Is Apretude (cabotegravir) recommended as a first-line Pre-Exposure Prophylaxis (PrEP) option for women at risk of Human Immunodeficiency Virus (HIV) infection?

Apretude (Cabotegravir) for Women: First-Line PrEP Recommendation

Apretude (long-acting injectable cabotegravir) is highly effective and recommended as a first-line PrEP option for cisgender women at risk of HIV infection, demonstrating superior efficacy compared to daily oral TDF/FTC. 1, 2

Evidence for Superior Efficacy in Women

• Long-acting cabotegravir reduced HIV acquisition risk by 89% compared to oral TDF/FTC in cisgender women in sub-Saharan Africa (hazard ratio 0.11,95% CI 0.04-0.32), representing the strongest prevention efficacy data available for women. 3, 4

• The pooled analysis across all populations showed a 79% reduction in HIV risk with cabotegravir versus oral PrEP (relative risk 0.21,95% CI 0.07-0.61). 2

• This superior efficacy addresses a critical gap, as adherence to daily oral PrEP has been particularly challenging for women in real-world settings. 4

Dosing Schedule and Administration

• Initiate with two loading doses of 600 mg intramuscularly, administered one month apart, followed by maintenance doses every 2 months (8 weeks). 1

• An optional oral cabotegravir lead-in period (30 mg daily for 4 weeks) can be used to assess tolerability before starting injections, though this is not mandatory. 5

• The long-acting formulation eliminates daily adherence requirements, which is particularly advantageous given documented adherence challenges with oral PrEP among women. 3, 4

Pre-Initiation Requirements

Before prescribing Apretude to women, confirm the following:

• HIV-negative status using fourth-generation antigen/antibody testing - this is critical as starting cabotegravir during undiagnosed HIV infection leads to integrase resistance. 6, 2

• HIV RNA testing if any symptoms of acute infection (fever, headache, muscle soreness, rash, swollen lymph nodes) are present, as antibody tests may miss acute infection. 6

• Pregnancy test for women of childbearing potential. 7, 6

• Baseline creatinine clearance, hepatitis B and C serology, and comprehensive STI screening. 7

Safety Profile

• Injection site reactions are the most common adverse event (pain, nodules, swelling), occurring more frequently than with oral PrEP but generally well-tolerated. 4

• Cabotegravir causes less decrease in creatinine clearance compared to TDF/FTC, making it advantageous for women with borderline renal function. 4

• Non-injection-related adverse events (headache, nasopharyngitis, upper respiratory infections) occur at similar rates to oral PrEP. 4

Monitoring Schedule

• HIV testing every 2 months before each injection using fourth-generation antigen/antibody assay. 7, 8

• Quarterly STI screening and pregnancy testing. 7

• Renal function monitoring every 6 months (less intensive than with TDF-based PrEP). 7

Pregnancy and Breastfeeding Considerations

• Limited safety data exist for cabotegravir use during pregnancy - this is a critical knowledge gap compared to TDF/FTC, which has extensive pregnancy safety data. 2

• If pregnancy occurs during cabotegravir use, discuss risks and benefits individually, recognizing that the long half-life means drug exposure continues for months after the last injection. 6, 8

• For women planning pregnancy or who are pregnant, daily oral TDF/FTC remains the preferred option due to established safety data showing no adverse fetal effects. 8

Critical Resistance Concerns

• Of 19 HIV infections occurring in cabotegravir recipients, 7 developed integrase strand transfer inhibitor (INSTI) resistance - this is a significant concern. 2

• Resistance most commonly occurs when cabotegravir is initiated during undiagnosed acute HIV infection or when breakthrough infection occurs. 2

• The long half-life of cabotegravir (weeks to months) means subtherapeutic drug levels persist after discontinuation, creating a window for resistance development if HIV infection occurs. 3

• This makes rigorous HIV testing before each injection absolutely mandatory - never skip or delay HIV testing before administering the next dose. 2

Comparison to Oral PrEP

While daily oral TDF/FTC remains the gold standard with the most extensive evidence base across all populations 7, cabotegravir offers distinct advantages for women:

• Superior efficacy (89% vs. variable efficacy with oral PrEP depending on adherence). 3

• Eliminates daily adherence burden, addressing the primary failure mode of oral PrEP in women. 4

• Better renal safety profile compared to TDF-based regimens. 4

However, oral TDF/FTC retains advantages in specific situations:

• Established pregnancy safety data. 8

• Immediate discontinuation possible if needed. 3

• No injection site reactions. 4

• Lower cost and simpler logistics. 3

Implementation Challenges

• Requires HIV RNA testing capability for optimal safety monitoring, which may not be widely available in all settings. 3

• Demands additional clinic time, space, and trained staff for intramuscular injections. 3

• Oral bridging medication needed during interruptions in dosing schedules. 3

• Delayed HIV diagnosis can occur with standard antibody/antigen tests due to cabotegravir's antiretroviral activity masking seroconversion. 3

Key Pitfalls to Avoid

• Never initiate cabotegravir without confirming HIV-negative status - the resistance risk is substantial. 2

• Do not skip HIV testing before any injection - the long dosing interval does not reduce infection risk between doses. 2

• Do not assume cabotegravir prevents other STIs - counsel that condoms remain essential for comprehensive STI prevention. 7

• Do not use cabotegravir as first-line in women planning pregnancy - choose oral TDF/FTC instead due to established safety data. 8

• Do not forget that cabotegravir persists for months after discontinuation - this affects both ongoing HIV risk coverage and potential resistance development. 3