Tuberculosis (TB) and HIV coinfection poses a significant challenge, especially in developing countries. In 2023, TB affected millions worldwide, causing over a million deaths, with a substantial number occurring in HIV-positive individuals. The economic burden is immense, with an estimated loss of $30 trillion from 2020 to 2050.
Many patients with TB-HIV coinfection undergo antiretroviral treatment (ART) alongside anti-TB therapy, leading to potential drug interactions and adverse effects. This is a critical issue, as TB treatment success rates are lower for HIV-positive individuals.
Anti-TB medications have unique properties, and research suggests that low body weight can impact drug clearance, especially in HIV-TB coinfected individuals. This nonlinear relationship is further complicated by HIV, which can cause malnutrition and affect drug pharmacokinetics. Additionally, HIV patients may experience reduced drug clearance due to impaired transporter function and enzyme expression.
Pharmacogenetics, the study of how genetic variations influence drug metabolism, is crucial in understanding these interactions. Certain genes, like NAT2, impact the metabolism of anti-TB and ART medications. For example, the NAT2 slow acetylator phenotype can lead to increased isoniazid concentrations and hepatotoxicity. Similarly, CYP2B6 poor metabolizers may have elevated efavirenz blood concentrations, requiring dosage adjustments.
Drug-gene interactions are complex and can vary between individuals. Host genetic factors can influence susceptibility and treatment outcomes in TB and HIV patients. Pharmacogenes, which regulate drug metabolism, can impact the activity of enzymes like CYPs, UGTs, and NATs. Alterations in pharmacokinetics can result in suboptimal drug concentrations, increasing the risk of toxicity or treatment failure.
The interplay between drugs, genes, and diseases is intricate, and TB-HIV coinfection adds another layer of complexity. Current guidelines primarily focus on CYP2B6 genotyping and efavirenz dosing in HIV patients, but more research is needed to understand the unique pharmacogenetic profiles of TB-HIV populations.
This systematic review aims to fill this gap by assessing pharmacogenetic factors related to ART and anti-TB medications in TB-HIV coinfected patients. It highlights the need for further research and the potential economic benefits of pharmacogenetic testing.
The review includes 39 studies, with most focusing on efavirenz pharmacokinetics. It identifies serious biases in participant selection and confounding factors. The primary CYPs involved in TB-HIV medication interactions are CYP3A4 and CYP2B6.
The review also explores the impact of genetic variations on antiretroviral response, with efavirenz being the most studied drug. CYP2B6*6 polymorphism, for instance, can elevate efavirenz concentrations, and dosage recommendations vary based on genotype.
Similarly, genetic variations influence the anti-TB response. Isoniazid, the most studied anti-TB drug, is associated with several genes, including NAT2, SLCO1B1, and PXR. Slow acetylators may have higher isoniazid concentrations and an increased risk of hepatotoxicity.
The review concludes that the interpretation of pharmacogenetic results in TB-HIV populations may differ from those with only TB or HIV. It emphasizes the need for high-quality research, such as randomized controlled trials, to guide clinical practice and improve treatment outcomes.
Despite the challenges, pharmacogenetic testing has the potential to enhance treatment efficacy and reduce adverse reactions. However, implementation in low- and middle-income countries requires addressing policy, reimbursement, and healthcare system barriers.
In conclusion, this systematic review highlights the complex interplay between drugs, genes, and diseases in TB-HIV coinfection. It underscores the importance of further research and the potential benefits of pharmacogenetic testing in improving treatment outcomes and patient care.
