Clinical Infectious Diseases MAJOR ARTICLE HIV/AIDS
Using HIV Sequence and Epidemiologic Data to Assess the Effect of Self-referral Testing for Acute HIV Infection on Incident Diagnoses in San Diego, California Sanjay R. Mehta,1,2 Ben Murrell,1 Christy M. Anderson,1 Sergei L. Kosakovsky Pond,1 Joel O. Wertheim,1 Jason A. Young,1 Lorri Freitas,3 Douglas D. Richman,1,2 W. Chris Mathews,1 Konrad Scheffler,1 Susan J. Little,1,a and Davey M. Smith1,2,a 1 Department of Medicine, University of California, San Diego, 2Department of Medicine, San Diego Veterans Affairs Medical Center, and 3Epidemiology and Immunization Services Branch, County Department of Public Health, San Diego
Background. Because recently infected individuals disproportionately contribute to the spread of human immunodeficiency virus (HIV), we evaluated the impact of a primary HIV screening program (the Early Test) implemented in San Diego. Methods. The Early Test program used combined nucleic acid and serology testing to screen for primary infection targeting local high-risk individuals. Epidemiologic, HIV sequence, and geographic data were obtained from the San Diego County Department of Public Health and the Early Test program. Poisson regression analysis was performed to determine whether the Early Test program was temporally and geographically associated with changes in incident HIV diagnoses. Transmission chains were inferred by phylogenetic analysis of sequence data. Results. Over time, a decrease in incident HIV diagnoses was observed proportional to the number primary HIV infections diagnosed in each San Diego region (P < .001). Molecular network analyses also showed that transmission chains were more likely to terminate in regions where the program was marketed (P = .002). Although, individuals in these zip codes had infection diagnosed earlier (P = .08), they were not treated earlier (P = .83). Conclusions. These findings suggests that early HIV diagnoses by this primary infection screening program probably contributed to the observed decrease in new HIV diagnoses in San Diego, and they support the expansion and evaluation of similar programs. Keywords. molecular epidemiology; models/projections; HIV diagnostic tests; prevention of sexual transmission; incidence. More than 1 million individuals in the United States are infected with human immunodeficiency virus (HIV), and 50 000 new infections occur every year [1]. Given the high infectiousness of individuals during acute and early or primary infection, these recently infected individuals are thought to be main drivers of local HIV epidemics [2]. Likely factors associated with this increased infectiousness include high viral loads [3, 4], increased viral infectivity [5], higher risk behavior, and lack of knowledge about one’s infection [6–8]. Most estimates attribute between 30% and 50% of new HIV infections to transmissions from recently infected individuals [9–11]. Given the impact of primary infection on epidemic spread and the narrow time frame during which these transmissions occur, prevention efforts targeted to these individuals may represent an efficient way to affect the epidemic [9–12]. Testing for HIV has been a cornerstone of prevention efforts since 1985 [13]. The San Diego Department of Public Health
Received 8 January 2016; accepted 9 March 2016; published online 11 May 2016. a S. J. L. and D. M. S. contributed equally to this work. Correspondence: S. R. Mehta, Department of Medicine, 9500 Gilman Dr, MC 8208, La Jolla, CA 92093 ([email protected]). Clinical Infectious Diseases® 2016;63(1):101–7 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/cid/ciw161
(SDDPH) has provided voluntary HIV counseling and testing for >16 years [14]. In 1997, the San Diego Primary Infection Cohort (SDPIC) started offering nucleic acid testing (NAT) to screen for acute HIV infection in individuals negative for HIV antibody. From 1997 to 2007, NAT was limited to persons with symptoms consistent with an acute retroviral syndrome [15]. In 2007, the SDPIC introduced a screening program, the “Early Test,” in which all negative HIV antibody tests were followed up with NAT. The Early Test was offered in the Health and Human Services Agency (HHSA) Central region of San Diego and marketed to men who have sex with men (MSM) living in this region, mainly in zip codes 92103 and 92104 [16]. Outreach efforts marketed the Early Test as a way to identify HIV infection earlier than standard HIV testing, as early as 7– 10 days after exposure [17]. In this study, we evaluated the impact of this self-referral testing program on local HIV incident diagnoses, using epidemiologic, geographic, and molecular sequence information. METHODS Regional Analysis
HIV, Sexually Transmitted Infections, and Demographic Data
This study was approved by the Institutional Review Board at the University of California San Diego (UCSD), and data HIV/AIDS
•
CID 2016:63 (1 July)
•
101
collected from several sources were analyzed for the study time period (1996–2012). Aggregate HIV prevalence data by zip code for 2010 were obtained from SDDPH. Similarly, HIV incident diagnosis and sexually transmitted infection (STI) data were obtained by HHSA region, and for zip codes 92103 and 92104 for 2006–2012 from SDDPH. (Before “name-based reporting” in 2006, accurate data on incident HIV diagnoses were not available.) HIV testing data by zip code and HHSA region were obtained from SDDPH and SDPIC (Supplementary Figure 1). Since 2003, SDDPH has used a “rapid” HIV antibody test for screening, which reliably diagnoses infection after 12 weeks [14, 18]. From 1997 to 2007, SDPIC used NAT for HIV screening only for individuals with symptoms and history consistent with acute infection. Since 2007, the SDPIC has offered self-referral testing through the Early Test program, in which all negative antibody tests (Oraquick) were reflexed to NAT [16]. The estimated date of infection was inferred for 73% of SDPIC participants using HIV laboratory data, as described elsewhere [19]. Sociodemographic data from the 2010 census were downloaded from the American FactFinder Web site [20]. Antiretroviral treatment (ART) adherence and “community viral load” data [21] were obtained from the UCSD Owen Clinic [22]. Location of residence data were collected from SDPIC participants from SDPIC. Early Test Analysis
To evaluate whether the observed decline in overall incident HIV diagnoses could be explained by the annual number of acute or early HIV (AEH) diagnoses from the Early Test in each HHSA region, we used Poisson regression and Wald test analyses. Because the hypothesized effect follows after diagnosis, we grouped AEH diagnoses in November and December with the following calendar year. Because Poisson regression assumes that the response variance is equal to the mean, but infections occurring in bursts could violate this, we also tested for overdispersion or underdispersion, using a test by Cameron and Trivedi [23]. Within our regression model, we also allowed region-specific effects to vary linearly over time. For 8 AEH diagnoses, zip codes were missing, so these diagnoses were excluded. SDPIC Analysis
Sequences and Transmission Linkages
Partial HIV-1 pol sequences were generated [Geneseq (Monogram Biosciences) or ViroSeq (Applied Biosystems)] from 660 unique SDPIC participants with AEH infection (1996–2012). All sequences were evaluated for hypermutation, duplication and contamination using online tools [24]. All sequences were subtyped using SCUEAL [25], and only HIV-1 subtype B sequences were analyzed (n = 652). Of these, 565 participants had paired sociodemographic and geographic data available. Transmission linkages in SDPIC were inferred between sequences using pairwise distance comparisons, as described elsewhere (Tamura-Nei 93 evolutionary model) [26, 27]. A putative 102
•
CID 2016:63 (1 July)
•
HIV/AIDS
linkage was inferred when any 2 sequences had a genetic distance 5% [27–29] and that only 0.014% of pairwise sequence measures nationally and
Using HIV Sequence and Epidemiologic Data to Assess the Effect of Self-referral Testing for Acute HIV Infection on Incident Diagnoses in San Diego, California Sanjay R. Mehta,1,2 Ben Murrell,1 Christy M. Anderson,1 Sergei L. Kosakovsky Pond,1 Joel O. Wertheim,1 Jason A. Young,1 Lorri Freitas,3 Douglas D. Richman,1,2 W. Chris Mathews,1 Konrad Scheffler,1 Susan J. Little,1,a and Davey M. Smith1,2,a 1 Department of Medicine, University of California, San Diego, 2Department of Medicine, San Diego Veterans Affairs Medical Center, and 3Epidemiology and Immunization Services Branch, County Department of Public Health, San Diego
Background. Because recently infected individuals disproportionately contribute to the spread of human immunodeficiency virus (HIV), we evaluated the impact of a primary HIV screening program (the Early Test) implemented in San Diego. Methods. The Early Test program used combined nucleic acid and serology testing to screen for primary infection targeting local high-risk individuals. Epidemiologic, HIV sequence, and geographic data were obtained from the San Diego County Department of Public Health and the Early Test program. Poisson regression analysis was performed to determine whether the Early Test program was temporally and geographically associated with changes in incident HIV diagnoses. Transmission chains were inferred by phylogenetic analysis of sequence data. Results. Over time, a decrease in incident HIV diagnoses was observed proportional to the number primary HIV infections diagnosed in each San Diego region (P < .001). Molecular network analyses also showed that transmission chains were more likely to terminate in regions where the program was marketed (P = .002). Although, individuals in these zip codes had infection diagnosed earlier (P = .08), they were not treated earlier (P = .83). Conclusions. These findings suggests that early HIV diagnoses by this primary infection screening program probably contributed to the observed decrease in new HIV diagnoses in San Diego, and they support the expansion and evaluation of similar programs. Keywords. molecular epidemiology; models/projections; HIV diagnostic tests; prevention of sexual transmission; incidence. More than 1 million individuals in the United States are infected with human immunodeficiency virus (HIV), and 50 000 new infections occur every year [1]. Given the high infectiousness of individuals during acute and early or primary infection, these recently infected individuals are thought to be main drivers of local HIV epidemics [2]. Likely factors associated with this increased infectiousness include high viral loads [3, 4], increased viral infectivity [5], higher risk behavior, and lack of knowledge about one’s infection [6–8]. Most estimates attribute between 30% and 50% of new HIV infections to transmissions from recently infected individuals [9–11]. Given the impact of primary infection on epidemic spread and the narrow time frame during which these transmissions occur, prevention efforts targeted to these individuals may represent an efficient way to affect the epidemic [9–12]. Testing for HIV has been a cornerstone of prevention efforts since 1985 [13]. The San Diego Department of Public Health
Received 8 January 2016; accepted 9 March 2016; published online 11 May 2016. a S. J. L. and D. M. S. contributed equally to this work. Correspondence: S. R. Mehta, Department of Medicine, 9500 Gilman Dr, MC 8208, La Jolla, CA 92093 ([email protected]). Clinical Infectious Diseases® 2016;63(1):101–7 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/cid/ciw161
(SDDPH) has provided voluntary HIV counseling and testing for >16 years [14]. In 1997, the San Diego Primary Infection Cohort (SDPIC) started offering nucleic acid testing (NAT) to screen for acute HIV infection in individuals negative for HIV antibody. From 1997 to 2007, NAT was limited to persons with symptoms consistent with an acute retroviral syndrome [15]. In 2007, the SDPIC introduced a screening program, the “Early Test,” in which all negative HIV antibody tests were followed up with NAT. The Early Test was offered in the Health and Human Services Agency (HHSA) Central region of San Diego and marketed to men who have sex with men (MSM) living in this region, mainly in zip codes 92103 and 92104 [16]. Outreach efforts marketed the Early Test as a way to identify HIV infection earlier than standard HIV testing, as early as 7– 10 days after exposure [17]. In this study, we evaluated the impact of this self-referral testing program on local HIV incident diagnoses, using epidemiologic, geographic, and molecular sequence information. METHODS Regional Analysis
HIV, Sexually Transmitted Infections, and Demographic Data
This study was approved by the Institutional Review Board at the University of California San Diego (UCSD), and data HIV/AIDS
•
CID 2016:63 (1 July)
•
101
collected from several sources were analyzed for the study time period (1996–2012). Aggregate HIV prevalence data by zip code for 2010 were obtained from SDDPH. Similarly, HIV incident diagnosis and sexually transmitted infection (STI) data were obtained by HHSA region, and for zip codes 92103 and 92104 for 2006–2012 from SDDPH. (Before “name-based reporting” in 2006, accurate data on incident HIV diagnoses were not available.) HIV testing data by zip code and HHSA region were obtained from SDDPH and SDPIC (Supplementary Figure 1). Since 2003, SDDPH has used a “rapid” HIV antibody test for screening, which reliably diagnoses infection after 12 weeks [14, 18]. From 1997 to 2007, SDPIC used NAT for HIV screening only for individuals with symptoms and history consistent with acute infection. Since 2007, the SDPIC has offered self-referral testing through the Early Test program, in which all negative antibody tests (Oraquick) were reflexed to NAT [16]. The estimated date of infection was inferred for 73% of SDPIC participants using HIV laboratory data, as described elsewhere [19]. Sociodemographic data from the 2010 census were downloaded from the American FactFinder Web site [20]. Antiretroviral treatment (ART) adherence and “community viral load” data [21] were obtained from the UCSD Owen Clinic [22]. Location of residence data were collected from SDPIC participants from SDPIC. Early Test Analysis
To evaluate whether the observed decline in overall incident HIV diagnoses could be explained by the annual number of acute or early HIV (AEH) diagnoses from the Early Test in each HHSA region, we used Poisson regression and Wald test analyses. Because the hypothesized effect follows after diagnosis, we grouped AEH diagnoses in November and December with the following calendar year. Because Poisson regression assumes that the response variance is equal to the mean, but infections occurring in bursts could violate this, we also tested for overdispersion or underdispersion, using a test by Cameron and Trivedi [23]. Within our regression model, we also allowed region-specific effects to vary linearly over time. For 8 AEH diagnoses, zip codes were missing, so these diagnoses were excluded. SDPIC Analysis
Sequences and Transmission Linkages
Partial HIV-1 pol sequences were generated [Geneseq (Monogram Biosciences) or ViroSeq (Applied Biosystems)] from 660 unique SDPIC participants with AEH infection (1996–2012). All sequences were evaluated for hypermutation, duplication and contamination using online tools [24]. All sequences were subtyped using SCUEAL [25], and only HIV-1 subtype B sequences were analyzed (n = 652). Of these, 565 participants had paired sociodemographic and geographic data available. Transmission linkages in SDPIC were inferred between sequences using pairwise distance comparisons, as described elsewhere (Tamura-Nei 93 evolutionary model) [26, 27]. A putative 102
•
CID 2016:63 (1 July)
•
HIV/AIDS
linkage was inferred when any 2 sequences had a genetic distance 5% [27–29] and that only 0.014% of pairwise sequence measures nationally and
