advance about the pink discolouration of secretions due to this medicine.

Likely adverse events with drugs used for TPT

The following paragraphs discuss some of the adverse events associated with drugs used in preventive treatment and their management.


  • Asymptomatic elevation of serum liver enzyme concentrations occurs in 10–20% of people taking isoniazid which usually return to normal even if treatment is continued. However, it is generally recommended that isoniazid be withheld if transaminase levels exceed three times the upper limit of normal and symptoms develop, or five times the upper limit of normal even in the absence of symptoms.
  • Clinical hepatitis leading to death occurs in about 0.1% of people taking isoniazid and is more common when it is combined with other hepatotoxic agents. Factors that may increase either the rate or severity of hepatitis include daily alcohol consumption, underlying liver disease or risk for liver disease, age > 65 years, and concurrent use of other medications which are metabolized in the liver. Symptomatic hepatitis is rare among people younger than 20 years of age, although severe and fatal cases have been reported. Younger people with underlying risk factors for liver disease should be monitored clinically with the same precautions as older people.
  • Peripheral neuropathy (paraesthesia, numbness and limb pain) occurs in less than 0.2% of people taking isoniazid at normal doses. It is more likely in the presence of other conditions associated with neuropathy, such as diabetes, malnutrition, HIV, renal failure and alcoholism. Routine pyridoxine (vitamin B6) supplementation is recommended only in such conditions or when there is other risk of isoniazid toxicity.
  • Isoniazid is recognized as a secondary cause of pellagra. It interrupts cellular niacin (vitamin B3) production in persons with underlying nutritional deficiency. Niacin plays a vital role in numerous metabolic processes. Pellagra is clinically diagnosed by its characteristic skin rash. Other symptoms include diarrhoea and neuropsychiatric changes. Populations at increased risk for pellagra include persons who consume excess alcohol and those with an undiversified reliance on unfortified maize staples.
  • Other known side-effects due to isoniazid are skin rash, sleepiness and lethargy.


  • Gastrointestinal symptoms, such as nausea, anorexia and abdominal pain, are rarely severe enough to discontinue treatment.
  • Hepatotoxicity, evidenced by transient asymptomatic hyperbilirubinemia, may occur in 0.6% of persons taking rifampicin. Hepatitis is more likely when rifampicin is combined with isoniazid.
  • Cutaneous reactions, such as pruritis (with or without a rash), may occur in about 6% of persons taking rifampicin. These are generally self-limiting and may not be true hypersensitivity. Continued treatment may be possible.
  • Rifamycin hypersensitivity syndrome has been reported in the past with use of rifampicin characterized by flu-like symptoms. The syndrome, when it occurs, typically develops after a few weeks from start and in most instances, TB treatment can be tolerated subsequently (96,97). Rarely, rifamycins can be associated with hypersensitivity reactions, including hypotension, nephritis or thrombocytopenia manifested by symptoms such as fever, headache, dizziness/light-headedness, musculoskeletal pain, petechiae and pruritis.
  • Orange discolouration of body fluids is expected and harmless, but persons prescribed rifamycins should be advised beforehand.


  • Overall rifapentine is associated with fewer number of adverse events on TPT and is well-tolerated, even among individuals with varying degrees of hepatic dysfunction (98).
  • Clinically significant systemic drug reactions, mostly flu-like, are reported in up to 3.5% individuals receiving 3HP, most being mild and resolved within 24 hours (99). However, clinical monitoring and continued vigilance for systemic drug reactions are warranted. While there are reports of people experiencing hypotension or syncope after taking 3HP, hypersensitivity episodes overall are uncommon and usually resolve quickly after medication is stopped without any long-term effect.
  • Other common side-effects include change in the colour of body fluids to orange–red (benign), gastrointestinal side-effects (such as nausea, vomiting, loss of appetite), decrease in white and red blood cell counts, skin rash or itching, joint pain and red eyes (100).

A network meta-analysis conducted in 2014 (updated in 2017) compared adverse events associated with the use of standard isoniazid regimen versus 3–4R and 3–4HR (45,101). The rifampicin only and rifampicin plus isoniazid regimen were reported to have a lower risk of hepatotoxicity compared to isoniazid monotherapy. Another systematic review that included data from 23 randomized and 55 nonrandomized studies in 2017 (102) reported high hepatotoxicity rates with 6H/9H (2–6%) and lowest rates with 3HP (1%) and 3–4R (0.01–2%) (Table 6.2). However, this review clearly stated overall weak documentation of adverse events, heterogeneity in data (different definitions of hepatotoxicity) and high risk of bias in the studies. The data however provided pointers to the frequency of any adverse events and events that eventually lead to stopping preventive treatment. The highest median rates for withdrawals from adverse events were associated with 6H, followed by 9H and lowest rates with 3HP. Possible hypersensitivity reactions were reported in up to 4% of individuals on 3HP and 2% on 3HR. Data on deaths due to any cause during TPT is reported less often, but in the studies included in the analysis no deaths were reported among participants on 9H, 3HP and 3–4R, while few deaths occurred in those on 6H and 3–4HR largely from studies in People with HIV not on ART or other comorbid conditions. Reassuringly, anaphylaxis was rarely reported for any regimen.

Summary of adverse events and treatment

A study that compared tolerability of 3HP versus 9H among HIV-positive and HIV-negative individuals found higher rates of grade 3 and 4 toxicity, hepatotoxicity and serious adverse events among HIVpositive persons receiving 9H. However, People with HIV experienced lower rates of flu-like or systemic drug reactions (1.0% vs 4.6%; P = 0.01) compared to HIV-negative individuals (53).

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