Cytomegalovirus (CMV) is a betaherpesvirus found in 50-100% of the human population. Primary CMV infection typically occurs during childhood, often with minimal or no symptoms, followed by latent infection throughout life in CD34+ myeloid progenitor cells. Latent CMV infection in healthy individuals is controlled by a well-functioning immune system, thus not causing symptoms. However, in HIV patients or those with immunocompromised conditions, CMV can reactivate or when CD4 counts are <200 cells/mm³, leading to clinical manifestations in various organs, which can increase the risk of mortality. This is due to impaired cellular immunity that hinders control over CMV replication, thereby increasing the risk of severe clinical manifestations such as retinitis, colitis, and encephalitis.¹

Cytomegalovirus manifestations such as retinitis, pneumonitis, and colitis are the most commonly found CMV manifestations in Africa. Individuals infected with HIV who are CMV seropositive will progress to acquired immunodeficiency syndrome (AIDS) more rapidly, approximately 30 months, and will experience more aggressive disease compared to patients who are CMV seronegative.² A large study in the United States in 2021 analyzing more than 2,000 HIV patients showed that although ART has significantly reduced the incidence of CMV retinitis, CMV is still found in 15% of patients with CD4 <50/uL and associated with increased long-term mortality. This suggests that even HIV-controlled patients can experience subclinical CMV reactivation, which increases systemic inflammation.³

Cytomegalovirus infection in HIV patients who have started ARV therapy has been found to be associated with advanced infection. Studies on the factors that contribute to the clinical manifestation of CMV in HIV patients are rare, particularly in Indonesia. This study aims to identify the factors that contribute to the clinical manifestation of CMV in HIV patients.

This study is an analytical observational study using a cross-sectional design among patients diagnosed with HIV and CMV who were hospitalized and outpatient clinic of Wahidin Sudirohusodo Hospital, Makassar, Indonesia, from February - July 2025.

A total of 160 patients were diagnosed with HIV and CMV. Patients were grouped into two categories based on the presence or absence of clinical manifestations of CMV. Inclusion criteria involved patients over 18 years of age diagnosed with HIV and CMV. The sampling technique used in this study was consecutive sampling, meaning all eligible population members were directly included in the study according to the specified time period.

HIV diagnosis was confirmed based on ELISA (Enzyme-linked immunoassay) test. CMV diagnosis was confirmed based on serological test (IgG and IgM anti-CMV). Data analysis was performed using SPSS version 25. The statistical test used was the Chi-square test. Statistical test results were considered significant if the p-value was <0.05.

This study involved 160 patients diagnosed with HIV. 83.8% were male and 16.2% were female. 80% of patients were <45 years old and 20% were >45 years old. 70% had low-risk occupations and 30% had high-risk occupations. Disease duration was <1 year in 20%, 1–5 years in 33.8%, and >5 years in 45.6%. 66.3% received the Teladi therapy regimen and 33.8% received Tenolam E. CD4 counts were <200 cells/µL in 58.8% and >200 cells/µL in 41.3%. Most patients had no comorbidities (70.6%), while 29.4% had comorbid conditions. (Table 1)

Table 1. Study characteristics

In this study, factors contributing to the clinical manifestations of CMV infection in HIV patients were analyzed. The factors evaluated in this study included gender, age, occupation, duration of illness, type of treatment regimen, CD4 count, and comorbidities. It was found that gender, age, length of illness, type of treatment regimen, and CD4 count were significantly associated with clinical manifestations of CMV in HIV patients.

Male patients were 7.2-fold to experience clinical manifestations of CMV than female patients (OR = 7.2, 95% CI = (2.35 – 22.10), p = 0.000). Age < 45 years was 2.2-fold to experience clinical manifestations of CMV compared to age > 45 years (OR = 2.2, 95% CI = (0.99–5.01), p = 0.048). Lenght of illness < 1 year is 4.4-fold and 1–5 years is 2.8-fold to experience clinical manifestations of CMV compared to those >5 years of illness (OR = 4.4, 95% CI = (1.88–10.71), p = 0.001) and (OR = 2.8, 95% CI = (1.35–5.78), p = 0.001). Patients receiving the telado therapy regimen had a 0.5-fold developing clinical manifestations of CMV compared to those receiving tenolam E (OR = 0.5, 95% CI = (0.26–0.99), p = 0.045). Patients with CD4 counts below 200 cells/µL were 10-fold to experience clinical manifestations of CMV than those with CD4 > 200 cells/µL (OR = 10.10, 95% CI = (4.76 – 21.49), p = 0.000). (Table 2)

Table 2. Analysis of factors contributing to the clinical manifestation of cytomegalovirus in HIV patients

Multivariate analysis was performed on variables significantly associated with clinical manifestations based on the results of previous analyses, specifically Gender, Age, Length of Illness, Regimen Therapy, and CD4 Value. The analysis results indicated that CD4 value and gender were the most significant factors associated with clinical manifestations. Based on the odds ratio values, patients with CD4 < 200 cells/µL had a 10.2-fold higher risk of developing clinical manifestations compared to patients with CD4 > 200 cells/µL, and males had a 7.4-fold higher risk of developing clinical manifestations compared to females. (Table 3)

Table 3. Multivariate analysis of factors contributing to the clinical manifestation of cytomegalovirus in HIV patients

This study involved 160 patients diagnosed with HIV and CMV at Wahidin Sudirohusodo Hospital in Makassar during the study period from February to July 2025 to determine the factors that contribute to the clinical manifestations of cytomegalovirus (CMV) in HIV patients.

This study found an association between gender and clinical manifestations of CMV in HIV patients. It was found that males were 7.2-fold more likely to experience clinical manifestations of CMV than females (OR = 7.2, 95% CI = (2.35–22.10), p = 0.000). In this study, the majority of the study sample were males 134 patients (83.8%), while females 26 patients (16.3%). The study showed that CMV DNA was more frequently detected in HIV-positive men than in women. In a cohort study in the United States, 53% of men had detectable CMV DNA compared to only 29% of women. This suggests that CMV reactivation occurs more frequently or is more easily detected in men.⁴

A study in Nigeria found that among HIV-infected individuals undergoing antiretroviral therapy, CMV IgM antibodies were detected in 18.3% of men and 9.4% of women, indicating a higher rate of CMV infection in men. CMV IgG antibodies, which indicate previous infection, were found in 76.3% of men and 72.7% of women.⁵ Another study has shown that CMV is commonly found among HIV-positive men, particularly men who have sex with men (MSM). In a sexually active group of HIV-infected MSM in Southern California, 85% showed detectable CMV DNA over a 48-week period. This occurrence was observed in various mucosal sites, including genital secretions, and was associated with younger age but not with CD4⁺ T-cell count, HIV RNA levels, duration of HIV infection, or use of antiretroviral therapy (ART).⁶

In this study, it was found that individuals under the age of 45 were 2.2-fold more likely to experience clinical manifestations of CMV compared to those over the age of 45 (OR = 2.2, 95% CI = (0.99–5.01), p = 0.048). The relationship between age and cytomegalovirus (CMV) infection in HIV patients involves numerous factors, including immunological and clinical aspects. CMV infection remains a significant issue in HIV patients, particularly those with advanced immunosuppression. Age is a factor influencing CMV reactivation; however, its effects vary among HIV-positive individuals. A retrospective study analyzing CMV infection in HIV-infected patients during Combination Antiretroviral Therapy (cART) found that CMV infection was found on average at the age of 39 years.⁷

The duration of HIV infection significantly affects the risk and progression of CMV in HIV patients. Chronic HIV infection, especially without effective antiretroviral therapy (ART), causes sustained immunosuppression, thereby increasing susceptibility to opportunistic infections such as CMV.  In this study, it was found that the length of illness of less than 1 year was associated with a 4.4-fold risk and 1–5 years with a 2.8-fold risk of experiencing clinical manifestations of CMV compared to those who had been ill for more than 5 years (OR = 4.4, 95% CI = (1.88–10.71), p = 0.001). and (OR = 2.8, 95% CI = (1.35–5.78), p = 0.001). However, studies show that CMV infection is associated with a shorter duration of HIV disease at diagnosis. In a study of HIV-infected individuals, those infected with CMV had a shorter duration from HIV diagnosis (19.1 months) compared to those not infected with CMV (49.5 months).⁸

This study found that patients with CD4 counts less than 200 cells/µL were 10-fold to experience clinical manifestations of CMV than those with CD4 counts greater than 200 cells/µL (OR = 10.10 CI 95% = (4.76 – 21.49) p= 0.000). CMV infection remains a significant opportunistic infection in individuals with advanced HIV, especially those with low CD4+ T cell counts. Fang et al. found that CMV with clinical manifestations such as retinitis and gastrointestinal disorders were present in HIV patients with CD4 counts less than 50 cells/µL.⁹ A study analyzing 808 HIV/AIDS patients found that the prevalence of CMV infection increased with decreasing CD4 counts and increasing HIV viral load. This underscores the importance of monitoring these parameters to assess CMV risk.¹⁰

This study shows that male gender, age less than 45 years, length of illness less than 5 years, type of therapy, and CD4 count are associated with clinical manifestations of CMV in HIV patients. A large-scale study involving multiple healthcare facilities is needed to validate these findings.

ACKNOWLEDGEMENT

This research was supported by the Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia

FUNDING

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

ETHICS COMMITTEE APPROVAL

This research was approved by the Ethics Committee for Biomedical Research on Humans, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia. Based on recommendation letter Number: 149/UN4.6-4.5.3U PP36l 2025

STATEMENT OF CONFLICT OF INTEREST

Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interests, patent/licensing arrangements, etc.) that might give rise to a conflict of interest with respect to the submitted article.

AUTHOR CONTRIBUTIONS

RC (Concept, Design, Sources, Materials, Data Collection and Processing, Analysis and Interpretation, Literature Search, Manuscript Writing). SK (Concept, Design, Supervision, Analysis and Interpretation, Literature Search). HK (Concept, Design, Supervision, Analysis and Interpretation, Literature Search). SB (Concept, Design, Supervision, Analysis and Interpretation, Literature Search).  AMA (Concept, Design, Supervision, Analysis and Interpretation, Literature Search). AS (Concept, Design, Analysis and Interpretation, Critical Review). All authors were involved in drafting the manuscript, revising it, and evaluating its content. They have all read and approved the manuscript, confirming the accuracy and integrity of the research details. All author read and approve the final manuscript.

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