A tale of two-component generalised HIV epidemics

A tale of two-component generalised HIV epidemics

Comment the medical intervention to the needs of the population, but it would also be cost inefficient. Analyses by Kim and Goldie4 have shown that the...

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the medical intervention to the needs of the population, but it would also be cost inefficient. Analyses by Kim and Goldie4 have shown that the vaccine is not particularly cost effective when given to girls who will ultimately have regular access to the Pap test, but reasonably cost effective when given to girls who will not. In September, 2009, the CDC released the first statelevel statistics for Gardasil use in girls in the USA.5 As predicted, the vaccine is not going to those girls who stand to gain the most. Only 15·8% of girls in Mississippi have received the vaccine, compared with 54·7% of girls in Rhode Island. More generally, residence in a state with a high cervical cancer mortality rate predicted a low vaccination rate (figure A, p=0·001 for the correlation), as did residence in a state with a low median income (figure B, p<0·001 for correlation). This pattern of uneven distribution of health-care services in the USA is not unusual. People who are affluent or white often receive more beneficial services than do those who are poor and black.8 But rarely are these inequitable gaps also inefficient. In most situations both groups of patients stand to benefit to about the same degree. In this respect, what is occurring with this vaccine is notably inefficient, a fact further exacerbated by the dual sources of vaccine efficacy. The vaccine is both a medical intervention delivered to a patient for the benefit of that patient and a community-level intervention aimed at lowering the prevalence of an oncogenic virus, which benefits girls who do not receive the vaccine too.

The current maldistribution of this vaccine raises questions. Should the CDC consider setting vaccination targets for those states where the cervical cancer burden is high? Should manufacturers be encouraged to play a greater role in marketing and distribution of the vaccine to the populations who will benefit the most? Both steps might help to ensure that this shining example of bench-to-bedside research actually makes its way to the people it was designed to help. Peter B Bach Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA [email protected] I thank Joshua N Mirkin for his assistance. I declare that I have no conflicts of interest. 1

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Advisory Committee on Immunization Practices. Record of the proceedings. June 29–30, 2006. http://www.cdc.gov/vaccines/recs/acip/ downloads/min-jun06.pdf (accessed Dec 9, 2009). Rothman SM, Rothman DJ. Marketing HPV vaccine: implications for adolescent health and medical professionalism. JAMA 2009; 302: 781–86. Akers AY, Newmann SJ, Smith JS. Factors underlying disparities in cervical cancer incidence, screening, and treatment in the United States. Curr Probl Cancer 2007; 31: 157–81. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008; 359: 821–32. Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among adolescents aged 13–17 years—United States, 2008. MMWR Morb Mortal Wkly Rep 2009; 58: 997–1001. Horner MJ, Ries LAG, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2006. 2009. http://seer.cancer.gov/csr/1975_2006/results_merged/ sect_05_cervix_uteri.pdf (accessed Oct 20, 2009). US Census Bureau. Two-year-average median household income by state: 2005 to 2008. 2008. http://www.census.gov/hhes/www/income/ statemedfaminc.html (accessed Oct 20, 2009). Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care, Institute of Medicine, National Academy of Sciences. Unequal treatment: confronting racial and ethnic disparities in health care. Washington, DC: National Academies Press, 2002.

A tale of two-component generalised HIV epidemics The 5-year strategy from the US President’s Emergency Plan for AIDS Relief, released in December, 2009, proposed a laudable goal: the prevention of 12 million HIV infections.1 But success will require resolving a deep gulf dividing the prevention community. One camp sees that multiple sexual partnerships drive infection in generalised epidemics in eastern and southern Africa, dispersed through the broad population.2 The other emphasises the large number of already infected individuals, particularly the many existing discordant couples, and stresses widespread HIV testing.3 But careful examination of these complex generalised epidemics reveals a crucial role 964

for both components (figure), and provides a basis for a unifying approach. A sexual epidemic necessarily depends on multiple partnering. But in view of the HIV virus’s low infectivity in heterosexual sex, how generalised epidemics materialise is rather mystifying. Risk during the dominant multiyear latent phase is remarkably low, well below one per 1000 acts of intercourse.4 This low infectivity results from the body’s eventual effective immune response, but also probably from adaption of the rapidly mutating virus in the short term to survival in the host rather than for transmission.5 Accordingly, serial monogamy, even with unrealistically high changes www.thelancet.com Vol 375 March 20, 2010

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in the number of partners, fails to emulate a generalised epidemic in credible modelling.6 However, acute phase infectivity is estimated at up to 43 times that of the latent phase.7 Thus the dangerous duo of acute-phase infectiousness and overlapping sexual partnerships provide a compelling explanation. For example, in the historic genesis of these epidemics, incidence rose explosively.8 In view of the low infectivity in the latent phase and dearth of people yet in the final advanced phase, acute infection with substantial overlap of partners seems inescapably culpable. Although mature epidemics are undoubtedly more complex, this synergy of acute infection and concurrency remains biologically compelling—probably spawning smaller clusters of infection. Moreover, modelling indicates that concurrency amplifies transmission independent of acute infection.9 Also incriminating concurrency are the commonness of overlapping partnerships in the region,10 the higher risk in people whose partners have other partners,10 and evidence of mini-epidemic spatial clusters.11 But the large accumulated reservoir of people with existing infection also merits serious attention. Indeed, in Kenya, discordant couples decisively outnumber concordant-positive couples.12 Moreover, although most HIV-infected individuals are in the lower-infectivity latent phase, many are in the advanced stage when infectiousness rises substantially. Thus we face two components. The first, relating to multiple partnering, is widely dispersed, moves relatively rapidly and erratically, and demands wide-scale response. The second, relating to identifiable HIV-positive individuals and discordant partnerships, is also widespread but slower and more stable, and calls for more targeting. How much does each contribute? Simplistically, infection occurring within stable discordant couples is less than 50%, because the first infected partner must be infected from outside. Accordingly, a Ugandan national serosurvey of new infections in couples found 38% arose when spouses had longstanding infection.13 But additionally, phylogenetic evidence indicates 25% or more of infections to the uninfected partner originate from an outside partner.10 So the slower component represents, perhaps generously, roughly one-third of infections, depending on the epidemic’s maturity. But beyond the proportions, multiple partnering is strategically profound. It is the underlying driver, like gasoline poured on the fire of the epidemic and the primary source of discordant partnerships. www.thelancet.com Vol 375 March 20, 2010

Component 1: rapid

Component 2: slow

Multiple partnering (especially concurrency and largely acute infection)

Long-term discordant partnerships

~2/3 of new infections

~1/3 of new infections

Figure: Two-component generalised HIV epidemic

Recognising that country programmes need multiple prevention interventions and individual tailoring, I offer the following priority tiers. Priority one is quelling the gasoline on the fire. Thus tier 1 includes interventions directed at the necessary wide-scale population level. State-of-the-art behaviour change focusing on partner limitation addresses individual and social norms with consistent messaging through multiple channels. It includes youth interventions toward delayed sexual debut and addresses enablers such as alcohol and gender norms. Unfortunately, we lack formal smallscale research assessing impact. But partner reduction aims directly at the epidemic’s prime driver, following established behaviour-change principles. Moreover modelling suggests sexual networking affects transmission exponentially, indicating substantial impact from modest reductions.9 Accordingly, major national reductions in HIV incidence have occurred, recently found for Zimbabwe8 related to behaviour change. Condoms are certainly scalable, but the challenge is achieving consistent use, and reserving them strategically for residual risky sex without undermining partner-reduction efforts. Male circumcision offers immense promise. The challenge is reaching widespread coverage, especially in older men at highest HIV risk. Tier 2 approaches include counselling and testing, and prevention for persons living with HIV/AIDS, aimed at reducing transmission within discordant couples and other onward transmission. Although evidence supports some effect for counselling and testing if done well, this approach has limitations in reaching effective scale.14 Prevention for persons living with HIV/AIDS also faces challenges reaching 965

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scale, but has the advantage of contact in the treatment context when many seem motivated to reduce risk and enables client continuity. As our best tools against slow-component transmission, these two approaches merit vigorous support. Tier 2 also includes prevention with most-at-risk populations, especially sex workers and men having sex with men. Though important, these groups are a small fraction in generalised epidemics. Finally, political and social leadership that openly acknowledges HIV also facilitates HIV prevention. Tier 3 approaches probably have limited impact or need additional evidence. Disappointingly, intervention trials of the treatment of sexually transmitted infection find little use in HIV prevention.15 Structural approaches, such as alcohol taxation, have a distinguished public health history. They merit pursuit. However, in these country contexts, they appear distal to the infection dynamic, or problematic to implement. Antiretroviral treatment has considerable collateral prevention value by radically reducing infectivity. Further, the test-and-treat approach for additionally identified HIV-positive individuals holds theoretical promise, potentially at wide scale. However, various reservations, notably the practicalities of widescale implementation, seem daunting, mandating additional research.16 Our prevention goal is ambitious, but imperative. We must somehow come together, and deploy our best tools strategically for combination prevention.

Bureau for Global Health, US Agency for International Development, Washington, DC 20523, USA [email protected] My views are not necessarily those of USAID. I declare that I have no conflicts of interest. 1

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PEPFAR. The U.S. President’s emergency plan for AIDS relief: five year strategy. 2009. http://www.pepfar.gov/documents/organization/133035. pdf (accessed Dec 12, 2009). Halperin D, Epstein H. Concurrent sexual partnerships help explain Africa’s high HIV prevalence: implications for prevention. Lancet 2004; 364: 4–6. Bunnell RB, Cherutich P. Universal HIV testing and counselling in Africa. Lancet 2008; 371: 2148–50. Boily M-C, Baggaley RF, Wang L, et al. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. Lancet Infect Dis 2009; 9: 118–29. Sagar M, Laeyendecker O, Lee S, et al. Selection of HIV variants with signature genotypic characteristics during heterosexual transmission. J Infect Dis 2009; 199: 580–89. Hollingsworth DT, Anderson RM, Fraser C. HIV transmission by stage of infection. J Infect Dis 2008; 198: 687–93. Pinkerton S. Probability of HIV transmission during acute infection in Rakai, Uganda. AIDS Behav 2008; 12: 677–84. Hallet TB, Gregson S, Mugurungi O, Gonese E, Garnett GP. Assessing the evidence for behavior change affecting the course of HIV epidemics: new mathematical modeling approach and application to data from Zimbabwe. Epidemics 2009; 1: 108–17. Morris M, Kretzschmar M. Concurrent partnerships and the spread of HIV. AIDS 1997; 11: 641–48. Mah TL, Halperin D. The evidence for the role of concurrent partners in Africa’s HIV epidemics: a response to Lurie and Rosenthal. AIDS Behav 2010; 14: 25–28. Tanser F, Barnighausen T, Cooke GS, Newell M-L. Localized spatial clustering of HIV infections in a widely disseminated South African epidemic. Int J Epidemiol 2009; 38: 1008–16. National AIDS and STI Control Programme, Ministry of Health, Kenya. Kenya AIDS indicator survey 2007: preliminary report. July, 2008. http:// www.kanco.org/KANCO/pdf/KAIS%20-%20Preliminary%20Report_ July%2029.pdf (accessed Jan 29, 2009). Mermin J, Musinguzi J, Opio A, et al. Risk factors for recent HIV infection in Uganda. JAMA 2008; 300: 540–48. Shelton JD. Counselling and testing for HIV prevention. Lancet 2008; 372: 273–75. Gray RH, Waiwer MJ. Reassessing the hypothesis on STI control for HIV prevention. Lancet 2008; 371: 2064–65. Dieffenbach C, Fauci A. Universal voluntary testing and treatment for prevention of HIV transmission. JAMA 2009; 301: 2380–82.

James D Shelton

Cardiology—a call for papers

To submit a paper go to http://ees.elsevier.com/thelancet

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The Lancet is producing a special cardiology issue to coincide with the European Society of Cardiology Congress to be held Aug 28 to Sept 1, 2010, in Stockholm. We will consider high-quality original research papers that will influence clinical practice— especially those that describe the results of randomised trials. If your work is being presented at the meeting and falls under an embargo policy, please tell us the date, time, and manner of presentation (poster or oral). If your paper is accepted here, publication on our website can be scheduled to coincide with the presentation.

The deadline for normal submissions is May 30, 2010, via our online submission system. Please state in your covering letter that the submission is in response to this call for papers. For “Hot Line Trials” only, we will particularly welcome submission of such clinical trials. If your manuscript is accepted for a hot-line session, the deadline for submissions is Aug 1. Stuart Spencer The Lancet, London NW1 7BY, UK

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