What are the FDA's recommendations for designing clinical trials to test Antiretroviral Therapy (ART) in treatment-naive Human Immunodeficiency Virus (HIV) populations?

FDA Recommendations for Designing Clinical Trials of ART in Treatment-Naïve HIV Populations

The FDA recommends 48 weeks as the primary efficacy endpoint for antiretroviral trials in treatment-naïve populations, with virologic suppression (HIV-1 RNA <50 copies/mL) as the primary efficacy measure, though 24 weeks has traditionally been used and remains acceptable for certain trial designs. 1

Primary Endpoint Selection

• 48-week assessment is recommended for most contemporary trials to better evaluate durability of viral suppression and emergence of resistance, particularly for switch trials and newer agents 1
• 24-week assessment remains acceptable as a traditional primary efficacy timepoint, providing sufficient time to assess virologic response while maintaining feasible trial duration 1
• Virologic endpoints are prioritized over clinical endpoints (mortality, AIDS-defining illnesses) as the primary efficacy measure because viral suppression correlates with clinical benefit and allows for shorter, more feasible trial durations 1

Trial Design Framework

Participant Selection Criteria

The FDA considers ART-controlled HIV-infected individuals who are asymptomatic with many available treatment options to be more similar to healthy volunteers than patients with life-threatening conditions, which has important implications for acceptable risk thresholds 2

Key enrollment considerations include:

• CD4 count thresholds: Consensus supports stable CD4 counts ≥500 cells/μL for experimental studies, though ≥350 cells/μL may be acceptable depending on intervention risk 2
• Baseline viral load stratification: Randomization should be stratified by screening plasma viral load (typically <100,000 vs ≥100,000 copies/mL) and CD4+ cell count 3
• Demographic representation: Age limits should reflect the broader HIV-infected population (e.g., up to 65-70 years) rather than overly restrictive criteria that limit generalizability 2
• Sex/gender balance: Enhanced strategies are needed to ensure adequate representation of women, who have been historically underrepresented in HIV trials 2

Standard Regimen Comparisons

Treatment-naïve trials should compare investigational regimens against established first-line therapies, specifically:

• Integrase strand transfer inhibitor (InSTI)-based regimens (dolutegravir or bictegravir) plus 2 NRTIs as the contemporary standard comparator 4, 5
• Fixed background regimens consisting of tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) with emtricitabine or lamivudine are standard 4, 3
• Historical trials used efavirenz-based regimens or boosted protease inhibitors (darunavir/ritonavir) as comparators, which remain acceptable controls 3, 5, 6

Analytical Considerations

Statistical Methods

• Baseline covariate adjustment is good statistical practice, though FDA guidance does not universally mandate that primary efficacy analysis must be adjusted for at least one covariate 1
• Time to Loss of Virologic Response (TLOVR) has been used historically but is not specifically mandated by FDA as the required analytical method 1
• Confirmed viral suppression (HIV-1 RNA <50 copies/mL) should be the primary virologic outcome measure 3

Monitoring Requirements

Frequent viral load monitoring is essential to assess treatment response:

• Within 6 weeks of starting ART for initial assessment 4
• Every 3 months until viral load <50 copies/mL for 1 year 4
• Every 6 months thereafter once sustained suppression is achieved 4

Critical Safety Considerations

Risk Mitigation Strategies

Investigators must carefully consider potential ramifications of interventions given the lower acceptability of risk to healthy volunteers in clinical research 2

Key safety monitoring includes:

• Genotype resistance testing should be performed before initiating therapy to guide regimen selection 4
• Regular monitoring for drug toxicities is essential, particularly renal function for tenofovir-based regimens and neuropsychiatric symptoms for efavirenz 4
• Discontinuation criteria must be clearly defined, including virologic failure thresholds and safety stopping rules 2

Special Populations

Pediatric considerations require distinct approaches given neurodevelopmental risks and immune system uncertainties across different age ranges from neonates to 24 years 2

Co-infection considerations:

• For hepatitis B co-infection, regimens must include agents active against HBV (avoid abacavir-based regimens) 4
• For renal impairment, TDF should be avoided or dose-adjusted if creatinine clearance <60 mL/min 4

Evidence Quality and Trial Design Challenges

Network Geometry Issues

The proliferation of antiretroviral combinations (hundreds of possible combinations from 28+ drugs) creates challenges in conducting head-to-head comparisons, leading to reliance on drug class comparisons that have their own limitations 2

Non-inferiority designs predominate in contemporary HIV trials, which can complicate interpretation of comparative effectiveness across studies 2

Heterogeneity Concerns

Substantial heterogeneity exists in ATI trial designs, hindering ability to compare efficacy and safety across trials 2

Adverse event documentation varies considerably across trials, making safety comparisons challenging 2

Common Pitfalls to Avoid

• Insufficient preclinical rationale: ATIs or novel interventions should not be used simply to generate hypotheses without supporting preclinical data demonstrating measurable effects on relevant biomarkers 2
• Overly restrictive enrollment criteria that limit generalizability while making recruitment difficult 2
• Inadequate duration of follow-up that fails to capture durability of response and emergence of resistance 1
• Failure to account for transmitted drug resistance in regions where TDR prevalence is high, which may necessitate PI-based rather than NNRTI-based comparators 7