Incidence and audiometric outcomes of hearing loss among tuberculosis patients receiving all-oral treatment regimens: A prospective cohort study in Nigeria

INTRODUCTION

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains one of the leading causes of infectious disease morbidity and mortality worldwide.^[1] According to the World Health Organization (WHO), an estimated 10.6 million people developed TB and 1.3 million died from the disease in 2022, with the highest burden occurring in low- and middle-income countries, particularly in subSaharan Africa.^[1,2] Nigeria ranks among the top high-burden countries globally, accounting for a substantial proportion of incident TB cases and deaths, thereby highlighting the need for continued evaluation of treatment outcomes and adverse effects in this setting (Zumla et al., 2015; WHO, 2020).^[1,2]

In addition to its pulmonary and systemic manifestations, TB and its treatment may adversely affect auditory function. TB can directly involve the auditory system through tuberculous otitis media, resulting in conductive hearing loss due to granuloma formation, ossicular destruction, and tympanic membrane perforation.^[3-5] However, of greater clinical concern is sensorineural hearing loss (SNHL) resulting from the ototoxic effects of anti-TB medications. Ototoxicity primarily occurs through damage to cochlear hair cells, spiral ganglion neurons, and supporting structures, often mediated by oxidative stress, mitochondrial dysfunction, and apoptosis.^[6-8] Such hearing impairment may be permanent and significantly reduce quality of life, communication ability, and treatment adherence.^[9]

Historically, hearing loss among TB patients has been strongly associated with the use of injectable aminoglycosides such as streptomycin, kanamycin, and amikacin, which were integral components of multidrug-resistant TB (MDR-TB) treatment regimens.^[10-12] These agents have well-established ototoxic potential, with reported hearing loss incidence ranging from 18% to over 60% depending on treatment duration, cumulative dose, and monitoring methods.^[10,13] The high frequency and severity of aminoglycoside-induced ototoxicity contributed to poor treatment adherence and long-term disability among TB survivors.^[14]

In response to these concerns, the WHO has recommended all-oral regimens for drug-resistant TB, replacing injectable agents with newer and repurposed oral medications such as bedaquiline, linezolid, and fluoroquinolones.^[2,15] These regimens have improved treatment outcomes, reduced toxicity, and enhanced patient acceptability.^[16,17] However, emerging evidence suggests that some second-line oral agents, including fluoroquinolones, may still have potential auditory effects, although at substantially lower frequencies than aminoglycosides.^[18,19] Consequently, concerns remain regarding the audiological safety of newer MDR-TB regimens, particularly in real-world programmatic settings.

Despite the transition to all-oral regimens, there is limited prospective evidence evaluating hearing outcomes among TB patients receiving these newer treatments, especially in high-burden countries such as Nigeria. Most previous studies reporting high ototoxicity rates were conducted during the era of injectable-based therapy and may not reflect current treatment practices.^[10,20] Furthermore, few studies have prospectively compared hearing outcomes between patients with drug-susceptible (DS-TB) and MDR-TB receiving contemporary oral regimens using standardized audiometric monitoring.

Understanding the incidence and pattern of hearing loss associated with modern TB treatment is essential for improving patient safety, informing clinical monitoring protocols, and guiding treatment policy. Early identification of ototoxicity allows timely intervention, which may prevent permanent disability and improve quality of life.

Therefore, this study aimed to determine the incidence of hearing loss and evaluate audiometric outcomes among patients with DS and MDR-TB receiving all-oral anti-TB regimens at a tertiary health institution in Nigeria.

MATERIALS AND METHODS

RESULTS

DISCUSSION

In this prospective cohort study conducted in a high TB burden setting, we found that the overall incidence of SNHL among patients receiving all-oral anti-TB therapy was low (4.1%) after 3 months of treatment. However, the risk was substantially higher among patients treated for MDRTB, with an incidence of 16.7%, compared with only 1.3% among those receiving treatment for DS-TB. These findings highlight that although all-oral regimens have reduced the risk of ototoxicity compared with historical injectable-based regimens, hearing impairment remains an important potential adverse effect, particularly among MDR-TB patients.

The overall low incidence observed in this study is consistent with emerging evidence demonstrating improved safety profiles of contemporary all-oral TB regimens. The shift away from injectable aminoglycosides followed recommendations by the WHO, which prioritized oral regimens to improve tolerability and reduce permanent disability.^[2,15] Injectable agents such as kanamycin and amikacin have well-established ototoxic effects mediated through oxidative stress and irreversible cochlear hair cell damage.^[6,7] Earlier studies conducted during the injectable era reported substantially higher hearing loss incidence, including 22.9% in Nigeria,^[13] 58% in Namibia,^[10] and 61% in southern Nigeria.^[20] The markedly lower incidence observed in our study supports the growing evidence that elimination of aminoglycosides has significantly reduced ototoxicity risk.

Despite the overall reduction in incidence, our finding of a significantly higher risk among MDR-TB patients is notable. Similar findings have been reported in recent studies evaluating newer oral regimens. For example, KhozaShangase and Prodromos reported measurable hearing function deterioration in MDR-TB patients receiving bedaquiline-based therapy^[19] although the incidence was lower than that associated with injectable agents. This suggests that while newer regimens are safer, the risk of ototoxicity has not been completely eliminated.

Possible explanations include cumulative drug exposure, mitochondrial susceptibility, and potential ototoxic effects of certain oral agents such as fluoroquinolones, which have been shown in experimental models to affect cochlear function.^[8,18] In addition to treatment-related factors, it is also plausible that TB itself may contribute to cochlear vulnerability through systemic inflammation, immune-mediated mechanisms, or microvascular compromise.^[1] This suggests that hearing impairment in TB patients may be multifactorial, reflecting both disease-related and treatment-related effects. Therefore, attributing observed auditory changes solely to pharmacologic exposure should be approached with caution.

Importantly, although 4.1% of participants developed clinically significant hearing loss, mean audiometric thresholds across treatment groups did not differ significantly compared with controls. This suggests that most patients tolerate these regimens without measurable audiometric deterioration over short-term follow-up. However, it is important to note that small upward shifts in audiometric thresholds, even when remaining within the clinically normal range, may represent early subclinical cochlear changes. Such shifts have been described as potential early markers of ototoxicity, particularly in the context of cumulative drug exposure.^[8] Higher frequencies (6–8 kHz), which are typically more sensitive to early ototoxic damage, may demonstrate subtle changes before clinically significant hearing loss becomes apparent.^[8]

In our study, while extended high-frequency audiometry was not available, the observed pattern of threshold changes suggests the need for cautious interpretation and continued monitoring. Similar findings were reported by another study that observed improved safety and tolerability among patients receiving all-oral MDR-TB regimens in programmatic settings.^[16] The absence of significant threshold shifts in the majority of patients supports the safety advantage of oral regimens and reinforces their continued use as standard of care.

The higher incidence of hearing loss observed among MDRTB patients compared with those with DS-TB may reflect several factors. MDR-TB treatment typically involves a greater number of drugs, longer duration of therapy, and exposure to second-line agents with less well-characterized toxicity profiles.^[15,28] In addition, patients with MDR-TB often have more severe disease and prior treatment exposure, which may increase vulnerability to adverse drug effects. These findings highlight the importance of continued audiological monitoring in MDR-TB patients, even in the absence of injectable therapy.

An important consideration in interpreting these findings is the relatively short duration of follow-up. Ototoxicity associated with some second-line anti-TB agents, including linezolid and fluoroquinolones, may have a delayed onset and may not be fully captured within a 3-month period.^[16,18] Consequently, the incidence reported in this study may underestimate the true burden of hearing impairment over the full course of treatment. Longer-term audiometric monitoring is therefore recommended in future studies to better characterize the temporal pattern and cumulative risk of ototoxicity.

Our findings have important clinical and public health implications. Hearing loss can significantly impair communication, reduce quality of life, and negatively affect treatment adherence.^[29] In resource-limited settings such as Nigeria, where access to hearing rehabilitation services is limited, prevention and early detection of ototoxicity are particularly important. Routine audiometric monitoring should therefore remain an integral component of MDRTB management programs, consistent with international recommendations.^[30] This is particularly important given the potential for subclinical auditory changes and delayed-onset ototoxicity, which may not be evident during early treatment phases.^[8,16]

This study adds to the limited prospective evidence evaluating hearing outcomes associated with contemporary all-oral TB regimens in sub-Saharan Africa. Most previous studies in the region evaluated injectable-based regimens and reported substantially higher ototoxicity rates.^[10,13] By focusing on newer oral regimens, our findings provide important evidence supporting their improved safety profile in real-world clinical practice.

CONCLUSION

This prospective cohort study suggests a low overall incidence of hearing loss among TB patients receiving contemporary all-oral regimens. However, patients treated for MDR-TB appeared to have a higher risk than those with DS disease. Although injectable-free regimens are associated with improved auditory safety, ototoxicity may not be fully eliminated. Continued audiological monitoring and longer-term studies are recommended, particularly for MDR-TB patients.