Immediate ART in Subjects With Opportunistic Diseases

Impact of the Timing of Antiretroviral Therapy Initiation (Immediate Versus Early) on the Mortality Rate of HIV/AIDS Patients Hospitalized With an Opportunistic Disease

The aim of this study is to compare the clinical response and mortality rate due to opportunistic disease in HIV-infected individuals who start immediate versus conventional antiretroviral therapy (ART).

Immediate ART (iART) is defined as starting antiretroviral therapy within the first 48 hours after hospitalization. Conventional ART (cART) is defined as starting antiretroviral therapy once the opportunistic infection is under control at the discretion of the infectious disease specialist.

This is an open-label, randomized clinical trial conducted at the Center for Research in Infectious Diseases (CIENI) of the National Institute of Respiratory Diseases "Ismael Cosío Villegas" (INER) in Mexico City. Adults (≥18 years) with confirmed HIV diagnosis and active opportunistic infections or AIDS-related malignancies are eligible. Participants must be ART-naïve or have discontinued ART for at least 3 months. Key exclusions include suspected cryptococcal meningitis, tuberculous meningitis, or cytomegalovirus retinitis.

Sample Size Calculation Sample size was calculated using a difference in proportions formula with 95% confidence level, 90% power, and 5% expected difference between groups. Based on 2022 hospitalization data (145 patients with HIV hospitalized) and a 6.9% mortality rate, assuming a 5% absolute reduction in mortality (from 6.9% to 1.9%) in the experimental group, the initial required sample size was 359 participants. This was adjusted for finite population (n=145), yielding 103 participants. Accounting for an anticipated 10% loss to follow-up, the final sample size was set at 114 participants (57 per group).

Study Procedures

Participants are stratified by CD4+ T-cell count (<50 vs. ≥50 cells/μL) and randomized 1:1 to either:

• Immediate ART (iART): Initiation of ART within 48 hours of hospital admission
• Conventional ART (cART): Initiation of ART once the opportunistic infection is controlled, at the discretion of the treating physician.

Follow-up and Assessments

Participants are followed for 48 weeks with visits at days 7, 14, 30, 90, 180, and 365. At each visit, the following are measured:

• HIV-1 RNA viral load.
• CD4+ and CD8+ T-cell counts.
• Inflammatory markers (C-reactive protein, D-dimer).
• Clinical outcomes (opportunistic infection resolution/recurrence, IRIS, adverse events, mortality).

Primary Outcome All-cause mortality at 30 days from ART initiation.

Secondary Outcomes

• Mortality at 90, 180, and 360 days.
• Length of hospital stay.
• Time to opportunistic infection resolution or recurrence.
• Incidence and severity of Immune Reconstitution Inflammatory Syndrome (IRIS).
• Incidence of adverse events Grade 2, 3, and 4.
• Kinetics of HIV viremia and CD4+ T-cell count

Interim Analysis A planned preliminary analysis will be conducted once 50% of the sample size completed 90 days of follow-up, to assess the safety and efficacy of immediate ART initiation .

Ethics and Registration The study was approved by the INER Research and Ethics Committee (Approval Number C09-18). All participants provided written informed consent.

Inclusion Criteria:

• HIV infection documented by ELISA or rapid test.
• Age 18 years or older.
• Hospitalized at the emergency department, intensive care unit, or clinical pulmonology ward of the National Institute of Respiratory Diseases (INER) with clinical criteria of an opportunistic infection or AIDS-related malignancy.
• Candidate to initiate first ART regimen or presenting with first- or second-line ART failure.
• ART-naïve or with ART discontinuation for at least 3 months prior to enrollment.

Exclusion Criteria:

• Diagnosis or clinical symptoms suggestive of cryptococcal meningitis, tuberculous meningitis, or meningitis of any other cause.
• Pregnant women.
• Admitted exclusively for treatment of neurosyphilis without any other active opportunistic infection.