AIDS free generation. Bob Colebunders Institute of Tropical Medicine

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1 AIDS free generation Bob Colebunders Institute of Tropical Medicine

2 Why this optimism? Rapid scale-up of antiretroviral therapy Treatment can prevent new infections Expanded coverage of programmes to prevent mother-to-child transmission of HIV Strategies for functional cure?

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4 Dramatic gains in life expectancy in rural South Africa at population level (Bor & Bärnighausen, TULBE) Adult life expectancy (15+e 15 ) Year Public Sector ART Rollout 60.6 years in years in 2003

5 Rwanda: Health Insurance and ART coverage rise in tandem Insurance Coverage 100% 93% 80% 73% 86% 60% 40% 44% 20% 27% 0% 7% ART Coverage (%) * Nsanzimana, session MOSY03

6 % HIV care and treatment cascade in sub-saharan Africa 100% 72% N = 58,779 persons % 25% 0 Diagnosed with HIV CD4 measurement Eligible for ART Start of ART Mugglin C & IeDEA (in press), c/o Hirnschall, Thursday plenary

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9 The use of cell phones, as part of an active community tracking program has benefited the Haiti early infant diagnosis program and increased adherence

10 Malawi uptake of Option B+ Number of pregnant and breastfeeding women starting ART Breastfeeding women starting ART Pregnant women starting ART Q4 Q Q2 Q3 Q4 Q Q2 Q3

11 Still a long way to go to reach 15 million on ART, let alone treating everyone Treatment gap Receiving antiretroviral therapy PLHIV in need of ART % Estimated gap: CD4 cell count 350/mm 3 but not on ART 53% 3% Patients receiving ART 47% WHO, 2011

12 How to close the gap? In 2015, billion $ per year will be needed Since 2009 international AIDS funding remained stagnant at 8.2 billion per year

13 Resources available for HIV in low- and middle- income countries

14 Male circumcision Auvert B, PloS Med 2005 Gray R, Lancet 2007 Bailey R, Lancet 2007 Treatment of STIs Grosskurth H, Lancet 2000 Male & female condoms HIV PREVENTION combined interventions PMTCT Structural /Social HIV Counselling and Testing Coates T, Lancet 2000 Harm Reducation/Needl e exchange Behavioural Intervention

15 Roll-out of male circumcision: substantial country differences % of target achieved The protective effect of mail circumcision was sustained at 65% 66 months post intervention

16 Decrease of the rate of new HIV infections between 2001 and 2011

17 But increase of new infections in Eastern Europe Central Asia Middle East North Africa 2.5 million new infections in 2011

18 Strategies to cure Sterilising cure (elimination of the virus) Functional cure (life-long remission after stopping therapy)

19 Main problem: HIV persists as a latent provirus

20 The Berlin patient HIV-infected with acute myeloid leukemia, treated with Total body irradiation: destruction of his own immune system Transplantation with hematopoietic stem cell with the Δ32 mutation: no functional CCR5 After this treatment cart was not restarted and yet: No viral rebound High CD4 T cells Good health Nevertheless: some traces of latent proviral DNA in tissues

21 The Berlin patient The interpretation: Hematopoetic stem cells developed into new immune system, resistant to HIV infection Some latently infected cells remain BUT were kept under control an example of functional cure?

22 Possible strategies 1) Gene therapy: render target cells resistant to HIV infection 2) Anti-Latency therapy: rescue AND PURGE the latent reservoir 3) Therapeutic vaccine: improve CD8 T cell function to suppress virus

23 Genetic therapy deleting CCR5 Genetic deletion of CCR5 in by so called Zinc finger nucleases induces resistance to HIV infection SB-728 treatment in a Phase 1 clinical trial

24 Possible strategies 1) Gene therapy: render target cells resistant to HIV infection 2) Anti-Latency therapy: rescue AND PURGE the latent reservoir 3) Therapeutic vaccine: improve CD8 T cell function to suppress virus

25 Latency is in fact an active state May be we will never get of this latency state but we will be able to cope with it

26 Human endogenous retrovirusses (HERVs) HERVS are genetic elements that reside as provirusses in the host genome Constitute about 7-8% of the human body Have been associated with diseases (neoplasia, auto-immunity, fetal malformations) Are also having beneficial effects coding of proteins, gene regulation, DNA repair and also resistance to exogenous retrovirusses (activation of cellular factors such as Apobec, Trim, )

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28 Anti-Latency treatment

29 Possible strategies 1) Gene therapy: render target cells resistant to HIV infection 2) Anti-Latency therapy: rescue AND PURGE the latent reservoir 3) Therapeutic vaccine: improve CD8 T cell function to suppress virus

30 DIVA trial: DC therapeutic vaccination Apheresis WBC Monocytes Differentiation HIV + subjects under cart Injection 4X Gag-expressing DC = vaccine Dendritic cells (DC) Electroporation with HIV-1 gag mrna Van Gulck et al. AIDS 2012

31 Integration of various approaches 1. Gene therapy: resistant HIV targets : CD4 T cells, DC, macrophages 2. Anti-latency: induces expression of viral epitopes for CD8 T cells 3. Therapeutic vaccination: improves CD8 T cell responses Together could be enough to stop cart while maintaining: - High CD4 T cells - NO plasma VL and low proviral load - Good health = Functional cure!

32 Conclusion More access to ART More options for prevention We can start to dream about a functional cure and an AIDS free generation AIDS is not over