• drug induced lung disease
• respiratory infection
• viral infection

Accelerated lung function decline is relatively common from the late 20s and indicates chronic lung disease in many communities, including those living with HIV.1 2 The factors influencing and mechanisms of lung function decline in people living with HIV (PLWH) or without HIV are complex and multifactorial.2 This includes changes in the lungs and respiratory system, decreased muscle mass, and decreased lung elasticity. As we age, the lungs lose their ability to expand and contract as quickly, which can lead to a decrease in lung capacity and difficulty breathing.3 Other factors, such as smoking, exposure to pollution and chronic health conditions, can also accelerate lung function decline.4 5

Previous studies demonstrated that PLWH who are receiving adequate treatment may also have a higher prevalence of chronic respiratory disease, includingchronic obstructive pulmonary disease (COPD), emphysema and lung function decline compared with those without HIV; the decline could be even faster.2 6 This is likely due to the chronic inflammation and damage to the immune system caused by HIV, which can lead to an increased risk for lung infections and other lung-related complications.6 However, with the advancement of antiretroviral therapy (ART), PLWH can now expect a much longer life expectancy and a better quality of life. When taken correctly, ART can reduce the amount of viral load in the body by suppressing the virus and improving the immune system, preventing HIV to AIDS, but it may not entirely prevent lung function decline.7 Furthermore, long-term use of certain classes of ART drugs, such as nucleoside reverse transcriptase inhibitors and protease inhibitors, can cause some side effects, such as lipodystrophy, which can also contribute to lung function decline.8 However, cross-sectional studies conducted to date have limitations, and prospective cohort studies were limited with inappropriate selection of controls and also lack of adjustment with potential confounders, which were needed to discern the role of HIV infection on lung function decline.

In this issue, Thudium et al reported results from the large prospective matched cohort study, including ART-treated PLWH from the Copenhagen Comorbidity in HIV Infection Study and the INSIGHT Strategic Timing of Antiretroviral Treatment Pulmonary Substudy and matched controls from the Copenhagen General Population Study.9 Over a median follow-up of 2.5 years for cohorts with PLHW and 10.4 years in controls, the analysis included participants from two cohorts and matched controls aged ≥25 years with two pre bronchodilator (BD) spirometry separated by at least 2 years of follow-up. The analysis only included PLWH who received ART treatment for a minimum of 6 months at baseline.

Forced expiratory volume in 1 s (FEV1) declined over time in all participants, and rapid declines in FEV1 >40 mL/year and forced vital capacity (FVC) were observed in well-treated PLWH compared with controls, similar to that seen in other healthy population-based cohorts.10 11 The authors reported that the associations were largely modified by smoking, and a faster lung function decline was observed in never-smokers, suggesting HIV-related factors independent of smoking in the pathogenesis of the condition. The baseline smoking was adjusted, as well as several sensitivity analyses were performed, including stratified analysis by smoking, cumulative tobacco consumption as a confounder in the model, restricting the analysis to Caucasians and use of Z-score to define lung function.

Previous study has shown that the decline in lung function is more rapid in PLWH who smoke than those who do not smoke.6 Notably, Thudium et al reported an interaction between HIV and smoking with lung function decline that may indicate a synergistic effect between HIV and smoking on lung function, particularly for PLWH who are well treated with ART compared with controls.9 Smoking can worsen the inflammation caused by HIV and interact with ART, reducing the effectiveness of the drugs and increasing the risk of drug resistance.12 The author of this study also reported that the nadir CD4 count and longer time living with HIV were independently associated with faster decline of FEV1 and FVC, supporting the hypothesis that HIV-related factors may lead to decline in lung function for PLWH.

The study also found a rapid FEV1 decline of more than 40 mL/year, which was present in a higher number of smokers and non-smokers, and was also associated with HIV in the adjusted analysis. This further indicates that PLWH who were non-smokers had higher risk of faster lung function decline leading to obstructive and restrictive airway disease compared with controls. They also described that PLWH who were smokers even had more considerable lung function decline compared with matched controls who currently smoked. The study highlights the importance of careful respiratory health monitoring and smoking cessation among PLWH. This has not been investigated in earlier studies.

There are a few methodological limitations in the current study that need to be considered when interpreting the results, some of which were discussed by the authors. The controls were followed up for years longer than the PLWH. Given that there were only two lung function measures per group, this makes it difficult to account for temporal impacts on the lung function decline slope. The authors also mentioned survival bias in the controls, but another potential factor is time after starting ART, which is an initial improvement in lung function usually seen after ART initiation and then a plateau in trajectory. Lung function was measured pre-BD in some and post-BD in other participants.

There are still a few questions that the study did not address. The majority of the participants are Caucasians (>70%) in PLWH and 99.9% in the controls, as well as only a few females. That raised questions about whether women and other ethnic populations have accelerated lung function decline.13 Despite the limitations, the current study contributes significantly to our understanding that PLWH have a more rapid lung function decline; however, other contributors like smoking and air pollution need to consider in future research to fully understand the underlying causes of accelerated lung function decline in these populations. Regular monitoring of lung function, adherence to HIV treatment and management of other risk factors specifically smoking can help slow lung function decline.