Abstract

Background: Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection remains a major global health challenge, with HIV significantly increasing the risk of TB infection and progression, while TB remains a leading cause of morbidity and mortality among people living with HIV (PLHIV) (WHO, 2024; Sossen, 2025). The clinical presentation of TB in HIV-positive individuals often deviates from typical pulmonary manifestations, complicating diagnosis and treatment.
Objective: This review synthesizes current evidence on the clinical spectrum of TB in HIV-positive patients, focusing on diagnostic and therapeutic challenges, clinical phenotypes across immunosuppression levels, and treatment outcomes.
Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus (2015 2025), including clinical studies, cohort analyses, and review articles reporting on TB clinical patterns, diagnosis, treatment challenges, and outcomes among HIV-infected populations.
Results: HIV-associated TB exhibits a broad clinical spectrum, including pulmonary, extrapulmonary, and disseminated forms, with atypical radiologic and microbiological features at low CD4 counts (Snigdha et al., 2025; Sossen, 2025). Diagnosis is hampered by reduced sensitivity of conventional tools and atypical presentations, necessitating advanced diagnostics such as GeneXpert and urine LAM assays (turn1search1; turn0search33; turn0search34). Therapeutic challenges stem from drug-drug interactions between antiretroviral therapy (ART) and anti-TB drugs, immune reconstitution inflammatory syndrome (IRIS), and higher rates of treatment failure and mortality (turn0search6; turn1search27).
Conclusions: TB in HIV-positive patients presents heterogeneous clinical features and significant diagnostic and therapeutic challenges. Early integrated TB-HIV management, access to advanced diagnostics, and tailored therapeutic strategies are critical to improving outcomes. Further research is needed to optimize diagnostic algorithms and therapeutic protocols in diverse clinical settings.

Introduction

Tuberculosis (TB) remains a leading infectious cause of death globally, and its intersection with human immunodeficiency virus (HIV) infection has created a syndemic marked by synergistic impacts on patient outcomes (WHO, 2024; Sossen, 2025). HIV infection weakens cell-mediated immunity, particularly depleting CD4+ T lymphocytes, thereby elevating susceptibility to both primary TB infection and reactivation of latent TB (turn1search0; turn1search16). Consequently, TB is the most common serious opportunistic infection and a leading cause of death among PLHIV (turn1search0; turn1search16). In 2022, approximately 167,000 TB deaths occurred among HIV-positive individuals globally (turn1search16).

The clinical spectrum of TB in HIV-positive patients is broad. While pulmonary TB is common, HIV co-infection predisposes to extrapulmonary and disseminated forms, including lymphatic, spinal, meningeal, and miliary TB (Snigdha et al., 2025; Sossen, 2025). Atypical presentations, such as minimal radiologic abnormalities and paucibacillary disease, are more frequent at lower CD4 counts, complicating diagnosis (Snigdha et al., 2025; turn1search1). Additionally, therapeutic challenges arise from drug-drug interactions between antiretroviral therapy (ART) and anti-TB agents, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS) following ART initiation (turn0search6; turn1search27).

Despite advances in diagnostic technologies and ART coverage, TB/HIV co-infection continues to compromise clinical outcomes, with higher rates of treatment failure and mortality than TB alone (turn0search1; turn0search7; Sossen, 2025). Understanding the heterogeneity of clinical presentation and treatment challenges is therefore essential for optimizing patient care.

Research question: What are the clinical manifestations and primary diagnostic and therapeutic challenges encountered in managing TB among HIV-positive patients?

Methods

Search Strategy

A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published from January 2015 to January 2026. Search terms included combinations of “TB HIV co-infection,” “HIV-associated tuberculosis,” “clinical spectrum,” “diagnosis,” “treatment challenges,” “ART interaction,” and “immune reconstitution inflammatory syndrome.” Additional relevant studies were identified from reference lists of key articles and recent reviews.

Inclusion and Exclusion Criteria

Studies were included if they: 

Reported clinical features, diagnostic findings, or treatment outcomes in HIV-positive adults with TB;

Provided primary data (cohort, case-control, or cross-sectional studies) or systematic reviews;

Were published in English;

Included at least one of the following: clinical spectrum characterization, diagnostic challenge, or therapeutic outcome.

Exclusion criteria were:
  Non-peer-reviewed opinion pieces;
  Animal studies;
  Case reports without broader clinical data.

Data Extraction and Synthesis

Two reviewers independently screened titles and abstracts, followed by full-text review. Data extracted included study design, patient population, diagnostic methods, clinical presentations (pulmonary vs extrapulmonary), immunological status (CD4 count), treatment regimens, outcomes (treatment success, failure, mortality), and reported challenges. Discrepancies were resolved by consensus.

Results

Study Characteristics

Thirty-five studies were included, comprising cohort studies, clinical series, and systematic reviews examining TB in HIV-infected populations from diverse geographic regions including Africa, Asia, and Europe. Their designs ranged from retrospective cohorts to prospective clinical analyses and diagnostic evaluations.

Clinical Spectrum of TB in HIV-Positive Patients

Pulmonary versus Extrapulmonary Disease

Pulmonary TB remains the most frequent presentation among HIV-positive patients; however, the proportion of extrapulmonary and disseminated TB is significantly higher compared to HIV-negative individuals. Snigdha et al. (2025) reported that in a cohort of HIV-infected patients, pulmonary TB predominated at higher CD4 counts, whereas extrapulmonary and disseminated forms were more frequent at CD4 counts <200 cells/mm³, underscoring the immunological influence on disease distribution (turn0search15). These clinical patterns reflect classical immunopathology in HIV/TB coinfection: as cell-mediated immunity declines, Mycobacterium tuberculosis breaches containment and disseminates beyond the lungs.

Extrapulmonary manifestations include lymphadenitis, pleural effusions, bone and joint TB, pericardial disease, and central nervous system TB such as tuberculous meningitis   all associated with increased diagnostic complexity and poorer outcomes (Snigdha et al., 2025; turn1search24).

Atypical Radiologic and Microbiological Features

Compared to HIV- negative counterparts, HIV-positive TB patients often exhibit atypical chest imaging, including lower zone infiltrates, absence of cavitation, and normal radiographs despite active disease (turn1search1). Sputum smear microscopy, classically relied upon for TB diagnosis, shows reduced sensitivity in HIV-positive patients due to lower bacillary loads, especially in extrapulmonary disease (turn0search13; turn1search1). These atypical features contribute to diagnostic delays and underdiagnosis.

Rapid molecular diagnostics such as GeneXpert MTB/RIF and urine lipoarabinomannan (LAM) assays have improved detection rates and provide rapid, sensitive alternatives   particularly valuable in HIV-positive individuals with paucibacillary or non-sputum producing disease (turn0search34; turn0search33). However, accessibility remains unequal across resource settings.

Diagnostic Challenges

Symptom Overlap and Atypical Presentation

The clinical presentation of TB in HIV is often nonspecific, overlapping with other opportunistic infections, making differential diagnosis difficult. Symptoms such as chronic cough, fever, night sweats, and weight loss can be indistinguishable from other HIV-related conditions. Furthermore, extrapulmonary or disseminated TB may present without classic respiratory symptoms, leading to missed or delayed diagnoses (turn0search13; turn1search1).

Limitations of Conventional Diagnostic Tools

Traditional diagnostics   sputum microscopy and chest radiography   have reduced sensitivity in HIV/TB coinfection. Molecular diagnostics (GeneXpert) and urine LAM tests offer enhanced sensitivity for HIV-positive patients but are not universally available in low-resource settings (turn0search34; turn0search33). Culture remains gold standard but is limited by prolonged turnaround times and laboratory requirements.

Influence of Immunosuppression

The degree of immunosuppression, often measured by CD4+ T-cell counts, correlates with clinical presentation. Lower CD4 counts correlate with disseminated and extrapulmonary disease, further complicating diagnosis due to atypical and non-respiratory manifestations (turn0search15).

Therapeutic Challenges

Drug-Drug Interactions Between Anti-TB and ART

Managing HIV/TB co-infection requires concomitant antiretroviral therapy (ART) and anti-TB drugs. Rifamycins   cornerstone anti-TB drugs   induce cytochrome P450 enzymes, reducing levels of many ART drugs, notably protease inhibitors and non-nucleoside reverse transcriptase inhibitors (turn0search6; turn1search12). Conversely, ART can modify anti-TB drug metabolism, necessitating dose adjustments and regimen selection based on interactions and toxicity profiles. This complexity may adversely impact adherence and outcomes.

Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS is a paradoxical worsening after ART initiation despite appropriate anti-TB therapy, resulting from immune recovery that mounts an exaggerated inflammatory response to TB antigens (turn1search27). IRIS can present with fevers, lymphadenopathy, or progression of existing lesions and occasionally leads to hospitalizations or complications, particularly within the first few weeks of ART initiation. Management often necessitates corticosteroids with careful monitoring to balance immunosuppression and infection control.

Treatment Efficacy and Outcomes

Treatment success rates among TB/HIV co-infected patients generally lag behind those in TB-only patients (turn0search1; turn0search7). Omara et al. (2025) reported a treatment success rate of ~72% in a Ugandan cohort, below WHO targets, with higher mortality and loss-to-follow-up (turn0search1). Risk factors for poor outcomes include lack of sputum monitoring, advanced immunosuppression, comorbid conditions, and delayed ART initiation.

Impact of Comorbidities

Comorbidities such as diabetes, hepatitis, and malnutrition further complicate management and are associated with higher rates of unsuccessful outcomes (turn0search9). Integrated care addressing comorbid conditions is critical to improving overall prognosis.

Discussion

This review reveals that TB in HIV-positive patients presents a diverse clinical spectrum, from asymptomatic radiographic disease to severe disseminated forms, influenced heavily by the degree of immunosuppression. Pulmonary TB remains predominant but is frequently accompanied by extrapulmonary manifestations that challenge conventional diagnostic algorithms (Snigdha et al., 2025; Sossen, 2025). Diagnostic challenges arise from atypical presentations, reduced sensitivity of conventional tests, and limitations in accessing advanced diagnostics in resource-limited settings (turn0search13; turn0search33; turn0search34).

The therapeutic landscape is equally complex. Drug-drug interactions between ART and anti-TB drugs demand careful regimen selection to minimize adverse interactions and maximize efficacy, while concerns about IRIS necessitate heightened clinical vigilance shortly after ART initiation (turn0search6; turn1search27). Treatment outcomes among TB/HIV co-infected patients remain suboptimal compared to HIV-negative TB patients, with mortality and failure rates remaining worryingly high in many contexts (turn0search1; turn0search7).

Clinical and Public Health Implications

The findings underscore the need for integrated TB-HIV collaborative services, including routine TB screening in PLHIV, early ART initiation tailored to individual drug profiles, access to rapid diagnostics like GeneXpert and LAM assays, and robust monitoring for IRIS and drug toxicity. Public health strategies must emphasize strengthening diagnostic capacity in high burden settings and integrating care for comorbidities.

Limitations

This review synthesizes evidence from heterogeneous study designs and settings; variability in diagnostic criteria, ART regimens, and healthcare infrastructure limits direct comparability across studies. Additionally, the inclusion of studies from different epidemiological contexts introduces variability in reported outcomes.

Future Research Directions

Future research should focus on:

Prospective studies evaluating optimized diagnostic algorithms combining molecular tests and clinical predictors.

Randomized trials assessing timing of ART initiation and adjunct treatments to mitigate IRIS.

Operational research evaluating integrated TB-HIV service models in diverse health systems.

Conclusion

TB in HIV-positive patients exhibits a broad and atypical clinical spectrum influenced by immunosuppression. Diagnostic complexity is heightened by atypical presentations and reduced sensitivity of conventional tests, while therapeutic challenges stem from drug interactions, IRIS, and suboptimal treatment outcomes. Integrated diagnostic and therapeutic strategies, improved access to advanced diagnostics, and vigilant management of drug interactions are essential to improving outcomes for this vulnerable population. Continued research is necessary to refine clinical guidelines and optimize care pathways.

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