HIV Cluster and Outbreak Detection and Response: The Science and Experience.

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.

Time From HIV Infection to Diagnosis in the U.S., 2014-2018.

INTRODUCTION: Understanding the role of sociologic, structural, and biomedical factors that influence the length of time from HIV infection to diagnosis and reducing the time from infection to diagnosis are critical for achieving the goals of the Ending the HIV Epidemic initiative. In a retrospective analysis, the length of time from HIV infection to diagnosis and its association with individual- and facility-level attributes are determined. METHODS: Data reported by December 2019 to the U.S. National HIV Surveillance System for people with HIV diagnosed during 2014-2018 were analyzed during December 2020. A CD4 depletion model was used to estimate the time from HIV infection to diagnosis. RESULTS: During 2018, the median time from HIV infection to diagnosis was shorter for those infections diagnosed using the rapid testing algorithm (30.3 months, 95% CI=25.5, 34.5) than those diagnosed using the recommended (41.0 months, 95% CI=39.5, 42.0), traditional (37.0 months, 95% CI=29.5, 43.5), or other (35.5 months, 95% CI=32.5, 38.0) diagnostic testing algorithms. From 2014 to 2018, the time from HIV infection to diagnosis remained stable overall for all testing methods except for the traditional diagnostic testing algorithm. In multivariate analyses, those more likely to have HIV diagnosed closer to the time of infection were younger, were White, had transmission risk factors of injection drug use or heterosexual contact (for female individuals) or male-to-male sexual contact and injection drug use, or had HIV diagnosed at a correctional or screening facility (p<0.01). CONCLUSIONS: Providing access to expanded testing, including rapid testing in nonclinical settings, is likely to result in a decrease in the length of time a person is unaware of their HIV infection and thus reduce onward transmission of HIV infection.

Increasing Capacity to Detect Clusters of Rapid HIV Transmission in Varied Populations-United States.

Molecular cluster detection analyzes HIV sequences to identify rapid HIV transmission and inform public health responses. We describe changes in the capability to detect molecular clusters and in geographic variation in transmission dynamics. We examined the reporting completeness of HIV-1 polymerase sequences in quarterly National HIV Surveillance System datasets from December 2015 to December 2019. Priority clusters were identified quarterly. To understand populations recently affected by rapid transmission, we described the transmission risk and race/ethnicity of people in clusters first detected in 2018-2019. During December 2015 to December 2019, national sequence completeness increased from 26% to 45%. Of the 1212 people in the 136 clusters first detected in 2018-2019, 69% were men who have sex with men (MSM) and 11% were people who inject drugs (PWID). State-by-state analysis showed substantial variation in transmission risk and racial/ethnic groups in clusters of rapid transmission. HIV sequence reporting has increased nationwide. Molecular cluster analysis identifies rapid transmission in varied populations and identifies emerging patterns of rapid transmission in specific population groups, such as PWID, who, in 2015-2016, comprised only 1% of people in such molecular clusters. These data can guide efforts to focus, tailor, and scale up prevention and care services for these populations.

Geographic Distribution of HIV Transmission Networks in the United States.

BACKGROUND: Understanding geographic patterns of HIV transmission is critical to designing effective interventions. We characterized geographic proximity by transmission risk and urban-rural characteristics among people with closely related HIV strains suggestive of potential transmission relationships. METHODS: We analyzed US National HIV Surveillance System data of people diagnosed between 2010 and 2016 with a reported HIV-1 partial polymerase nucleotide sequence. We used HIV TRAnsmission Cluster Engine (HIV-TRACE) to identify sequences linked at a genetic distance of ≤0.5%. For each linked person, we assessed median distances between counties of residence at diagnosis by transmission category and urban-rural classification, weighting observations to account for persons with multiple linked sequences. RESULTS: There were 24,743 persons with viral sequence linkages to at least one other person included in this analysis. Overall, half (50.9%) of persons with linked viral sequences resided in different counties, and the median distance from persons with linked viruses was 11 km/7 miles [interquartile range (IQR), 0-145 km/90 miles]. Median distances were highest for men who have sex with men (MSM: 14 km/9 miles; IQR, 0-179 km/111 miles) and MSM who inject drugs, and median distances increased with increasing rurality (large central metro: 0 km/miles; IQR, 0-83 km/52 miles; nonmetro: 103 km/64 miles; IQR, 40 km/25 miles-316 km/196 miles). CONCLUSION: Transmission networks in the United States involving MSM, MSM who inject drugs, or persons living in small metro and nonmetro counties may be more geographically dispersed, highlighting the importance of coordinated health department efforts for comprehensive follow-up and linkage to care.

Novel Method for Rapid Detection of Spatiotemporal HIV Clusters Potentially Warranting Intervention.

Rapid detection of increases in HIV transmission enables targeted outbreak response efforts to reduce the number of new infections. We analyzed US HIV surveillance data and identified spatiotemporal clusters of diagnoses. This systematic method can help target timely investigations and preventive interventions for maximum public health benefit.

Viral Loads Within 6 Weeks After Diagnosis of HIV Infection in Early and Later Stages: Observational Study Using National Surveillance Data.

BACKGROUND: Early (including acute) HIV infection is associated with viral loads higher than those in later stages. OBJECTIVE: This study aimed to examine the association between acute infection and viral loads near the time of diagnosis using data reported to the US National HIV Surveillance System. METHODS: We analyzed data on infections diagnosed in 2012-2016 and reported through December 2017. Diagnosis and staging were based on the 2014 US surveillance case definition for HIV infection. We divided early HIV-1 infection (stage 0) into two subcategories. Subcategory 0α: a negative or indeterminate HIV-1 antibody test was ≤60 days after the first confirmed positive HIV-1 test or a negative or indeterminate antibody test or qualitative HIV-1 nucleic acid test (NAT) was ≤180 days before the first positive test, the latter being a NAT or detectable viral load. Subcategory 0ß: a negative or indeterminate antibody or qualitative NAT was ≤180 days before the first positive test, the latter being an HIV antibody or antigen/antibody test. We compared median earliest viral loads for each stage and subcategory in each of the first 6 weeks after diagnosis using only the earliest viral load for each individual. RESULTS: Of 203,392 infections, 56.69% (115,297/203,392) were reported with a quantified earliest viral load within 6 weeks after diagnosis and criteria sufficient to determine the stage at diagnosis. Among 5081 infections at stage 0, the median earliest viral load fell from 694,000 copies/mL in week 1 to 125,022 in week 2 and 43,473 by week 6. Among 30,910 infections in stage 1, the median earliest viral load ranged 15,412-17,495. Among 42,784 infections in stage 2, the median viral load declined from 44,973 in week 1 to 38,497 in week 6. Among 36,522 infections in stage 3 (AIDS), the median viral load dropped from 205,862 in week 1 to 119,000 in week 6. The median earliest viral load in stage 0 subcategory 0α fell from 1,344,590 copies/mL in week 1 to 362,467 in week 2 and 47,320 in week 6, while that in subcategory 0ß was 70,114 copies/mL in week 1 and then 32,033 to 44,067 in weeks 2-6. The median viral load in subcategory 0α was higher than that in subcategory 0ß in each of the first 6 weeks after diagnosis (P<.001). CONCLUSIONS: In the 1st week after diagnosis, viral loads in early infections are generally several times higher than those in later stages at diagnosis. By the 3rd week, however, most are lower than those in stage 3. High viral loads in early infection are much more common in subcategory 0α than in subcategory 0ß, consistent with 0α comprising mostly acute infections and 0ß comprising mostly postacute early infections. These findings may inform the prioritization of interventions for prevention.

Age-Associated Trends in Diagnosis and Prevalence of Infection with HIV Among Men Who Have Sex with Men - United States, 2008-2016.

In 2016, two thirds of diagnosed human immunodeficiency virus (HIV) infections in the United States were attributed to male-to-male sexual contact (1). The risk for sexual acquisition and transmission of HIV changes through the lifespan (2); to better guide prevention efforts for gay, bisexual, and other men who have sex with men (MSM*), CDC analyzed National HIV Surveillance System† (NHSS) data for MSM aged ≥13 years by age group (13-29, 30-49, and ≥50 years) in 50 states and the District of Columbia (DC). During 2008-2016, the annual number of diagnoses of HIV infection increased 3% per year among MSM aged 13-29 years, decreased 4% per year among those aged 30-49 years and was stable for MSM aged ≥50 years. The number of HIV diagnoses among MSM aged 13-29 years was four times that of MSM aged ≥50 years. During 2008-2015, the number of MSM aged ≥50 years living with diagnosed HIV infection (prevalence of HIV infection) increased an average of 11% per year and at year-end 2015 was three times that of MSM aged 13-29 years. Racial/ethnic disparities in HIV infection persisted, particularly among younger black/African American MSM who accounted for 49% of all diagnoses among MSM aged 13-29 years during 2008-2016. To avert the most infections and improve health outcomes (3), sexually active MSM at risk for HIV infection should be tested at least once a year, and, if positive, linked to and retained in HIV medical care to achieve viral suppression (4). Those testing negative should be provided HIV prevention services, including preexposure prophylaxis (PrEP) (5).

Country of Birth of Children With Diagnosed HIV Infection in the United States, 2008-2014.

BACKGROUND: Diagnoses of HIV infection among children in the United States have been declining; however, a notable percentage of diagnoses are among those born outside the United States. The impact of foreign birth among children with diagnosed infections has not been examined in the United States. METHODS: Using the Centers for Disease Control and Prevention National HIV Surveillance System, we analyzed data for children aged <13 years with diagnosed HIV infection ("children") in the United States (reported from 50 states and the District of Columbia) during 2008-2014, by place of birth and selected characteristics. RESULTS: There were 1516 children [726 US born (47.9%) and 676 foreign born (44.6%)]. US-born children accounted for 70.0% in 2008, declining to 32.3% in 2013, and 40.9% in 2014. Foreign-born children have exceeded US-born children in number since 2011. Age at diagnosis was younger for US-born than foreign-born children (0-18 months: 72.6% vs. 9.8%; 5-12 years: 16.9% vs. 60.3%). HIV diagnoses in mothers of US-born children were made more often before pregnancy (49.7% vs. 21.4%), or during pregnancy (16.6% vs. 13.9%), and less often after birth (23.7% vs. 41%). Custodians of US-born children were more often biological parents (71.9% vs. 43.2%) and less likely to be foster or nonrelated adoptive parents (10.4% vs. 55.1%). Of 676 foreign-born children with known place of birth, 65.5% were born in sub-Saharan Africa and 14.3% in Eastern Europe. The top countries of birth were Ethiopia, Ukraine, Uganda, Haiti, and Russia. CONCLUSIONS: The increasing number of foreign-born children with diagnosed HIV infection in the United States requires specific considerations for care and treatment.

HIV Testing Experience Before HIV Diagnosis Among Men Who Have Sex with Men - 21 Jurisdictions, United States, 2007-2013.

Gay, bisexual, and other men who have sex with men (MSM) continue to be the population most affected by human immunodeficiency virus (HIV) in the United States. In 2014, 81% of diagnoses of HIV infection were among adult and adolescent males, and among these, 83% of infections were attributable to male-to-male sexual contact (1). Since 2006, CDC has recommended HIV testing at least annually for sexually active MSM to foster early detection of HIV infection and prevent HIV transmission (2,3). Several initiatives and strategies during the past decade have aimed to expand HIV testing among MSM to increase early diagnosis and treatment and reduce transmission. To better understand HIV testing patterns among MSM with diagnosed HIV infection, CDC analyzed data for 2007-2013 from jurisdictions conducting HIV incidence surveillance as part of CDC's National HIV Surveillance System (NHSS). Findings from this analysis suggest that increasing percentages of MSM have had a negative HIV test during the 12 months before diagnosis (48% in 2007, 56% in 2013, among those with a known date of previous negative HIV test), indicating a trend toward increased HIV testing and earlier HIV diagnosis among persons most at risk for HIV.

Sensitive sentinel mutation screening reveals differential underestimation of transmitted HIV drug resistance among demographic groups.

OBJECTIVE: To examine the association of majority and minority-level transmitted HIV drug resistance (TDR) among diverse demographic populations in the United States and assess what different mutations may infer about TDR risk and engagement in care. DESIGN: Used sensitive assays to screen 1070 deidentified convenience plasma specimens from United States national HIV surveillance conducted in 2009-2011 on newly diagnosed persons with no evidence of antiretroviral drug use. METHODS: We applied validated allele-specific PCR for five HIV reverse transcriptase mutations as sentinel markers of TDR. The total and minority-level prevalence of TDR by demographic characteristics was compared. RESULTS: Sensitive screening identified 72% more TDR than conventional sequencing for the five mutations assessed (13.6 vs. 7.9%, P < 0.0001), with K65R having the greatest increase (0-1.7%). One-third of K65R was in persons who also had at least one of the other mutations screened. The total TDR prevalence among whites (16.4%) and blacks (14.9%) was significantly higher than that among Hispanics/Latinos (6.4%) (P = 0.005 and 0.013, respectively). TDR prevalence was highest (23.1%) in those 13-19 years (85% black). TDR prevalence among women (72% black) was nearly as high as among MSM (47% black) (14.3 vs. 15.1%, respectively). CONCLUSION: A significant proportion of TDR, primarily in older, white MSM, was undetected by conventional testing. The greatest underestimation was for rapid-decaying mutations typically associated with the source virus having recent exposure to antiretroviral therapy. However, total TDR prevalence was highest in the less than 20-year age group who were predominantly black, underscoring the importance of prevention efforts for at-risk youth.

Health Department HIV Prevention Programs That Support the National HIV/AIDS Strategy: The Enhanced Comprehensive HIV Prevention Planning Project, 2010-2013.

OBJECTIVE: The Enhanced Comprehensive HIV Prevention Planning project was the first initiative of the Centers for Disease Control and Prevention (CDC) to address the goals of the National HIV/AIDS Strategy (NHAS). Health departments in 12 U.S. cities with a high prevalence of AIDS conducted comprehensive program planning and implemented cost-effective, scalable HIV prevention interventions that targeted high-risk populations. We examined trends in health department HIV prevention programs in these cities during the project. METHODS: We analyzed the number of people who received partner services, condoms distributed, and people tested for HIV, as well as funding allocations for selected HIV prevention programs by year and by site from October 2010 through September 2013. We assessed trends in the proportional change in services and allocations during the project period using generalized estimating equations. We also conducted thematic coding of program activities that targeted people living with HIV infection (PLWH). RESULTS: We found significant increases in funding allocations for HIV testing and condom distribution. All HIV partner services indicators, condom distribution, and HIV testing of African American and Hispanic/Latino populations significantly increased. HIV tests associated with a new diagnosis increased significantly among those self-identifying as Hispanic/Latino but significantly decreased among African Americans. For programs targeting PLWH, health department activities included implementing new program models, improving local data use, and building local capacity to enhance linkage to HIV medical care, retention in care, and treatment adherence. CONCLUSIONS: Overall, these findings indicate that health departments in areas with a high burden of AIDS successfully shifted their HIV prevention resources to scale up important HIV programs and make progress toward NHAS goals.

Evaluation of supplemental testing with the Multispot HIV-1/HIV-2 Rapid Test and APTIMA HIV-1 RNA Qualitative Assay to resolve specimens with indeterminate or negative HIV-1 Western blots.

BACKGROUND: The use of Western blot (WB) as a supplemental test after reactive sensitive initial assays can lead to inconclusive or misclassified HIV test results, delaying diagnosis. OBJECTIVE: To determine the proportion of specimens reactive by immunoassay (IA) but indeterminate or negative by WB that could be resolved by alternative supplemental tests recommended under a new HIV diagnostic testing algorithm. STUDY DESIGN: Remnant HIV diagnostic specimens that were reactive on 3rd generation HIV-1/2 IA and either negative or indeterminate by HIV-1 WB from 11 health departments were tested with the Bio-Rad Multispot HIV-1/HIV-2 Rapid Test (Multispot) and the Gen-Probe APTIMA HIV-1 RNA Qualitative Assay (APTIMA). RESULTS: According to the new testing algorithm, 512 (89.8%) specimens were HIV-negative, 55 (9.6%) were HIV-1 positive (including 19 [3.3%] that were acute HIV-1 and 9 [1.6%] that were positive for HIV-1 by Multispot but APTIMA-negative), 2 (0.4%) were HIV-2 positive, and 1 (0.2%) was HIV-positive, type undifferentiated. 47 (21.4%) of the 220 WB-indeterminate and 8 (2.3%) of the 350 WB-negative specimens were HIV-1 positive. CONCLUSION: Applying the new HIV diagnostic algorithm retrospectively to WB-negative and indeterminate specimens, the HIV infection status could be established for nearly all of the specimens. IA-reactive HIV-infected persons with WB-negative results had been previously misclassified as uninfected, and HIV diagnosis was delayed for those with WB-indeterminate specimens. These findings underscore the limitations of the WB to confirm HIV infection after reactive results from contemporary 3rd or 4th generation IAs that can detect HIV antibodies several weeks sooner than the WB.

Racial/ethnic disparities in HIV diagnoses among persons aged 50 years and older in 37 US States, 2005-2008.

OBJECTIVES: We examined racial/ethnic disparities in HIV diagnosis rates for persons aged 50 years and older. METHODS: We analyzed surveillance data from the Centers for Disease Control and Prevention regarding HIV diagnoses during 2005 through 2008 in 37 states. Average annual rates of diagnoses were calculated for persons aged 50 years and older and compared with rates for persons aged 13 to 49 years. RESULTS: The average annual rate of diagnosis (per 100,000 persons) for older persons was 9.8. Rates among older Blacks (49.2) and Hispanics/Latinos (19.5) were 12.6 and 5.0 times, respectively, the rate among older Whites (3.9); rates among younger Blacks (102.5) and Hispanics/Latinos (39.0) were 7.7 and 2.9 times, respectively, the rate among younger Whites (13.3). Older persons were more likely than younger persons to receive a late HIV diagnosis (prevalence ratio=1.5, P<.001). CONCLUSIONS: Racial/ethnic disparities in HIV diagnosis rates are greater among persons aged 50 years and older than among younger persons. The greater HIV diagnosis rates in Blacks and later diagnosis among older persons of all races/ethnicities indicate a need to increase their awareness of risk factors for HIV infection.

Standardization and monitoring of laboratory performance and quality assurance by use of the less-sensitive HIV incidence assay: seven years of results.

BACKGROUND: The Performance Evaluation Program for HIV-1 incidence tests provided quality assurance services to laboratories conducting the serological testing algorithm for recent HIV seroconversion by use of a modified less-sensitive version of the Vironostika HIV-1 MicroElisa System assay. We report on the performance of the assay using proficiency testing and quality control materials tested from 2001 to 2008. METHODS: Two sets of 5 blinded serum panels using common calibration and quality control materials were tested. The mean, standard deviation, and coefficient of variation were calculated. Results were analyzed for misclassifications: false recent HIV infection errors (long-term infection classified as HIV infection less than 1 year), false long-term infection errors (HIV infection less than 1 year classified as long-term infection), and differences in standardized optical density means and variances over time. RESULTS: The false recent error rate was 1.26% (n = 2219). The false long-term error rate was 0.25% (n = 1618). No significant trends were observed for misclassification rates by year, and no significant trend in the standardized optical density over 7 years was observed. CONCLUSIONS: Laboratories using the less-sensitive Vironostika HIV-1 assay produced consistent results by use of a common calibrator and quality control materials.

HIV seroincidence among patients at clinics for sexually transmitted diseases in nine cities in the United States.

Although the numbers of newly reported diagnoses of AIDS decreased in the 1990s, it is not clear whether they reflect a decreasing number of new HIV infections. Direct measurement of HIV incidence through follow-up cohort studies is difficult and costly. We estimated HIV incidence and trends in incidence among men who have sex with men (MSM) and heterosexual men and women at clinics for sexually transmitted diseases (STDs) by using a recently developed serologic testing algorithm that requires only a single blood specimen. Cross-sectional anonymous serosurveys were conducted at 13 STD clinics in nine cities in the United States from 1991 through 1997. Before anonymous HIV testing, demographic and clinical information was abstracted. Of 129,774 specimens tested, 362 (0.28%) were from persons estimated to be recently infected. Incidence among MSM was 7.1% (95% confidence interval (CI): 4.8-10.3), 14 times higher than that among heterosexuals, which was 0.5% (CI: 0.4- 0.7). Incidence among MSM and heterosexuals remained unchanged during the time studied. Decreasing rates of new AIDS diagnoses in the 1990s do not reflect stable rates of new HIV infections among MSM and heterosexual patients attending these clinics.

Unrecognized HIV infection among patients attending sexually transmitted disease clinics.

OBJECTIVES: This study examined voluntary HIV testing rates in sexually transmitted disease (STD) clinics. METHODS: Anonymous, unlinked surveys of HIV seroprevalence and medical chart abstractions were conducted in 28 STD clinics in 14 US cities in 1997. RESULTS: Among the 52 260 patients included in the anonymous HIV serosurveys, voluntary HIV testing rates by clinic ranged from 30% to 99% (median = 58%). Patients not tested were more likely to be HIV infected than were patients who were tested, even after those with documented HIV infection were excluded, regardless of demographic characteristics, risk group, or STD diagnosis. CONCLUSIONS: HIV infection is unrecognized in substantial numbers of patients with HIV infection visiting STD clinics. Efforts are needed to increase HIV testing and counseling of all patients visiting these clinics.