The US Food and Drug Administration's clinical hold on Gilead Sciences' once-weekly combination of GS-1720 and GS-4182 due to unexpected CD4 T-cell and lymphocyte count declines represents a key safety signal in long-acting HIV therapy development. This event parallels the earlier islatravir trials, in which similar immunological effects led to a downsized development programme with lower doses of the drug. The current safety signal must involve different mechanisms, as the combination contains an integrase inhibitor and a capsid inhibitor rather than a nucleoside reverse transcriptase translocation inhibitor. Although GS-1720 appears well tolerated in early studies, the high doses used might have contributed to toxicity. As GS-4182 is a prodrug that converts to lenacapavir, the parent compound warrants careful evaluation, particularly given lenacapavir's anticipated widespread use for HIV prevention. Existing lenacapavir data show favourable safety profiles. However, CD4 T-cell reporting has been inconsistent across trials, and different study populations and dosing regimens might not fully capture all potential immunological effects. CD4 T-cell declines represent a key concern for people with HIV. Future trials should implement standardised monitoring protocols with individual participant trajectories, predefined decline thresholds, and clear discontinuation criteria. As long-acting antiretroviral therapy advances, maintaining rigorous immunological surveillance becomes essential to balance dosing convenience against potential immunological risks.