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Modelling the Strategic Use of Antiretroviral Therapy for the Treatment and Prevention of HIV


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Published in the journal: . PLoS Med 10(10): e32767. doi:10.1371/journal.pmed.1001535
Category: Perspective
doi: https://doi.org/10.1371/journal.pmed.1001535

Summary

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Linked Research Article

This Perspective discusses the following new study published in PLOS Medicine:

Hontelez JAC, Lurie MN, Bärnighausen T, Bakker R, Baltussen R, et al. (2013) Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study. PLoS Med 10(10): e1001534. doi:10.1371/journal.pmed.1001534

Using 9 structurally different models, Jan Hontelez and colleagues investigate timeframes for HIV elimination in South Africa using a universal test and treat strategy.

The impact of increased access to antiretroviral therapy (ART) has principally been measured in lives saved, and justifiably so: over the last decade the scale-up of ART has averted over 4 million deaths in low- and middle-income countries [1]. Almost 10 million people in these countries are currently receiving ART, and widespread access to treatment has transformed HIV from a life-threating infection to a chronic disease. Less than 20 years ago, patients presenting at clinics in Africa with an AIDS-defining illness would on average have just 9 months to live [2]. Today, people living with HIV in Africa can, with timely and continuous access to effective ART, have a relatively normal life expectancy [3],[4].

Yet the benefits of ART extend beyond saving lives, and increasingly attention is being given to the potential for ART to prevent new HIV infections. The specific contribution of ART to reducing HIV infection through mother-to-child transmission of HIV is well described—over 800,000 children have avoided infection over the last decade [1]—but the extent to which ART prevents sexual transmission has until recently been less clear. Data from several observational studies have suggested decreased acquisition of HIV among sexual partners of people on ART [5],[6], an association convincingly confirmed by the results of the HPTN 052 trial demonstrating significantly reduced rates of sexual transmission with early ART initiation [7]. At the population level, increased access to ART has been associated with reductions in sexual transmission in ecological studies [8], but the overall proportion of new infections that have been averted by ART is not known. In the absence of such data, mathematical modelling has made an essential contribution.

Models have been used to predict the potential impact of widespread ART on HIV transmission for over two decades [9], but the potential preventive impact of widespread ART access captured international attention only recently, with the landmark publication of what has become known as the “Granich” model in 2009 [10]. Assuming high rates of treatment uptake, coverage, and adherence this model put forward the notion that universal HIV testing and treatment, combined with other interventions, could reduce transmission to low levels such that epidemic would eventually decrease towards elimination. Subsequent models have all pointed in the same direction of reduced incidence with expanded ART access, albeit with varying assumptions and timeframes [11].

In this issue of PLOS Medicine Jan Hontelez and colleagues systematically assessed the universal test and treat intervention suggested by Granich and colleagues by running nine different models with increasing degrees of complexity and realism—including sexual networks, HIV stages with different degrees of infectiousness, and updated treatment effectiveness assumptions—to explore how different scientific approaches to modelling would influence the results [12]. Encouragingly, all models were found to predict that HIV would eventually be eliminated through universal HIV testing and treatment, although timeframes for reaching the elimination phase ranged from 7 to 39 years depending on assumptions about demography, sexual behavior, transmission and natural history, coverage of other prevention interventions (male medical circumcision and condom use), and sexually transmitted infection (STI) co-factors [12]. Of particular note, while previous models have suggested reduced incidence even if treatment is started at a lower CD4 threshold of 350 cells/mm3 [11], this is the first study to predict that the elimination phase will eventually be reached at this threshold, albeit within a longer time horizon and provided very high treatment coverage is attained.

The notion that ART could help curb the HIV epidemic has fundamentally reframed the global HIV response over the past 5 years. For donors, the clinical and public health benefits provided by expanded ART access make a clear case that ART is a good investment [13], while for care providers the possibility that ART could help control or even eliminate the HIV epidemic has provided a renewed impetus to further expand coverage [14].

The latest ART guidelines released by the World Health Organization (WHO) in June 2013 recognize the multiple benefits of ART for both treatment and prevention of HIV, and provide a number of recommendations for expanded eligibility [15]. ART initiation is recommended at CD4 <500 cells/mm3 (with priority given to those with a CD4 <350 cells/mm3) and three new recommendations are made to provide immediate ART initiation based on clinical benefits and programmatic and prevention considerations: pregnant women, people in serodiscordant couples, and children under 5 years of age. Similar to previous guidelines, people co-infected with tuberculosis and hepatitis B infection are also eligible for immediate ART after diagnosis. In order to develop these guidelines WHO commissioned a series of modelling studies done by the HIV Modelling Consortium, which showed that expanding the criterion for ART eligibility to CD4 cell count ≤500 cells/mm3 was highly cost-effective in low- and middle-income settings, in particular if expanded eligibility was coupled with a large increase in HIV testing and linkage to care [16].

With the preventive benefit of ART firmly established in evidence and policy, what could be the future contribution of modelling to treatment scale-up? Rather than continuing to model the magnitude and speed of the preventive impact of ART, modelling efforts could be redirected towards helping programmes make choices about which interventions need to be prioritized in order to achieve the levels of enrolment and retention in care required to achieve optimal prevention benefit. There are three key areas where modelling could help, and encouragingly early work has already started in some of these areas.

First, modelling can help define actions to improve access and retention in care. A positive consequence of the recent focus on universal HIV testing and treatment has been to direct attention on the cascade of care. While much of the modelling work to date has focused on refining the horizons for achieving HIV elimination through ART provision, individuals involved in programme implementation have expressed concern about the feasibility of achieving the high rates of ART uptake, coverage, retention, and adherence upon which these models are based [14]. Recent systematic reviews have highlighted substantial patient attrition at every step from HIV testing to ART initiation to long term retention on treatment [17],[18]. A number of interventions have recently shown promising results in increasing uptake in HIV testing [19], speeding up eligibility assessments for ART [20], and reducing attrition on ART [21]. Modelling work has already been done to help provide a more nuanced understanding of the dynamics of the treatment cascade [22]. Drawing on data from trials underway to assess the impact of ART initiation on HIV transmission [23], future modelling work could assist decision making about where and how to intervene along the treatment cascade to maximize the treatment and prevention benefits of ART.

Second, modelling can help inform country decisions about who should be treated early in priority for maximum prevention benefit. Implementation of the new WHO recommendations for early ART initiation will require countries to make strategic choices around how best to use ART for treatment and prevention according to resource constraints, epidemic dynamics, and societal factors. WHO's guidelines include a chapter on decision making for programme managers that outlines how modelling can help support costing and planning [15]. Modelling studies have already assessed the preventive impact of immediate ART initiation among pregnant women and serodiscordant couples [24], and key populations [25],[26]. This work will continue to be critical to informing country choices in the strategic use of ART.

Finally, ongoing research will provide further data on the clinical and public health benefits of ART, and future guidelines will likely lead to a continued policy evolution towards earlier initiation. Modelling will make a key contribution to informing future WHO guidance and country decisions about how best to strategically provide ART as a broader package of interventions to save lives, reduce illness, and prevent new infections.

The case for ART impact on HIV transmission is proven. The priority now is to translate this concept into benefits for patients and communities by identifying and implementing approaches that work to maximize early HIV testing and ART uptake and long-term retention in care.


Zdroje

1. Anon. (2013) Global update on HIV treatment 2013: results, impact and opportunities. WHO report, in partnership with UNICEF and UNAIDS. Geneva: WHO.

2. MorganD, MaudeGH, MalambaSS, OkongoMJ, WagnerHU, et al. (1997) HIV-1 disease progression and AIDS-defining disorders in rural Uganda. Lancet 350: 245–250.

3. MillsEJ, BakandaC, BirungiJ, ChanK, FordN, et al. (2011) Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med 155: 209–216.

4. JohnsonLF, MossongJ, DorringtonRE, SchomakerM, HoffmannCJ, et al. (2013) International Epidemiologic Databases to Evaluate AIDS Southern Africa Collaboration (2013) Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies. PLoS Med 10: e1001418 doi:10.1371/journal.pmed.1001418

5. BunnellR, EkwaruJP, SolbergP, WamaiN, Bikaako-KajuraW, et al. (2006) Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. AIDS 20: 85–92.

6. DonnellD, BaetenJM, KiarieJ, ThomasKK, StevensW, et al. (2010) Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet 375: 2092–2098.

7. CohenMS, ChenYQ, McCauleyM, GambleT, HosseinipourMC, et al. (2011) Prevention of HIV-1 infection with early antiretroviral therapy. New Engl J Med 365: 493–505.

8. TanserF, BärnighausenT, GrapsaE, ZaidiJ, NewellML (2013) High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science 339: 966–971.

9. AndersonRM, GuptaS, MayRM (1991) Potential of community-wide chemotherapy or immunotherapy to control the spread of HIV-1. Nature 350: 356–359.

10. GranichRM, GilksCF, DyeC, De CockKM, WilliamsBG (2009) Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 373: 48–57.

11. EatonJW, JohnsonLF, SalomonJA, BärnighausenT, BendavidE, et al. (2012) HIV treatment as prevention: systematic comparison of mathematical models of the potential impact of antiretroviral therapy on HIV incidence in South Africa. PLoS Med 9: e1001245 doi:10.1371/journal.pmed.1001245

12. HontelezJAC, LurieMN, BärnighausenT, BakkerR, BaltussenR, et al. (2013) Elimination of HIV in South Africa through expanded access to antiretroviral therapy: a model comparison study. PLoS Med 10 ((10)) e1001534 doi:10.1371/journal.pmed.1001534

13. SchwartlanderB, StoverJ, HallettT, AtunR, AvilaC, et al. (2011) Towards an improved investment approach for an effective response to HIV/AIDS. Lancet 377: 2031–2041.

14. ZachariahR, HarriesAD, PhilipsM, ArnouldL, SabapathyK, et al. (2010) Antiretroviral therapy for HIV prevention: many concerns and challenges, but are there ways forward in sub-Saharan Africa? Trans R Soc Trop Med Hyg 104: 387–391.

15. Anon. (2013) 218 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: WHO.

16. Anon (2013) Modelling for the WHO 2013 Guidelines for use of antiretrovirals. Available: http://www.hivmodelling.org/projects/modelling-who-2013-guidelines-use-antiretrovirals. Accessed 19 September 2013.

17. RosenS, FoxMP (2011) Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review. PLoS Med 8: e1001056 doi:10.1371/journal.pmed.1001056

18. RosenS, FoxMP, GillCJ (2007) Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med 4: e298 doi:10.1371/journal.pmed.0040298

19. SutharABFN, BachanasPJ, WongVJ, RajanJS, et al. (2013) Towards universal voluntary HIV testing and counselling: a systematic review and meta-analysis of community-based approaches. PLoS Med 10: e1001496 doi:10.1371/journal.pmed.1001496

20. JaniIV, SitoeNE, AlfaiER, ChongoPL, QuevedoJI, et al. (2011) Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study. Lancet 378: 1572–1579.

21. KredoT, FordN, AdeniyiFB, GarnerP (2013) Decentralising HIV treatment in lower- and middle-income countries. Cochrane Database Syst Rev 6: CD009987.

22. HallettTB, EatonJW (2013) A side door into care cascade for HIV-infected patients? J Acquir Immune Defic Syndr 63 Suppl 2: S228–S232.

23. GranichR, GuptaS, SutharAB, SmythC, HoosD, et al. (2011) Antiretroviral therapy in prevention of HIV and TB: update on current research efforts. Curr HIV Res 9: 446–469.

24. Stover J PC, Bollinger L (2012) The effects of different ART eligibility strategies on HIV-related mortality and incidence. International AIDS Conference, Washington (D.C.); 23 July 23 2012. Abstract MOPDC0101.

25. CharleboisED, DasM, PorcoTC, HavlirDV (2011) The effect of expanded antiretroviral treatment strategies on the HIV epidemic among men who have sex with men in San Francisco. Clin Infect Dis 52: 1046–1049.

26. KatoM, GranichR, Duc BuiD, TranHV, NadolP, et al. (2013) The potential impact of expanding antiretroviral therapy and combination prevention in Vietnam: towards elimination of HIV transmission. J Acquir Immune Defic Syndr May 24. [Epub ahead of print].

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Interní lékařství

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