Chapter 5. TB preventive treatment

Chapter 5 Cover

Decision point on choice of TB preventive treatment

Which of the WHO recommended TPT regimens should be used for different individuals in the country?

TPT regimen recommendation and availability

TPT broadly falls into two categories: (i) isoniazid monotherapy for six or nine months, or (ii) rifamycin-based shorter preventive treatment, on the assumption that the infecting strain is susceptible to these medicines. Isoniazid preventive treatment (IPT) for six months has been the most widely used regimen under programmatic conditions and has emerged as a standard for TPT for both adults and children, HIV-positive and HIV-negative, and in high and low TB incidence countries. Several systematic reviews have consistently demonstrated the efficacy of IPT in preventing TB disease among those infected with M. tuberculosis. A systematic review of randomized control trials (RCTs) involving People with HIV in 2009 showed that IPT reduces overall risk for TB by 33% (RR 0.67; 95% CI 0.51;0.87), and the preventive efficacy reached 64% for people with a positive TST (RR 0.36; 95% CI 0.22;0.61) (44). This review also demonstrated that the efficacy of the six-month regimen was not significantly different from that of a 12-month daily isoniazid monotherapy (RR 0.58; 95% CI 0.3;1.12). A recent systematic review of RCTs also showed a significantly greater reduction in TB incidence among participants given the sixmonth regimen than in those given a placebo (odds ratio 0.65; 95% CI 0.50;0.83) (45).

Clinical trial evidence generated over the past two decades shows similar preventive efficacy with shorter rifamycin-based TPT regimen, both in HIV-positive and HIV-negative individuals, as monotherapy or in combination with isoniazid (45–48). The clear advantages of these regimens are better adherence due to the shorter duration and fewer adverse events. The use of shorter rifamycin-based regimens is associated with at least 20% greater treatment completion rate (82% vs 61%) (14). WHO recently assessed and recommended several shorter rifamycin-based regimens as alternatives to six months of isoniazid.

WHO recommendation:

17. The following options are recommended for the treatment of LTBI regardless of HIV status: 6 or 9 months of daily isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or a 3-month regimen of daily isoniazid plus rifampicin. A 1-month regimen of daily rifapentine plus isoniazid or 4 months of daily rifampicin alone may also be offered as alternatives.


The external experts convened by the WHO as Guideline Development Groups (GDGs) to advise on treatment policies assessed available evidence for the various TPT options, taking stock also of values and preferences of the beneficiaries and key considerations such as regimen acceptability, feasibility, resource implications and likely impact on health equity. Based on these elements the GDGs recommended various regimens where the benefits are likely to outweigh potential harms of acquiring TB disease or drug toxicity (see Recommendation 17 in Box above). When choosing a regimen, the health caregiver and the person taking the treatment should consider the circumstances under which TPT would be given to increase the likelihood of it being completed. The choice may also depend on availability of resources, fixed-dose combinations (FDCs), child-friendly formulations, concomitant medication (such as antiretroviral drugs (ARVs), opioid substitution therapy, oral contraception), as well as acceptability to recipients in the country context.

The 2020 guidelines broaden the applicability of a number of previous recommendations on testing for TB infection and on TPT treatment regimen options to any TB burden setting, on condition that: the country or treatment site has the capacity to rule out TB disease reliably before starting TPT, resources are available to implement TPT properly, and measures are in place to limit the risks of TB infection and reinfection. In this context, the importance of appropriate resource mobilization and health system strengthening is stressed.

Recommendations for IPT and other regimen alternatives have already featured in past WHO guidance (40,49,50). In the 2020 update of the WHO guidance two new regimens have been added for use regardless of the setting (but subject to certain conditions): (i) daily rifapentine plus isoniazid for one month (1HP), and (ii) daily rifampicin monotherapy for four months (4R). In addition, instead of a previous range of three to four months, WHO now recommends a duration of three months for daily isoniazid plus rifampicin (3HR) and four months for daily rifampicin alone (4R) to reflect the usual length of time for which these regimens are currently employed. Moreover, three previous recommendations on the use of 6H, 3HR among people below 15 years of age and 3HP in high TB prevalence settings that featured separately in previous guidance are now proposed as an equivalent alternative for TPT. The revised recommendations thus makes all TPT options applicable across all settings.

Key point: The 2020 update of WHO guidelines on TPT makes 9H, 6H, 4R, 3HP, 3HR, 1HP as alternative options for use across all disease burden settings and target populations including the People with HIV. The choice will depend on availability of appropriate formulations and considerations for age, safety, drug–drug interactions and adherence.


Table 5.1 below summarizes all currently available TPT options for introduction and programmatic scale-up. National programmes need to weigh various factors including country context, resources and capacity of the health system. Moreover, given the current availability of safer and shorter options, efforts to introduce and scale up shorter TPT regimen are likely to enhance coverage, improve adherence and ensure TPT completion.

Six or nine months daily isoniazid: has historically been most often used worldwide. However, it is anticipated that isoniazid will be increasingly replaced with rifamycin regimens that are becoming increasingly affordable and feasible, with more studies about their efficacy and safety in different populations expected to bear results in the coming years. It is likely that 6H or 9H will continue to be an important choice for TPT, particularly in situations where rifamycin-based regimens cannot be used. In such situations national programmes may consider the use of a triple pill combination of isoniazid, cotrimoxazole and B6 for People with HIV, available at a discounted price through the Stop TB Partnership’s Global Drug Facility (STBP/GDF) instead of isoniazid only regimen (51). Isoniazid is the preferred regimen among HIV infected children on protease inhibitor-based regimen (lopinavir– ritonavir), nevirapine, or integrase inhibitors (dolutegravir) due to potential drug–drug interactions. Isoniazid monotherapy should also be protective in contacts of TB patients with laboratory confirmed isoniazid-susceptible, rifampicin-resistant disease (mono rifampicin resistant TB).

Three-month weekly isoniazid plus rifapentine or one-month daily isoniazid plus rifapentine: National programmes may consider either of these two rifapentine-containing regimen options. Both regimens have been shown to have similar efficacy as that of isoniazid for TB prevention, but there is currently no direct evidence of efficacy from a head-to-head comparison between 1HP and 3HP (52–54). Due to lack of data on appropriate dosing of 1HP among children 12 years and younger, WHO currently recommends the use of 1HP among people aged 13 years and above (this was the age limit used for the study population in the single RCT of the regimen whose results have been published to date (54)). Also, rifapentine 150 mg tablets are now available at a discounted price from the STBP/GDF as well as the Global Fund Pooled Procurement Mechanism (55). A FDC tablet of rifapentine 300 mg/isoniazid 300 mg is expected to become available later in 2020, which will reduce the pill burden substantially for people prescribed 3HP. The 1HP regimen may be used where the shorter duration is preferred even if the total number of doses increases from 12 in 3HP to 28 (such as among prisoners incarcerated for a short term, patients awaiting start of anti-TNF treatment or preparing for transplantation). For younger children who cannot swallow pills, there is no childfriendly (i.e. dispersible) formulation of rifapentine currently available.

Four-month daily rifampicin: Rifampicin has a long history of use in TB treatment with national procurement systems experienced in acquiring it, but mostly with other TB medicines as part of FDC tablets. Rifampicin has an excellent safety profile compared to isoniazid and the cost is lower than rifapentine. This regimen is useful to give to contacts of people with confirmed isoniazid-resistant, rifampicin-susceptible TB disease (Hr-TB). One of the main challenges with 4R however may be to deal with the perception that rifampicin needs to be protected for use as a first-line TB medicine and concerns that its use in TPT may increase levels of rifampicin resistance in the community or promote misuse of the agent as monotherapy for TB disease. There is however no evidence till date demonstrating the significant increase in rifampicin resistance levels due to scale-up of TPT services. Other challenges to consider are: drug–drug interactions with ARVs (refer to the section on drug–drug interactions in Chapter 6), child-friendly formulations are not available currently, and the supply of single dose formulations may be limited due to widespread availability of FDCs of first-line TB treatment.

Three-month daily isoniazid plus rifampicin: Infants and young children (< 5 years of age) are particularly vulnerable due to increased risk of progressing to TB disease and of developing severe forms of TB (such as TB meningitis and disseminated TB). In addition, it is difficult to confirm TB disease given the paucibacillary nature of the disease (3,56). Therefore, averting paediatric TB by delivering preventive treatment is strategically important. For TPT among children, the 3HR regimen provides a better tolerated and child-friendly option compared to isoniazid, since dispersible FDC formulations are now available for young children. As data on rifapentine dosage for younger children are lacking, in the short term national programmes could consider (57) scale-up of 3HR for TB prevention among children of all age groups. Those weighing under 25 kg may receive (including children < 2 years of age) the same RH formulation used for the continuation phase of TB treatment (R/H, 75/50 mg), while children weighing more than 25 kg may either receive 3HP if it is rolled out for adults or 3HR using adult FDCs of RH. Child-friendly FDCs of RH have the added benefit of already being in the national supply chain for treatment of children < 25 kg.

Children on protease and integrase inhibitors (such as lopinavir/ritonavir, dolutegravir or nevirapinebased ART), could be given six-month isoniazid regimen. However, because of likely drug–drug interactions, due vigilance for signs of isoniazid-induced hepatitis (see section on drug–drug interactions in Chapter 6) is necessary. However, with the use of 3HR in adults the risk of hepatotoxicity is expected to be similarly high as with 6H/9H; hence 3HP may be a preferred option.

Over medium-to-long term, 3HP (or 1HP) may become the preferred regimen across all ages provided evidence on appropriate dose for children < 2 years of age as well as safety and tolerability are established, and dispersible FDC formulations of HP become available. The shorter duration of treatment with 3HP and the higher rates of treatment completion will likely make it more cost-effective in the long term. In the meantime, 3HR can be used for young children.

Key point: 3HR should be a preferred TPT option among children since child-friendly dispersible FDCs are available and already used for TB treatment. 3HP or 1HP may become the preferred option when data on dosage are available across all age groups, and adult and child-friendly FDC formulations become available, given its advantage of once-a-week or just one-month medication.

 preventive treatment options (58)4

 preventive treatment options (58)4

Note: B6 = pyridoxine, CPT = cotrimoxazole, DTG = dolutegravir, EFV = efavirenz, H = Isoniazid, LPV–RTV = lopinavir-ritonavir, NNRTI = non-nucleoside reverse transcriptase inhibitors, NVP = nevirapine, P = rifapentine, PIs = protease inhibitors, R = rifampicin, RAL = raltegravir, TAF = tenofovir alafenamide, TDF = tenofovir disoproxil fumarate

ᵃ Average available adult formulations: H-300 mg, R-300 mg/150 mg, P-150 mg.

ᵇ For women living with HIV (as well as HIV-negative) receiving rifamycin-based TPT and oral contraceptives, consider additional barrier contraception methods to prevent pregnancy.

ᶜ One randomized trial has shown increased risk of poor birth outcomes for mothers taking isoniazid during pregnancy; however, several other studies have shown benefits of IPT; hence caution is required.

ᵈ Bleeding attributed to hypoprothrombinaemia has been reported in infants and mothers following the use of rifampicin in late pregnancy. Vitamin K is recommended for both the mother and the infant postpartum if rifampicin is used in the last few weeks of pregnancy (FDA).

ᵉ Indicates that drug interaction has been studied in adults and not children; applies to adults taking DTG or RAL only.

Key point: Multiple TPT options are now recommended. National programmes should progressively transition to shorter rifamycin-based regimen given the better safety profile and better prospects of TPT completion.

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