Antiretroviral Therapy-Naïve People Living with HIV Tend to Have More Severe Symptoms of COVID-19
The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had profound economic and public health impacts worldwide. Concurrently, the human immunodeficiency virus (HIV) continues to pose a significant global health challenge, with approximately 39 million people living with HIV (PLWH) as of the end of 2022. Among these individuals, an estimated 9.2 million have not received antiretroviral therapy (ART), potentially placing them at a higher risk of immunodeficiency compared to those on ART. Despite the overlapping challenges posed by HIV and COVID-19, limited research has focused on the impact of COVID-19 on PLWH, particularly those who are ART-naïve. This study aims to address this gap by comparing the severity of COVID-19 between ART-experienced and ART-naïve PLWH through a retrospective case-control analysis.
The study was conducted at the Shanghai Public Health Clinical Center (SPHCC) and received ethical approval from the SPHCC Ethics Committee. Due to the retrospective and anonymous nature of the data analysis, the committee waived the requirement for written informed consent from participants. The study employed a case-control design with a 1:2 allocation ratio, reflecting the relatively low prevalence of cases in the target population. The sample size was calculated to ensure a two-tailed test with a significance level of 0.05 and a power of 0.9, resulting in a minimum requirement of 44 cases and 88 controls.
Medical records of patients co-infected with HIV and SARS-CoV-2, hospitalized between March 2022 and July 2023, were meticulously reviewed. Key parameters included age, gender, CD4+ T cell count, CD4+ T cell/CD8+ T cell ratio, HIV RNA viral load, ART history, specific ART regimen and duration, comorbidities, clinical manifestations, imaging findings of COVID-19 pneumonia, COVID-19 vaccination status, and duration of SARS-CoV-2 viral shedding. CD4+ T cell count, CD4+ T cell/CD8+ T cell ratio, and HIV RNA viral load were derived from the most recent test results post-COVID-19 diagnosis. Clinical symptoms such as fever, cough with expectoration, chest tightness, weakness, and peak body temperature were documented. Radiologically, COVID-19 pneumonia was characterized by bilateral ground-glass opacities and infiltrative patterns. Viral shedding time was defined as the interval from the first positive nucleic acid test result to its eventual negation.
Participants were categorized into ART-naïve and ART-experienced groups based on whether they were undergoing ART at the time of COVID-19 diagnosis. The clinical classification of COVID-19 severity followed the Corona Virus Disease 2019 Diagnosis and Treatment Program (Trial 10th Edition), which includes asymptomatic, mild, moderate, severe, and critical categories. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared using Student’s t-test, while non-normally distributed variables were expressed as median and interquartile range (IQR) and compared using the Wilcoxon rank-sum test. Categorical variables were expressed as frequency (percentage) and compared using the chi-square test. Statistical analyses were performed using Stata Statistical Software 16, and graphs were generated using GraphPad Prism version 9.0.0.
The study enrolled 132 participants, including 125 males and 7 females, with an average age of 45 years. The median CD4+ T cell count and CD4+ T cell/CD8+ T cell ratio were 72.58 cells/mm3 and 0.21, respectively, and the median HIV RNA viral load was 5.13 log10 copies/mL. Opportunistic infections were present in 34.85% of participants, with fungal infections being the most common. Comorbidities were observed in 51.51% of participants, with lymphoma being the most prevalent. Additionally, 74.24% of participants had received the SARS-CoV-2 vaccine.
The ART-naïve group consisted of 44 participants, while the ART-experienced group included 88 participants. The ART-naïve group was younger on average (41.52 years vs. 47.46 years) and had significantly lower CD4+ T cell counts (18.34 cells/mm3 vs. 127.94 cells/mm3) and CD4+ T cell/CD8+ T cell ratios (0.07 vs. 0.58) compared to the ART-experienced group. Conversely, the ART-naïve group had higher HIV RNA viral loads (5.83 log10 copies/mL vs. 1.34 log10 copies/mL) and a higher proportion of opportunistic infections (52.27% vs. 25.64%). There was no significant difference in COVID-19 vaccination rates between the two groups. In the ART-experienced group, the median duration of ART was 4 years, with non-nucleoside reverse transcriptase inhibitors (NNRTIs) being the most commonly used regimen.
Clinical manifestations of COVID-19 were more severe in the ART-naïve group. Fever, cough with expectoration, chest tightness, and weakness were all more prevalent in the ART-naïve group compared to the ART-experienced group. The maximum fever temperature was also higher in the ART-naïve group (39.05°C vs. 38.71°C), and a greater proportion of ART-naïve participants exhibited imaging manifestations of COVID-19 pneumonia (54.54% vs. 23.86%). Consequently, the ART-naïve group had a lower percentage of mild and asymptomatic cases (45.45% vs. 76.14%) and a higher proportion of moderate, severe, and critical cases.
Ordinal logistic regression analysis identified the absence of ART as a significant risk factor for COVID-19 severity among PLWH, with an odds ratio (OR) of 5.06. Other factors such as age, COVID-19 vaccination status, comorbidities, and low CD4+ T cell count were not significantly associated with disease severity. Kaplan-Meier analysis revealed that the median viral shedding time was significantly longer in the ART-naïve group compared to the ART-experienced group (30 days vs. 15 days).
The heightened severity of COVID-19 in ART-naïve PLWH can be attributed to several factors. First, the absence of ART likely results in greater immune suppression, impairing the ability to clear SARS-CoV-2 and increasing susceptibility to opportunistic infections. The median CD4+ T cell count in the ART-naïve group was alarmingly low at 18 cells/mm3, indicating profound immunosuppression. This finding aligns with studies in other immunocompromised populations, such as organ transplant recipients and individuals with hematologic malignancies, who also exhibit more severe COVID-19 outcomes.
Second, ART-experienced PLWH with well-controlled HIV typically exhibit COVID-19 outcomes similar to those of HIV-negative individuals. This suggests that effective ART not only preserves immune function but may also mitigate COVID-19 severity through mechanisms such as ribonucleic acid polymerase inhibition and modulation of inflammatory pathways. Notably, a significant proportion of ART-experienced participants in this study were on tenofovir-based regimens, which have been associated with reduced COVID-19 severity.
The prolonged viral shedding observed in the ART-naïve group is consistent with previous studies linking lower CD4+ T cell counts to extended SARS-CoV-2 shedding durations. The median viral shedding time in the ART-experienced group (15 days) was comparable to that reported in non-HIV individuals, further underscoring the role of ART in mitigating COVID-19 severity.
Despite its contributions, this study has several limitations. Its retrospective design introduces the potential for recall bias and missing data, such as viral load measurements for some participants. The higher prevalence of opportunistic infections in the ART-naïve group could be confounded by factors such as Pneumocystis jirovecii pneumonia, which were not specifically addressed. Additionally, the study focused solely on hospitalized patients, limiting its generalizability to outpatient populations.
In conclusion, this study demonstrates that ART-naïve PLWH experience more severe COVID-19 symptoms and prolonged viral shedding compared to ART-experienced PLWH. These findings underscore the importance of initiating ART promptly upon HIV diagnosis to mitigate the severity of COVID-19 and improve clinical outcomes.
doi.org/10.1097/CM9.0000000000002902
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