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In 2015, a large human immunodeficiency virus (HIV) outbreak occurred among persons who inject drugs (PWID) in Indiana. During 2016–2019, additional outbreaks among PWID occurred across the United States. Based on information disseminated by responding health departments and Centers for Disease Control and Prevention (CDC) involvement, we offer perspectives about characteristics of and public health responses to 6 such outbreaks. Across outbreaks, injection of opioids (including fentanyl) or methamphetamine predominated; many PWID concurrently used opioids and methamphetamine or cocaine. Commonalities included homelessness or unstable housing, previous incarceration, and hepatitis C virus exposure. All outbreaks occurred in metropolitan areas, including some with substantial harm reduction and medical programs targeted to PWID. Health departments experienced challenges locating case patients and contacts, linking and retaining persons in care, building support to strengthen harm-reduction programs, and leveraging resources. Expanding the concept of vulnerability to HIV outbreaks and other lessons learned can be considered for preventing, detecting, and responding to future outbreaks among PWID.

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The Respond pillar of the Ending the HIV Epidemic in the U.S. initiative, which consists of activities also known as cluster and outbreak detection and response, offers a framework to guide tailored implementation of proven HIV prevention strategies where transmission is occurring most rapidly. Cluster and outbreak response involves understanding the networks in which rapid transmission is occurring; linking people in the network to essential services; and identifying and addressing gaps in programs and services such as testing, HIV and other medical care, pre-exposure prophylaxis, and syringe services programs. This article reviews the experience gained through 30 HIV cluster and outbreak responses in North America during 2000−2020 to describe approaches for implementing these core response strategies. Numerous jurisdictions that have implemented these response strategies have demonstrated success in improving outcomes related to HIV care and viral suppression, testing, use of prevention services, and reductions in transmission or new diagnoses. Efforts to address important gaps in service delivery revealed by cluster and outbreak detection and response can strengthen prevention efforts broadly through multidisciplinary, multisector collaboration. In this way, the Respond pillar embodies the collaborative, data-guided approach that is critical to the overall success of the Ending the HIV Epidemic in the U.S. initiative.