International Society for Infectious Diseases Neglected Tropical Diseases Meeting Boston, July 8 10, 2011

Transcription

1 Endemic Cofactors of HIV Why are they still neglected? Eileen Stillwaggon International Society for Infectious Diseases Neglected Tropical Diseases Meeting Boston, July 8 10, 2011

2 Outline The HIV/AIDS policy paradigm Obstacles to addressing interactions between HIV and NTDs The role of NTDs in AIDS epidemics New avenues for modeling AIDS epidemics and NTD interactions

3 Adult Prevalence of HIV ivory = <0.1% tan = 0.1% to <0.5% yellow = 0.5% to <1% orange = 1% to <5% red = 5% to <15% dark red = 15% to 26%

4 Why are 26 % of adults in Swaziland and 15 % of adults in Zambia HIV-infected and fewer than 1 % in the USA and Western Europe?

5 Behavior and individual risk Early initiation of sex Premarital sex Multiple partners Unprotected sex Alcohol use and sex Concurrent sexual relationships

6 At a national level, risky sexual behaviors do not correlate with hhiv prevalence -extra- or pre-marital sex -early initiation of sex -multiple partners in previous year or lifetime -having any sexual partner Cleland and Ferry (eds.) Sexual Behaviour and AIDS in the Developing World. WHO. UNAIDS Fact Sheet on Differences in HIV Spread in African Cities. unaids.org. Stillwaggon AIDS and the Ecology of Poverty. Wellings et al Sexual behaviour in context: a global perspective Lancet 368:

7 Concurrent sexual partnerships: the latest attempt to find a behavioral anomaly The current conventional wisdom: Overlapping sexual partnerships are especially common in sub-saharan Africa and explain the region s high prevalence of HIV. For the Concurrency Hypothesis to be valid, both of the following must tbe true: long-term overlapping partnerships are far more commoninafrica long-term overlapping partnerships spread HIV much more rapidly than other sexual behaviors

8 Quantitative Evidence does not show that concurrency is more common in eastern/southern Africa Halperin, Epstein, and Mah cite 33 studies reporting on 43 surveys or other research. None of the surveys they cite clearly supports the assertion that concurrency is unusually high in eastern/southern Africa. Sawers, L. and E. Stillwaggon, Concurrent Sexual Partnerships Do Not Explain HIV Epidemics in Africa: A Systematic Review of the Evidence, Journal of the International AIDS Society 13(34), 2010.

9 The Model The concurrency hypothesis relies on a stochastic simulation model that purports to show that concurrency spreads HIV more rapidly than other sexual behaviors. To show that, the model requires four critical assumptions: Frequency of sexual activity: Every person has sex with every partner, every day Per-act transmission rate = 0.05 Higher prevalence of concurrency than exists in sub-saharan Africa and higher even than the modelers own data Gender symmetry Without those four assumptions, the model shows that concurrency leads to only a trivial difference in HIV infections compared to serial monogamy.

10 Modeling Sexual Networks and HIV Eaton, Hallett, Garnett AIDS and Behavior, September 2010 with staged transmission and up to 8% of individuals having concurrent partnerships, HIV fails to spread

11 Modeling Sexual Networks and HIV. Sawers, Isaac, and Stillwaggon Journal of the International AIDS Society, in press We use realistic values for frequency of sex and find that epidemics quickly drop to extinction We use realistic values for frequency of sex and find that epidemics quickly drop to extinction if only sexual behavior is included.

12 Why does the behavioral paradigm still drive AIDS policy in Africa? Racial stereotypes Stillwaggon, E., Racial Metaphors: Interpreting Sex and AIDS in Africa, Development and Change, 34(5): , Path dependence Stillwaggon, E. AIDS and the Ecology of Poverty, Oxford University Press, Lots of money

13 What else is going on besides sex?

14 Clinics and hospitals without medicines for curable STIs, and without sterilizing equipment or disposable equipment (next slide).

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16 Why is each sex act or each birth so much riskier in poor countries?

17 Transmission Efficiency men ml) A in Sem copies/m IV RNA (Log 10 c H ( /200 1/1000-1/10,000 1/500-1/ /30- Risk of Transmission Reflects Genital Viral Burden 1/100-1/1000

18 Correlation Between Viral Load & HIV Transmission All subjects Male-to-Female Transmission Female-to-Male Transmission Transmission rate per 1000 Person-Years < > < > < > Viral load (HIV-1 RNA copies/ml) and HIV transmission Quinn T, et al. N Engl J Med 2000; Fideli U, et al. AIDS Res Hum Retrovir 2001.

19 Increase in likelihood of heterosexual transmission Increase in risk of progression to AIDS or death 0.3 log 10 increase 0.5 log 10 increase 1.0 log 10 increase 18-20% 26-40% 100% progression 24-25% 44% 113%

20 Cofactor Infections: Sexually Transmitted Infections STIs promote HIV transmission Making those without HIV more vulnerable Making those with HIV more contagious Some STIs lead to genital ulceration Most STIs produce genital inflammation Most STIs promote viral shedding in the genital tract

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22 Malaria aa a causes chronic immune activation increases HIV replication 7 to 10 times Increases mother-to-child transmission of HIV increases sexual transmission of HIV HIV also increases malaria transmission. Abu-Raddad, LJ, P Patnaik, and JG Kublin Dual Infection with HIV and Malaria Fuels the Spread of Both Diseases in Sub-Saharan Africa, Science 314 (8 December):

23 Transmission Efficiency men ml) A in Sem copies/m IV RNA (Log 10 c H ( /200 1/1000-1/10,000 1/500-1/ /30- Risk of Transmission Reflects Genital Viral Burden 1/100-1/1000

24 Lymphatic filariasis is associated with higher risk of HIV infection and transmission.

25 Distribution of Lymphatic Filariasis

26 Distribution of helminths and HIV-1 1in Afi Africa Clinical Microbiology Reviews 2004, 17(4):

27 Helminths (Worms) More than 80% of people in poor communities have at least one type of worm Virtually all children in urban slums, shanty towns, and rural villages have worms

28 Helminths (Worms) Roundworm, hookworm, whipworm infect 25 to 35% of world population cause anemia cause Vitamin-A deficiency

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30 Helminths (Worms) Roundworm, hookworm, whipworm increase susceptibility to HIV increase HIV viral load and HIV transmission accelerate progression to AIDS

31 Difference in CD4 counts at 12 week follow-up visit Walson JL Otieno PA Mbuchi M Richardson BA Lohman Payne B et al Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, et al. Albendazole treatment among adults with HIV-1 and helminth co-infection: A randomized, double blind, placebo-controlled trial. AIDS 2008, 22:

32 Difference in plasma viral load at 12 week follow-up visit Walson JL Otieno PA Mbuchi M Richardson BA Lohman Payne B et al Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, et al. Albendazole treatment among adults with HIV-1 and helminth co-infection: A randomized, double blind, placebo-controlled trial. AIDS 2008, 22:

33 Restoring health, buying time Of the 22.5 million people infected with HIV-1 in Africa, only 31% of those in need are currently on ARVs. ART is expensive relative to other health care interventions (between $300 and $400 per individual per year). Delaying immunosuppression may buy time until the development of AIDS or the need for ART and will allow critical infrastructure to be developed. UNAIDS, 2007; Judd Walson

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37 Schistosomiasis (bilharzia) S. hematobium (urinary schistosomiasis) infects 33% of Africans, almost 200 million people. p Causes blood loss, malnutrition, anemia

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39 Schistosomiasis (bilharzia) S. hematobium (urinary schistosomiasis) infects 33% of Africans, almost 200 million people. p Causes blood loss, malnutrition, anemia In endemic areas, 75% of women with urinary schistosomiasis also have genital infection.

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41 Schistosomiasis (bilharzia) Worms and ova of S. hematobium infect the vagina, uterus, vulva, and cervix. S. hematobium lesions are indistinguishable from STIs without biopsy.

42 Schistosomiasis (bilharzia) Worms and ova of S. hematobium infect the vagina, uterus, vulva, and cervix. S. hematobium lesions are indistinguishable from STIs without biopsy. Lesions provide direct access to the blood stream for HIV. Worms and ova produce inflammation, attracting CD 4+ cells to the cervix and other sites in the reproductive tract. Infection blocks ability to utilize ARV therapy.

43 Schistosomiasis (bilharzia) GENITAL LESIONS OF SCHISTOSOMIASIS INCREASE WOMEN S RISK OF HIV 3-FOLD Kjetland, E, P Ndhlovu, et al Association between genital schistosomiasis and HIV in rural Zimbabwean women, AIDS 20(4):

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46 What are the obstacles? Technical or logistical? Methodological? Political?

47 Cost of Treating 7 NTDs US$ 0.50 all inclusive for treating 7 NTDs 4 DRUGS +d delivery + equipment + health heducation materials + training of personnel + monitoring and evaluation US$ 0.50 per person per year

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50 Weaknesses of cost-effectiveness analysis Single-input, single-output Short-term term O l l l f l i i di id l Only one level of analysis, individual or population

51 Matrix of disease and treatment interactions malnu worm malaria schist STI ART HIV malnu worm malaria 7-10 schist 3 STI ART? Х Х Х HIV

52 Weaknesses of CEA for disease prevention Intermediate inputs, NOT outcomes Interaction terms are rare No real theory of fdisease causation

53 What CEA needs to include for prevention and treatment Endogeneity Non-linearity linearity, non-convexity A multi-level l ltheory of fdisease causation Stillwaggon, E. Complexity, cofactors and the failure of AIDS policy in Africa, Journal of the International AIDS Society 12(12), 2009.

54 Pre-HAART Package of Care Suggested Septrin Micronutrients TB prophylaxis Unclear Macronutrients Acyclovir Deworming Bednets Water filters Annual Cost Dosing schedule Tolerability Septrin $10.00 DAILY ** Acyclovir $ DAILY *** Bednets $5.00 DAILY **** ART $ DAILY * Deworming $0.25 Every 4-6 months **** Source: Judd Walson

55 Economies of scale Increasing Returns Economies of scope Positive treatment t t spillovers, intra-individual i id Population effects

56 Biomedical research needs Insufficient research

57 Up to 2008, there had been Insufficient research 3 Randomized, controlled trials Walson 2008 Soil transmitted Helminths (Kenya) Nielson 2007 Lymphatic Filariasis (Tanzania) Kallestrup 2005 Schistosomiasis (Zimbabwe) 4 Observational studies, comparator groups have been: Helminth-uninfected individuals Same individuals pre/post treatment Individuals who clear infection vs. those who don t ONLY one RCT and one observational study had been adequately powered to detect a 0.3 log 10 difference in plasma HIV RNA. Walson J and G John-Stewart, Treatment of Helminth Co-Infection in Individuals with HIV-1: A Systematic Review of the Literature PLoS NTDs 1(3), 2007.

58 Biomedical research needs Insufficient research Conflicting results Small samples No control group No discrimination of species Short follow-up or no follow-up Kayvon Modjarrad, Sten H Vermund, Effect of treating co-infections on HIV-1 viral load: a systematic review, Lancet Infectious Diseases 10, An attentive audience and FUNDING from the AIDS policy community

59 The Spread of AIDS in Africa Source: AVERT.ORG

60 Multiple Regression Analysis of HIV prevalence with basic model and with cofactor infections R 2 =.80 Sawers, L. and Stillwaggon, E. Understanding the Southern Africa Anomaly : Poverty, Endemic Disease, and HIV, Development and Change 41(2): , 2010.

61 Explaining the southern Africa differential Regression can explain southern Africa differential by reducing the regression coefficient on southern Africa Regression without cofactor infections Explains about 10% of the southern Africa differential Regression with cofactor infections Explains about 70% of the southern Africa differential

62 Modeling Sexual Networks and HIV. Sawers, Isaac, and Stillwaggon Journal of the International AIDS Society, in press What will adding cofactors do?

63 Rapid growth of HIV/AIDS in sub-saharan Africa Source: AVERT.ORG

64 Determining cost-saving options Stillwaggon E, CS Carrier, MP Sautter, R McLeod, 2011, Maternal Serologic Screening to Prevent Congenital Toxoplasmosis: A Decision-Analytic Economic Model, forthcoming.

65 Risky behaviors that explain HIV for sub-saharan populations Early initiation of sex Premarital sex Multiple partners Extramarital sex Unprotected sex Alcohol use and sex Concurrent sexual relationships

66 Risky Behavior: Living with mosquitoes

67 Risky Behavior: Living with disease vectors

68 Risky Behavior: Living with soil-transmitted worms

69 Risky Behavior: Washing clothes in stream with schistosomiasis

70 Risky Behavior: Fishing in lake with schistosomiasis

71 Risky Behavior: Living with poor sanitation

72 Risky Behavior: Attending clinics that have no medicine

73 Nigeria's Triumph: Dracunculiasis Eradicated Emmanuel S. Miri, Donald R. Hopkins*, Ernesto Ruiz-Tiben, Adamu S. Keana, P. Craig Withers, Jr., Ifeoma N. Anagbogu, Lola K. Sadiq,Oladele O. Kale, Luke D. Edungbola, Eka I. Braide, Joshua O. Ologe, and Cephas Ityonzughul The Carter Center, Jos, Nigeria; The Carter Center, Atlanta, Georgia; World Health Organization/Nigeria and Federal Ministry of Health, Abuja, Nigeria Am. J. Trop. Med. Hyg., 83(2), 2010, pp

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75 Thanks for some slides from Judd L. Walson, MD, MPH Assistant Professor Departments of Global Health, Medicine (Infectious Diseases), Pediatrics and Epidemiology University of Washington Sten H. Vermund, MD, PhD Vanderbilt Institute t for Global l Health

76 Additional slides On sexual behavior On HIV cofactors

77 Percent 40 Genital herpes simplex virus type 2 - seroprevalence, by age, ( ) and ( ) NHANES II NHANES III Age Group Note: Bars indicate 95% confidence intervals. *National Health and Nutrition Examination Survey

78 Median age at first intercourse (selected countries, by gender) Derived from Singh S, et al Gender Differences in the Timing of First Intercourse: Data from 14 Countries, International Family Planning Perspectives 26(1):21 28, 43.

79 Source: John O. G. Billy, Koray Tanfer, William R. Grady, and Daniel H. Klepinger The Sexual Behavior of Men in the United States, Family Planning Perspectives 25(2):52 60.

80 Source: Kathryn Kost and Jacqueline Darroch Forrest American Women s Sexual Behavior and Exposure to Risk of Sexually Transmitted Diseases, Family Planning Perspectives 24(6):

81 Canada: first-year college students with more than 10 sexual partners Men: 21 % Women: 9 % Source:N.MacDonald,G.Wells,W. Fisher, et al High-Risk STD/HIV Behavior among College Students, Journal of the American Medical Association 263(23):

82 Canada: first-year college students with 5 or more sexual partners Men: 40 % Women: 25 % Source:N.MacDonald,G.Wells,W. Fisher, et al High-Risk STD/HIV Behavior among College Students, Journal of the American Medical Association 263(23):

83 Protein-energy malnutrition reduces integrity of skin and mucous membranes T-cell production.

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85 Iron-deficiency anemia reduces production of B cells T cells Natural Killer (NK) cells.

86 Zinc deficiency reduces Natural Killer cell activity i T-cell production integrity of the skin as a barrier to infection.

87 Vitamin-A deficiency reduces production of NK cells T cells B cells reduces skin and mucosal integrity increases viral load.

88 Maternal malnutrition increases MTC transmission Anemia increases viral shedding in the birth canal