Management of adverse events
Individuals receiving TPT are otherwise healthy, and therefore adverse events during preventive treatment must be minimized. If a severe adverse reaction is encountered, TPT must be immediately discontinued, and supportive medical care provided. Conservative management and continuation under observation can be considered in the presence of mild-to-moderate adverse events as determined by the health care provider.
Where available, clinician discretion should be exercised and a complete history, including concomitant medication and supplements, must be taken. The following steps may help in the assessment and actions for management of adverse events.
1. How severe is the adverse event (mild, moderate, severe)?
2. How serious is the event (i.e. likely to lead to death or a life-threatening experience; hospitalization or prolongation of hospitalization; persistent significant disability; congenital anomaly)?
3. What is the immediate management (reassurance, symptomatic relief, hold/discontinue TPT, or requires an intervention to avert severe outcomes)?
4. What is the underlying cause (drug related, other factors)?
5. How will the adverse event affect future adherence (tolerability, consideration of substitution with an alternative regimen)?
6. What is the next step (continue or restart, substitute, follow up and reassess)?
Key point: National programmes are encouraged to use communication technology, including SMS and video-calls, for early reporting of adverse events and prompt action by health care workers. A mechanism to record data on the occurrence and management of adverse events is advised.
A. Isoniazid and rifampicin (64)
- Drug-induced hepatitis
– Features that indicate the need to stop medication: Transient, asymptomatic increases in serum liver transaminases occur during the early weeks of treatment. There is no need to interrupt or change treatment unless there is anorexia, malaise, vomiting or clinically evident jaundice. Clinical features of concern include protracted vomiting, mental changes, and signs of bleeding – all of which suggest impending acute liver failure and require immediate discontinuation of medication.
– Management of jaundice and other severe features: If jaundice or any of the clinical features suggestive of acute liver failure develop, all drugs must be stopped until jaundice or hepatic symptoms have resolved, and liver enzymes have returned to baseline levels. If liver enzymes cannot be measured, it is advisable to wait two weeks after the jaundice has disappeared before starting TPT. Other causes of hepatitis must be explored.
– Reintroduction: Once hepatitis has resolved, the same drug regimen can be reintroduced, either gradually or all at once (“rechallenge”). However, if hepatitis has been life-threatening and was unlikely to have been caused by something else (such as alcohol, viral infection), it is probably safer to switch to an alternative regimen.
- Skin reactions
– Itching with no rash or with a mild rash: Symptomatic treatment with antihistamines may be tried and TPT continued.
– Itching with moderate/severe rash: If the rash is severe, or if there is evidence of mucosal involvement, hypotension or severe illness, corticosteroid treatment should be considered. Oral prednisolone (40–60 mg) should be given daily until there is a response; the dose should then be reduced gradually in the following days according to the clinical response. TPT should be withheld until the reaction has completely subsided. If the initial cutaneous reaction was severe, the full dose may be ramped up with smaller initial challenge doses. If a severe reaction occurs, the suspected medicine should not be given again, and an alternative regimen may be considered.
– Persons with isoniazid-associated pellagra who discontinue isoniazid and receive high-dose nicotinamide (a form of vitamin B3) treatment can fully recover, however pellagra may result in severe illness or death if untreated (103). The recommended treatment for pellagra is 300 mg of nicotinamide daily for three to four weeks. Good dietary sources of vitamin B3 are similar to those for vitamin B6.
- Peripheral neuropathy
– To prevent peripheral neuropathy, administer 10–25 mg daily dose of vitamin B6 (pyridoxine), or vitamin B complex.
– For established peripheral neuropathy, pyridoxine should be given at a larger dose of 100–200 mgdaily. Also see Chapter 5 for details on pyridoxine.
- Gastrointestinal reactions with rifampicin (abdominal pain, nausea, vomiting): If symptoms are mild, the episode is usually self-limiting, and reassurance may suffice. If gastrointestinal intolerance is severe enough to risk interruption of treatment, suspend rifampicin for three or four doses, use medications that provide symptomatic relief (such as metoclopramide to counteract vomiting), or as a last resort give rifampicin with small amounts of food to allow continued use of the medicine. Although concomitant ingestion of food reduces the absorption of rifampicin slightly, this is preferable to complete discontinuation of rifampicin.
- Lethargy: Reassurance.
- Discolouration of body secretions (urine, tears, semen and sweat) red or orange: reassurance.
B. Isoniazid and rifapentine
Please note: Rifamycins are potent enzyme inducers and any side-effects should be assessed and managed together with potential drug–drug interactions (see elsewhere in this chapter).
C. Routine monitoring: should include tolerability and adherence. Look for following components at every contact with the person on TPT,
- Signs or symptoms of TB disease (“breakthrough” or missed diagnosis at start of TPT)
- Pregnancy: discontinue 3HP, consider alternative TPT regimen (e.g. FDC of isoniazid, vit. B6 and CPT)
- Adverse event: type, onset and duration, severity
- Assess adherence and provide necessary support: any interruptions in treatment should be discussed with the person on treatment and her/his treatment supporter, and interventions to address problems in adherence should be instituted
- Other diseases, such as malaria
- Relevant physical examination
- Check for any medication (including traditional cures) that may interact with TPT
- LFTs among individuals: who had raised levels at baseline or previous visit; with history of regular use of alcohol. Routine LFTs are not indicated when IPT is given in pregnancy unless there are other risk factors for liver toxicity.
Key point: LFTs prior to initiating TPT are not routinely indicated. Baseline and follow-up LFTs are only needed when there is a defined risk, such as pre-existing liver dysfunction, liver cirrhosis or other indications.
National programmes should establish a mechanism for systematic recording of any adverse event reported by people on TPT. In addition to prompt management, suspected or confirmed adverse drug reactions should also be reported to the national authority responsible for pharmacovigilance as per local regulations. Periodic review of case files should be undertaken to assess the most frequent types of adverse events and adjust programme implementation to minimize these.
Rifamycins and ARVs
When rifamycins and ARVs are given together, there can be a change in effect of either drug on the body. A drug–drug interaction can increase or decrease the action of either or both drugs, reduce efficacy or cause adverse events. Rifamycins are potent inducers of metabolizing enzymes, including cytochrome P450 enzymes and may therefore interfere with medicines that depend on this metabolic pathway, accelerating their elimination. Rifampicin in particular is a potent inducer of hepatic CYP 450 (mostly 3A and 2C sub-families), P-glycoprotein (P-gp), and uridine diphosphate glucuronosyltransferase (UGT) 1A enzymes. Similarly, rifapentine induces P450 enzymes, specifically the CYP3A4, CYP2C8, and CYP2C9 isoenzymes (105). Rifampicin and rifapentine have similar potency as inducers, while rifabutin is a less powerful inducer. Consequently, rifamycins accelerate the metabolism of many companion drugs, including some ARV drugs. Coadministration of these ARVs with rifamycins therefore may cause reduction in ARV drug bioavailability and increase the risk of HIV treatment failure or resistance. ARVs most affected by CYP 450 induction due to rifamycin include all protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs) (such as dolutegravir) and CCR5 antagonist (such as maraviroc). Rifamycins also interact with many other medicines summarized in Table 6.4. Sound clinical judgement is therefore required when these medicines are to be coadministered with rifamycin-based TPT, either by avoiding these regimens or adjusting the dose of other coadministered drugs (106).
In general, care should be taken when prescribing regimens containing rifampicin and rifapentine to PLHIV who are on ART. These regimens should not be administered to PLHIV on a PIs or nevirapinebased regimen. While dose adjustment is not required when rifampicin is coadministered with efavirenz, the dose of dolutegravir needs to be increased to 50 mg twice daily for adults when given together with rifampicin (107). This dose is well tolerated and gives equivalent efficacy in viral suppression and recovery of CD4 cell count compared with efavirenz (108). 3HP can be administered to persons receiving efavirenz-based ARV regimens without the need for dose adjustment (109). Administration of rifapentine with raltegravir is also safe and well tolerated (110).
Coadministration of rifapentine and dolutegravir
While once-weekly rifapentine is known to reduce dolutegravir exposure, blood levels of dolutegravir remain above target concentrations associated with viral suppression in adults taking both medicines. One study showed that a reduction in dolutegravir concentration – even as high as 75–80% – is unlikely to be clinically significant as even a dose of 10 mg dolutegravir once daily (along with nucleotide reverse transcriptase inhibitor (NRTI) backbone) produces high rates of virologic suppression over 96 weeks, similar to efavirenz-containing regimen (111). Dolutegravir can therefore be given with weekly rifapentine without any dose modification.
Coadministration of these drugs is also shown to be safe overall. Phase I/II trials of 3HP and dolutegravir among adults with HIV with suppressed viral load reported good tolerance and maintenance of viral load suppression. No grade 3 adverse events were reported, and findings indicated that there was no need to adjust the dose of dolutegravir among adults living with HIV on dolutegravir-based ART (112).
However, there is a need for more studies on the pharmacokinetics of 3HP concomitantly administered with other medicines, particularly boosted PIs and tenofovir alafenamide, and including both pregnant women and children. Studies assessing dolutegravir levels with daily rifapentine and the need for dolutegravir dose adjustment with 1HP for adults and children are ongoing (ACTG 5372).
ARV options for concomitant administration with rifamycin-based TPT
A change of ART to accommodate a certain TPT regimen should be done with utmost caution. The clinician should seriously weigh the risks versus benefit of such a change since frequent change in ART is associated with loss of virologic control and hence should be avoided to the extent possible, particularly when the person is virologically suppressed with current ART. In addition, changing to efavirenz-based ART in many areas with high rates of NNRTI resistance (including many areas in sub-Saharan Africa) is not ideal. Overall, successful ART should have primacy in decision over choice of TPT regimen. The following options exist if changing of ART regimen is being considered for compatible use with rifamycin-containing TPT.
- Most NRTIs and fusion inhibitors do not have significant drug interactions with rifamycins.
- Pharmacokinetic data do not show significant drug–drug interactions of rifapentine with the NNRTI efavirenz (113–115) and INSTI raltegravir (110).
- No significant drug–drug interactions are reported with use of rifapentine and ART regimen containing abacavir (ABC), emtricitabine (FTC), tenofovir-disoproxil fumarate (TDF), lamivudine (3TC), or zidovudine (AZT). Efavirenz or raltegravir based regimens used in combination with either ABC/3TC or TDF/FTC can be used with 3HP.
Tenofovir alafenamide is a notable exception, where being a P-gp substrate may result in unacceptably low drug exposure as a result of rifamycin, such as rifapentine. Concomitant administration of tenofovir alafenamide and a rifapentine should therefore be avoided until further data are available to support their concurrent use (116). Of note, tenofovir alafenamide given with rifampicin produces similar intracellular levels of the active drug tenofovir diphosphate (TDF-DP) as TDF given alone, suggesting that this combination could be used together, but clinical data are limited (117).
Isoniazid is known to inhibit certain cytochrome P-450 enzymes. Coadministration of isoniazid with drugs that undergo biotransformation through these metabolic pathways may decrease elimination thereby increasing drug levels/exposure. Consequently, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly to maintain optimum therapeutic blood levels. Isoniazid has been reported to inhibit the metabolism of the following drugs: efavirenz, anticonvulsants, benzodiazepines, haloperidol, ketoconazole, theophylline and warfarin. The impact of the competing effects of rifampicin and isoniazid on the metabolism of these drugs is unknown, but the inducing effects of rifampicin tend to be more prominent. Similar drug–drug interactions of rifamycins are summarized in Table 6.4.
- Coadministration of commonly used ARVs with TPT is safe, and alternatives are available when low ARV exposure is suspected due to drug–drug interaction.
- Caution is required when an individual receiving TPT is also on treatment for a comorbidity.
- Women on hormonal contraceptives should use an additional barrier contraceptive to avoid pregnancy when using rifamycin-based TPT.
Rifamycin-based TPT and antimalaria treatment
Being potent CYP3A4 inducers, rifampicin and other rifamycins, decrease exposure to quinine in adults on malaria treatment, leading to a fivefold recrudescence rate (64). Similarly, concomitant administration with mefloquine causes threefold decrease in exposure to mefloquine. Similar decrease in levels of exposure was reported with coadministration of rifampicin and artemether, dihydroartemisinin and lumefantrine (9-, 6- and 3-fold decrease respectively). There is insufficient evidence to change the current mg/kg body weight dosing recommendations for these antimalarial agents, hence close monitoring should consider the higher risk of recrudescence. The following guidance may be applied until clear evidence becomes available on ways to enhance exposure to antimalarial drugs:
- If a person is diagnosed with malaria but is not yet on rifamycin-containing TPT, the episode of malaria should be prioritized and treated first.
- If a person is diagnosed with malaria while on rifamycin-based TPT, malaria treatment should be started concomitantly and clinically monitored according to national guidelines to ensure that the malaria is cured. There is insufficient evidence to indicate that doses of either TPT or ACT (artemisinin-based combination therapies) need to be adjusted.
- If a person has malaria recurrence while on TPT, he should be retreated for malaria according to national guidelines. Preventive treatment should be withheld only if the new malaria treatment also includes drugs with known interactions with rifamycins. TPT may be resumed once the episode of malaria is resolved.
- If a person meets diagnostic criteria for severe malaria (impaired consciousness, low blood glucose, high bilirubin/jaundice, bleeding, anaemia, kidney failure and parasitaemia > 10%) TPT should be withheld, and the person urgently treated according to national guidelines. TPT should be recommenced only when the episode of malaria is fully resolved.
How long does a course of TPT protect a person?
Durability of protection from TB is a function of both the potency of the TPT regimen to sterilize TB infection and the risk of reinfection post treatment. TB infection that is not adequately treated due to a less potent regimen or poor adherence to treatment may result in reactivation of TB infection leading to TB disease.
PLHIV have a high risk of reactivation of TB infection as well as progressing to TB disease when infected. In the pre-ART era, several studies found an escalating risk of TB after a course of TPT in high TB burden countries; and on the contrary a more lasting protection in low/medium TB burden countries in terms of reduced mortality and incident TB. Recent trials conducted in an era of widescale access to ART however, suggests that the protection offered by TPT even in high TB burden settings can last as long as in low/medium TB burden settings.
- In Côte d’Ivoire, where TB incidence was last reported as 159 per 100 000 people, six months of IPT had a strong protective effect in reducing mortality among HIV-infected people, who had started ART even when CD4 cell counts were high, and the protective effect lasted for up to six years (118).
- In Brazil (medium TB prevalence), IPT significantly reduced TB risk among HIV-infected patients with a positive TST. A six months course of isoniazid reduced TB risk for over seven years, in contrast to results from studies in high-burden settings in Africa where TB incidence increased immediately following IPT (119,120).
- Recent studies from Myanmar and Indonesia (high TB burden) reaffirm the durability of protection with six months IPT among PLHIV. In Myanmar, completing a course of IPT significantly reduced the risk of TB disease and death for as long as eight years. In Indonesia the protective benefit lasted more than five years (121,122).
- In the BRIEF-TB trial (97% of participants from high TB burden countries), TB incidence following a complete course of TPT using either one-month isoniazid and rifapentine or nine-month isoniazid regimen remained stable throughout the three-year follow-up period of the trial. Almost all PLHIV in this trial received ART (54). Among household contacts of TB patients receiving TPT in the preHIV era, IPT was demonstrated to have a long-lasting benefit even in settings with very high rates of TB disease.
- The United States Public Health Services sponsored several studies to assess the efficacy of IPT in the 1960s. A large group of individuals at risk of TB due to recent or remote contact with a pulmonary TB patient in Alaska were studied (123). In 1958, 2% of the population in this area was reported to have TB and a tuberculin survey revealed an average annual rate of TB infection of 8%. These levels were among the highest ever reported, even more than among the highest transmission settings, such as mines in South Africa, which had an estimated occurrence of 4.2% in 2005 (124). Participants received isoniazid 300 mg daily or 5 mg/kg for children or a matching placebo for one year. Active follow-up was done for two years and passive reporting for the next 10 years. Follow-up data from a study of 28 villages and two boarding schools in Alaska that started in 1958, showed that the protective effect of isoniazid persisted for up to 19 years (125). The calculation that six to nine months of preventive therapy was optimal was derived from follow-up data in this study and a study by the International Union Against Tuberculosis and Lung Disease that found that isoniazid given for more than nine months does not improve effectiveness (69,126).
- A systematic review published in 1999 (127) reaffirmed the effectiveness of isoniazid in preventing development of TB disease in approximately 60% of individuals in various at-risk groups including family contacts. For every 35 recent household contacts with a positive TST prescribed isoniazid for six months, one case of TB disease was prevented over the next five years.
When is it necessary to repeat or restart TPT?
There is no evidence to date on the utility of repeated courses of TPT. Therefore, WHO 2020 TPT guidelines do not specifically recommend a repeat course of TPT. However, in settings with high TB transmission (as defined by local authorities), isoniazid for 36 months (as a proxy for life long therapy) is recommended for PLHIV (see Recommendation below). One of the priority areas for research in such settings is to assess whether repeated courses of short course regimens are needed and if so, how frequently.
18. In settings with high TB transmission, adults and adolescents living with HIV who have an unknown or a positive LTBI test and are unlikely to have active TB disease should receive at least 36 months of daily isoniazid preventive treatment (IPT). Daily IPT for 36 months should be given whether or not the person is on ART, and irrespective of the degree of immunosuppression, history of previous TB treatment and pregnancy in settings considered to have a high TB transmission as defined by national authorities.
A randomized pragmatic trial (WHIP3TB), among PLHIV on ART in Ethiopia, Mozambique and South Africa, completed in late 2019, compared the effectiveness of 3HP given once (N=1802) or twice (N=1808) within 14 months versus one course of 6H (N=404). Treatment completion was better with 3HP than 6H. Follow-up for 24 months after randomization showed similar rates of TB incidence, incidence of rifampicin resistant TB and mortality between participants receiving 3HP once or twice, suggesting that 3HP for PLHIV on ART in high TB transmission settings provides protection and that repeating it annually did not improve benefits (128). Longer term follow-up of this trial will be important to understand the durability of this effect.
A repeat course of TPT should however be considered among HIV-positive or HIV-negative persons who previously completed a course of TPT but have been thereafter a household or close contact of a TB patient. Since currently available tests (TST and IGRA) do not convert to negative after a complete course of TPT, they cannot be used to determine eligibility for a repeat course if a new exposure or reinfection occurs. Therefore, careful assessment of intensity of exposure and balance between benefits and harms should guide the decision to administer a repeat course of TPT.
Restarting TPT may be necessary if there has been a significant interruption in the treatment given. Chapter 5 (Table 5.3) and Chapter 7 (Table 7.1) propose some thresholds to determine loss to follow-up for different regimens informed by criteria applied in trials. This is another area where reliable evidence about the “forgiveness” of regimen interruption is lacking.
Does TPT cause drug resistance?
One of the concerns commonly expressed about the large-scale use of TPT is its potential risk of propagating drug resistance. These concerns have not been supported by high quality evidence to date (58). Multiple trials have failed to find scientific evidence of a significant association between TB drug-resistance and the use of isoniazid or rifamycin for TPT (129,130). Concerns such as these have effectively deprived countless populations from the benefit of a potentially life-saving intervention. Most drug resistance arises from suboptimal treatment of TB disease. An increase in drug resistance is unlikely if good TPT practices are observed by programmes, namely that TPT is used in people without TB disease. Individuals with TB infection have a small number of slowly replicating bacteria in their body, and hence there is a low risk for TPT to select drug-resistant strains (129). On the contrary, TPT may actually lower the overall burden of TB disease and thus reduce the number of people who could receive suboptimal TB treatment that favours the development and spread of MDR-TB.
TB disease should be excluded using available tools before TPT is initiated, and regular follow-up done to ensure adherence to TPT and early identification of TB symptoms while on treatment. Surveillance may also be strengthened for drug resistance among individuals who develop microbiologically confirmed TB during or following TPT.
Key point: Common beliefs that large-scale use of TPT will fuel drug resistance are not supported by reliable evidence and represent the type of barriers that withhold vulnerable populations from access to interventions that can protect them and their communities from avoidable TB disease and death.
Isoniazid resistance after IPT
In a systematic review of 13 published studies since 1951, which included 18 095 people on IPT and 17 985 controls, there was no suggestion of increased risk of isoniazid-resistant TB after IPT; these results were similar when stratified for HIV (129). In addition, in the Thibela study cohort from South Africa, proportions of TB episodes with drug resistance among patients who had received IPT did not significantly differ from those in comparison groups (131).
Rifamycin resistance after TPT
In an analysis of six RCTs of rifamycin-containing regimens for TPT versus active control or placebo showed that the occurrence of rifampicin resistant cases was 0.09% in 6808 individuals receiving rifamycin-based TPT vs 0.01% in 7415 individuals receiving alternate regimens (RR = 3.45, 95%CI 0.72–16.56; P = 0.12) (130). In three of these studies where intermittent rifamycin-based TPT was used, there were two cases of rifampicin resistance among 4673 individuals on intermittent rifamycincontaining regimen compared to one case with rifampicin resistance among 4427 individuals from control regimens (RR = 3.89; 95%CI 0.44–34.56; P = 0.22). In placebo-controlled trials, there were no cases of rifampicin resistance among participants receiving rifamycin-containing regimens whereas several cases of rifampicin resistance occurred in those on placebo (RR 0.20, 95%CI 0.02–1.66) (130).
ᵃ H-isoniazid, R-rifampicin, P-rifapentine
ᵇ Grade-3 adverse event: medically significant but not an imminently life-threatening event. Grade-4 adverse event: life-threatening event.
⁹ Most adverse drug reactions associated with HP regimens are mild, self-resolving and without sequelae.
¹⁰ For many agents the magnitude may depend upon daily dosing of rifamycins versus once weekly dose (rifapentine).