We estimate the relative transmission rate in early versus later infection among men who have sex with men (MSM) in San Francisco, California, by studying the characteristics of a sample of transmitters, recruited through newly diagnosed, recently infected MSM between 1996 and 2009. Of 36 transmitters identified, 9 were determined on the basis of testing history and serologic testing to have been recently infected. The unadjusted odds ratio of transmitting during early infection was 15.2 (95% confidence interval [CI], 6.3–33.4; P < .001); the odds ratio was 8.9 (95% CI, 4.1–19.4) after adjustment for self-reported antiretroviral treatment. This high transmissibility could be due to both high infectiousness and high rates of sex partner change or concurrent partnerships

Deeks, SG

Fraser, C

Hecht, FM

Hollingsworth, TD

Pilcher, CD

The Journal of Infectious Diseases

English

PubMed

We estimate the relative transmission rate in early versus later infection among men who have sex with men (MSM) in San Francisco, California, by studying the characteristics of a sample of transmitters, recruited through newly diagnosed, recently infected MSM between 1996 and 2009. Of 36 transmitters identified, 9 were determined on the basis of testing history and serologic testing to have been recently infected. The unadjusted odds ratio of transmitting during early infection was 15.2 (95% confidence interval [CI], 6.3-33.4; P < .001); the odds ratio was 8.9 (95% CI, 4.1-19.4) after adjustment for self-reported antiretroviral treatment. This high transmissibility could be due to both high infectiousness and high rates of sex partner change or concurrent partnerships

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B R I E F R E P O R THigh Transmissibility During EarlyHIV Infection Among Men WhoHave Sex With Men—San Francisco,CaliforniaT. Déirdre Hollingsworth,1,2,3 Christopher D. Pilcher,5,a Frederick M. Hecht,5Steven G. Deeks,5 and Christophe Fraser4,a1Warwick Infectious Disease Epidemiology Research, Warwick MathematicsInstitute, 2School of Life Sciences, University of Warwick, Coventry, 3Department ofClinical Sciences, Liverpool School of Tropical Medicine, and 4MRC Centre forOutbreak Analysis and Modelling, Department for Infectious Disease Epidemiology,School of Public Health, Imperial College London, United Kingdom; and5HIV/AIDS Division, Department of Medicine, San Francisco General Hospital,University of California–San FranciscoWe estimate the relative transmission rate in early versus laterinfection among men who have sex with men (MSM) inSan Francisco, California, by studying the characteristics ofa sample of transmitters, recruited through newly diagnosed,recently infected MSM between 1996 and 2009. Of 36 trans-mitters identified, 9 were determined on the basis of testinghistory and serologic testing to have been recently infected.The unadjusted odds ratio of transmitting during early infec-tion was 15.2 (95% confidence interval [CI], 6.3–33.4;P < .001); the odds ratio was 8.9 (95% CI, 4.1–19.4) after ad-justment for self-reported antiretroviral treatment. This hightransmissibility could be due to both high infectiousness andhigh rates of sex partner change or concurrent partnerships.Keywords. HIV; transmission rate; early infection; menwho have sex with men; San Francisco.Estimates of the relative transmission rate of human immuno-deficiency virus (HIV) during early infection are essential forunderstanding the dynamics of transmission and the likelyimpact of intervention programs [1]. Early infection is associat-ed with high transmission rates among heterosexuals, but thereare limited estimates among men who have sex with men(MSM) [2]. High infectivity in early infection is thought to bedue to a combination of high viral loads, viral phenotype, orhost risk factors, such as coinfection. Studies that stratify trans-mission rates among MSM by viral load show a strong associa-tion between high viral loads and transmission rates, suggestingthat early infection, characterized by high viral loads in semen[3], is highly infectious among MSM. A recent review of HIVtransmission by anal intercourse found no significant differencein transmission probability per unprotected penile-analact among the heterosexual population, compared with theMSM population [4], and early infection has been shown tobe highly infectious among heterosexuals [5, 6].Phylogenetic studies of MSM-dominated epidemics haveshown a high degree of clustering among samples from earlyinfection, suggesting that chains of transmission during earlyinfection are contributing to a large proportion of transmissions(from 10% to 50% [7]), a consequence of both differential infec-tiousness, the stage of the epidemic, and the sexual risk behaviorin the population [8]. Direct estimation of the relative infec-tiousness of early infection in this way is inherently challengingbut can be done well [9]. An alternative approach is to use viralphylogenies to identify likely transmission pairs within a longi-tudinally studied cohort, using clinical data to infer the direc-tion of transmission, and to compare the pairs to randomlychosen members of the cohort to quantify the risk factors asso-ciated with transmission; Fisher et al estimated a rate ratio oftransmission during early infection of 3.88 (95% confidence in-terval [CI], 1.76–8.55; P = .0008) [10]. As with all indirect meth-ods, including the method used in the analysis described below,these estimates are affected by the dynamics of each particularepidemic, including variable behavior, diagnosis, and treatmentpatterns. Since all of these estimates each have their own limi-tations, multiple estimates of transmission rates using differentmethods are needed to develop a better understanding of thedynamics of the HIV epidemic.We estimated the relative transmission rate of early infectionamongMSM in San Francisco, California, by comparing the char-acteristics of a sample of transmitters with those of the generalHIV-infected population. This is similar to a case-control studyin which cases are source partners known to have transmittedHIV to their partners and controls are the HIV-infected popula-tion. We assume that the source partners are a random sample oftransmitters, ie, that the characteristics of both recent and chronictransmitters are similar to the characteristic of individuals withReceived 28 February 2014; accepted 17 December 2014; electronically published 26 Decem-ber 2014.Presented in part: Conference on Retroviruses and Opportunistic Infections, Seattle, Wash-ington, March 2012.aC. D. P. and C. F. contributed equally to this report.Correspondence: T. Deirdre Hollingsworth, PhD, Warwick Mathematics Institute, University ofWarwick, Coventry CV4 7AL, UK (deirdre.holingsworth@warwick.ac.uk).The Journal of Infectious Diseases® 2015;211:1757–60© The Author 2014. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permitsunrestricted reuse, distribution, and reproduction in any medium, provided the original work isproperly cited.DOI: 10.1093/infdis/jiu831BRIEF REPORT • JID 2015:211 (1 June) • 1757this stage of infection in the larger population. This is similar tothe method used by Fisher et al [10] but differs principally by themethods used to identify transmitters and to stage early infection.METHODSThe relative infectiousness of recently and chronically infectedindividuals can be estimated by comparing the distribution ofrecently infected individuals in a sample of transmitters withthat in the estimated HIV-infected MSM population at thetime of recruitment. A group of HIV-infected MSM were iden-tified by recruitment of their newly infected sex partners andgenetic confirmation of transmission (Supplementary Materi-als) [11]. This was a secondary analysis of anonymized data.The present analysis makes an assumption that the methodof selection gives an unbiased sample of transmitters becausethey were all recruited in a similar way. For this reason, we in-cluded only transmitters who were initially identified as being apotential source partner for a new recently infected index case.To estimate the role of early infection in transmission, the stageof infection for the majority of transmitters was characterizedusing an enzyme immunoassay (EIA) (Supplementary Materials).To allow for reduced transmission during chronic infectiondue to treatment, which could inflate the estimate of the relativetransmissibility during early infection, treatment status was alsorequested from each transmitter.The comparison group for this analysis was the HIV-infectedMSM population in San Francisco. The San Francisco Depart-ment of Public Health publishes yearly estimates of the HIV-infected population, including those with undiagnosed infec-tion and those with incident infection (Supplementary Materi-als). Since newly infected individuals were only in the earlyphase of infection for a portion of the year, we approximatedtheir presence in the epidemic by using the duration of themean interval between the time at which an HIV-infectedindividual tests positive for HIV antibody by a sensitive EIAand the time at which the individual tests negative for HIV an-tibody by a less sensitive EIA, with a cutoff of approximately164 days [12]. If k is defined as the number of new infectionsin a given year, approximately 164/365*k person-years of poten-tial transmission during early infection were assumed to haveoccurred.The distribution of transmitters and HIV-infected individu-als can be compared to estimate the odds ratio (OR) of transmis-sion during early infection; that is, the relative transmission ratein early infection, which is a combination of biological and be-havioral factors. These ORs were obtained using standard meth-ods, implemented using the function epi.2by2 in the packageepiR for R, including the Breslow Day test for homogeneityacross years [13].RESULTSFrom 1997 to 2009, 656 index cases with early infection wereseen, and partners were identified in 69 (10.5%; from 2000 to2003, when the most partners were recruited, transmitterswere successfully identified for 43 of 209 index cases [21%]).Twenty-seven transmitting pairs were excluded because (1)the index case was found not to be recently infected on furtheranalysis (6 pairs), (2) the transmitter was already in the cohort(11 pairs), (3) staging information was unavailable for thesource partner (9 pairs), or (4) a third individual was possiblythe source for both partners (1 pair). This left 42 transmittingpairs, of whom 36 were MSM. Of these, 9 had individuals whowere in the early phase of infection, and the remaining 27 hadindividuals whowere in the chronic phase of infection (Table 1).The mean duration of infection for these 9 recently infectedtransmitters was estimated to be 70 days (median duration, 72days; range, 24–153 days). Of the 27 chronic transmitters stud-ied here, 6 were reported as receiving or probably receivingTable 1. Characteristics of Human Immunodeficiency Virus (HIV) Transmitters and the HIV-Infected Population in San FranciscoYearHIV Transmitters HIV-Infected PopulationEarlyChronic Early ChronicUntreated Treated Total No. (Whole Year) Untreated Treated Total No.1997 0 (0) 2 (100) 0 (0) 2 283 (2) 7071 (59) 4628 (39) 11 9831998 1 (50) 1 (50) 0 (0) 2 399 (3) 6385 (52) 5586 (45) 12 3702000 2 (22) 6 (67) 1 (11) 9 631 (5) 6142 (47) 6371 (48) 13 1462001 2 (22) 6 (67) 1 (11) 9 748 (6) 5984 (44) 6801 (50) 13 5342002 1 (17) 2 (33) 3 (50) 6 752 (5) 5876 (43) 7193 (52) 13 8222003 1 (33) 2 (67) 0 (0) 3 757 (5) 5768 (41) 7585 (54) 14 1112004 0 (0) 1 (100) 0 (0) 1 762 (5) 5819 (40) 7817 (54) 14 3992008 2 (67) 1 (33) 0 (0) 3 697 (5) 5079 (35) 8869 (61) 14 6462009 0 (0) 0 (0) 1 (100) 1 659 (5) 4689 (32) 9131 (63) 14 480Overall 9 (25) 21 (58) 6 (17) 36 5688 (5) 52 813 (43) 63 981 (52) 122 491Data are no. (%) of individuals, unless otherwise indicated. Additional information is available in the Supplementary Materials.1758 • JID 2015:211 (1 June) • BRIEF REPORTantiretroviral treatment (ART) for HIV, although most if not allof these treated sources lacked evidence of having achieved andmaintained suppression of virus to levels below the limits of de-tection. Newly infected individuals made up approximately 5%of the HIV-infected population in the whole year (scaling to ac-count for the proportion of the year in early infection, this isapproximately 2%) but 25% of transmitters (Table 1), suggest-ing that recently infected individuals are highly overrepresentedin transmitters and contribute a considerable proportion of on-ward transmission. Conversely, treated chronically infected in-dividuals are underrepresented in the transmitters (17%),compared with the HIV-infected population (52%; Table 1).Early infection was estimated to be a highly infectious period(crude OR [vs chronic infection], 15.2; 95% CI, 6.3–33.4;P < .001), with evidence that the transmissibility was not thesame across years (P = .69). The analysis also suggested amarked reduction in the odds of transmitting due to treatment(OR [vs no treatment], 0.25; 95% CI, .08–.63; P = .001). Afteradjustment for the impact of treatment, the OR for early infec-tion decreased to 8.9 (95% CI, 4.1–19.4; P < .001).To investigate the impact of the uncertainty in the duration ofearly infection, the estimates were repeated for the 95% CI onthe estimated duration of early infection in the assay [12]; for139 days, the adjusted OR was 10.4 (95% CI, 4.8–22.8), andfor 199 days, the adjusted OR was 7.3 (95% CI, 3.3–15.9). Sen-sitivity to overestimation of the number of early infections wasconsidered by rerunning the analysis at a cutoff of 0.75 for theearly infection assay and a consequent duration of 129 days[12], giving an additional 2 cases during chronic infectionand an adjusted OR of 7.0 (95% CI, 3.4–18.7).DISCUSSIONWhen an event is rare, the OR is a good approximation of therelative risk. Therefore, an OR can be compared with previousestimates of the relative transmission rate of early infection. Anestimated 4–19-fold greater adjusted odds of transmission dur-ing early infection, compared with chronic infection, lies at themiddle to higher end of estimates for both MSM and heterosex-ual transmission [4, 14] but overlaps estimates for heterosexualpartners in general [8]and for heterosexual partners who engagein anal sex [4]. The estimated reduction in transmission is basedon self-reported ART use without confirmation of viral suppres-sion and is thus unsurprisingly lower than that associated withvalidated ART use with confirmed viral suppression [15]. Itshould be remembered that the estimate of transmissibility dur-ing early infection is a combination of both behavior and biol-ogy, the individual effects of which cannot be disentangled withthis study design.The role of high infectivity in population-level transmissionis limited by the short duration of this stage of infection but willbe increased by high rates of partner change [8]. Because ofinevitable delays in identifying transmission and transmitters,our definition of early infection at the time of transmission isdefined by the stage of infection of the transmitter at the timeof identification some months later. We therefore cannot be cer-tain of the exact stage of infection at the time of transmission,but this increased risk is an estimate of infectiousness duringthe first 6–9 months of infection. Given this interval, theseare very high estimates. A worrying consequence of high trans-missibility for MSM during early infection is that it would speedthe epidemic growth rate in expanding or re-expanding MSMepidemics. Thus, this study highlights the need for sustainedHIV-prevention efforts to help reduce HIV transmissionamong MSM and for finding ways to more effectively diagnoseinfection and treat MSM with early HIV infection to preventreversal of hard-won gains.The main limitations of our study are the assumptions thatthe source population in this study represents all sources inSan Francisco and that our data are an unbiased sample oftransmitters. Short of performing a prospective study of all po-tential transmitters and their partners, the study design used isthe only one we are aware of to address these questions.Although we are not aware of any systematic bias in our as-sumption, it is possible that the networks dominated by trans-misssion in early infection in San Francisco are more integratedand, hence, more likely to present to a research setting as iden-tified partners. Also, during the period of observation, a sub-stantial proportion of the chronically infected population inSan Francisco was receiving effective ART. This highlights theneed for further studies of this type.NotesAcknowledgments. We thank Ling Hsu and Willi McFarland(San Francisco Department of Public Health), for their assistance with gath-ering data on HIV infections; and Wendy Hartogensis, for assistance withthe data from transmitters.Financial support. This work was supported by Imperial College Lon-don ( junior research fellowship to T. D. H.), the Wellcome Trust(to T. D. H., via strategic award 097830/Z/11/A-C to the Liverpool Schoolof Tropical Medicine), the National Institutes of Health (grantsP01AI071713 [to F. M. H.], R34MH096606 and R01HD074511 [toC. D. P.], and K24AI069994 [to S. G. D.]), and the European ResearchCouncil (grant PBDR-339251 to C. F.).Potential conflicts of interest. All authors: No reported conflicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConflicts of Interest. Conflicts that the editors consider relevant to the con-tent of the manuscript have been disclosed.References1. Cohen MS, Dye C, Fraser C, Miller WC, Powers KA, Williams BG. HIVtreatment as prevention: debate and commentary–will early infectioncompromise treatment-as-prevention strategies? PLoS Med 2012; 9:e1001232.2. Baggaley RF, White RG, Boily MC. Infectiousness of HIV-infected ho-mosexual men in the era of highly active antiretroviral therapy. 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High Transmissibility During Early HIV Infection Among Men Who Have Sex With Men-San Francisco, California.

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