“A frank dialogue on the future of HIV treatment All the way from the factory to the patient”

1. “A frank dialogue on the future of HIV treatment All the way from the factory to the patient” Evidence and Policy Gaps on ART at500 CD4, TasP and PrEP.Why are we not scaling up the use of ART more aggressively? Pedro Cahn

2. Vision on treatment eligibility: Evolving scenarios Scenarios of ARV eligibility Estimated millions of people eligible for ART in LMIC in 2012 11 m 15 m 17.6 m 28.6 m 33 m Recommended since 2010 Recommended Since 2003 “Test and treat” CD4 ≤ 200 CD4 ≤ 350 CD4 ≤ 350 + TB/HIV HBV/HIV CD4 ≤ 500 + TB/HIV HBV/HIV All HIV+ 5 3 4 1 2 • ART regardless of CD4 count for: • Serodiscordant couples • Pregnant women • Children < 5 years

3. The promise of HIV treatment: Prevent HIV-related illness and disability Avert AIDS-related deaths Prevent new HIV infections

4. Why test and offer ARVs for all cases irrespective to CD4+ count Rational-based • HIV continuingly destroys the immune cells particularly CD4+ T cells • HIV, microbial translocation, co-infection are associated with chronic immune activation and inflammation that lead the association with the risk of non-AIDS-related death • More effective, more simple and more tolerable ART regimens are available • Treatment prevents further spread of HIV

5. Why should we start “early” • Because it makes sense! • Several cohorts have shown better CD4 recovery and survival with early ART • Starting with > 500 CD4 count, life expectancy is almost the same as HIV (-) individuals • Reduces TB incidence • Prevents IRIS • Prevents further spreading of HIV • Limits viral reservoir during acute infection • Nobody as shown that starting earlier produces any harm

6. HIV treatment prevents HIV-related illness and disability, and AIDS-related death, thereby normalizing survival Expected impact of HIV treatment in survival of a 20 years old person living with HIV in a high income setting (different periods)

8. Higher CD4 at ART Initiation Predicts Greater Long Term Likelihood of CD4 Normalization Years after cART initiation to achieving CD4 > 750 by CD4 stratum at cART initiation: 1996-2012 (N=1,327) Characteristics of EligiblePatients at HOPS by AI-CD4 (n = 1327) F. Palella et al., CROI 2014, Abstract 560

9. Immunodeficiency at the Start of CombinationAntiretroviral Therapy in Low-, Middle-, andHigh-Income Countries Conclusions: Median CD4 cell counts at the start of cART increased 2000–2009 but remained below 200 cells/mL in LIC and MIC and below 300 cells/mL in HIC. Earlier start of cART will require substantial efforts and resources globally. Trends of median CD4 cell counts at the start of cART (upper panel) and in proportions of men and women starting cART below 200 cells/mL (middle panel) or below 100 cells/mL (lower panel) in low-, middle-, and high-income countries, 2002– 2010. The shaded areas represent the 95% CI for each year. Results from mixed effects linear regression (model 3) are based on 379,865 patients; missing values imputed using multiple imputation. The IeDEA and ART Cohort Collaborations, J Acquir Immune Defic Syndr. 2014 Jan 1;65(1):e8-16.

10. IeDEAMultinationalCohorts (2004)

11. IeDEA Multinational Cohorts (2013)

12. At the country-level, the HIV response is already having a dramatic impact on life expectancy

13. A clear correlation exists between HIV treatment and incidence 1.1% (0.8%-1.4%) reduction in HIV incidence, for each 1.0% increase in treatment coverage. 1.0 p=0.325 p=0.003 0.8 p=0.0001 p=0.013 Incidence rate ratio 0.6 0.4 0.2 ART & HIV incidence: Hlabisa, South Africa 0 0% 30% 60% ART coverage Source: Tanseret al. Science 2013;339:966-971

14. Higher antiretroviral treatment coverage is associated with lower HIV infection rates: analysis of 51 low and middle-income countries Andrew Hill1, Anton Pozniak2, Alice Raymond3, Katherine Heath3, and Nathan Ford41Molecular and Clinical Pharmacology, University of Liverpool, UK, 2St Stephens Centre, Chelsea and Westminster Hospital, London, UK, 3 Department of Public Health, Imperial College London, UK,4WHO, Geneva, Switzerland LBPE29 Results ART coverage varied widely across different countries (Figure 1). In the 51 low and middle income countries, the mean percentage of HIV-infected individuals receiving antiretroviral treatment was 30% (range 0.6% in Madagascar to 62% in Botswana). The mean percentage of new HIV infections was 6.1% (range 2.0% in Thailand to 12.5% in Indonesia). There was a highly significant association between higher ART coverage and lower percentage incidence (Figure 2, p<0.00001). Higher ART coverage was also significantly correlated with lower annual AIDS-related deaths (Figure 2, p<0.00001). These results were consistent in separate analyses of African and non-African countries. Weighted least squares regression analysis showed that each 10% increase in ART coverage was associated with a 1.15% reduction in new HIV infections (Figure 2), and a 1.13% reduction in HIV-related deaths (Figure 3). According to these analyses, if all 51 low and middle income countries had had the same ART coverage as Botswana (62%), 1,243,647 of the 1,901,800 total HIV infections in 2012 (65%) could have been prevented. Under the same conditions, 998,732 of the total 1,427,200 deaths from HIV in 2012 in these 51 countries (70%) could have been avoided. Data from the 51 countries included in the analysis, plus seven high-income countries, are presented in Table 1. Countries were ranked according to the percentage of HIV-infected individuals receiving ART. Levels of ART coverage among high income countries ranged widely, from the United Kingdom (67%), to the United States (33%). Introduction In the HPTN 052 trial, antiretroviral treatment (ART) reduced the risk of HIV transmission by 96% in sero-discordant couples [1]. Increased ART coverage has also been associated with lower rates of HIV transmission at the community level [2]. The aims of this study were (1) to investigate the relationship between the percentage of HIV infected individuals on ART and both HIV incidence and HIV-related death in a multi-country analysis; (2) To compare ART coverage rates between low, middle and high-income countries. Methods This analysis was based upon UNAIDS standardised country-level estimates for 2012: number of people with HIV-infection, receiving antiretroviral treatment, new HIV infections and HIV-related deaths per year [3]. There were 36 African countries included, plus 15 non-African low and middle-income countries with at least 50,000 HIV-infected individuals . Data from high-income countries were extracted from national reports (United Kingdom [6], Netherlands [9], Australia [11]), conference proceedings (France [8]), and peer-reviewed articles (Denmark [7], British Columbia [10] and United States [12]). Weighted least squares and linear regression methods were used to investigate the association between the percentage of HIV-infected individuals receiving ART and both the numbers of new infections and AIDS-related deaths (as percentages of the national HIV epidemic). The relevance of GDP [4] and PEPFAR status [5] was assessed using nested models and likelihood ratio testing. The number of preventable HIV cases and deaths were calculated using the relevant regression coefficients of the fitted weighted least squares model. Table 1. Number of people taking antiretroviral treatment, new HIV infections and HIV-related deaths (2012 data) for 51 low/middle income and 7 high income countries Figure 2: HIV incidence (as a percentage of the total number of HIV-infected people) versus ART coverage in 51 countries, weighted by epidemic size (2012 data). Put a figure here that explores one particular outcome in a complicated table of results. Figure 3: AIDS-related death rates (as a percentage of the total number of HIV-infected people) versus ART coverage in 51 countries, weighted by epidemic size (2012 data). Figure 1. The percentage of all HIV-infected people taking antiretrovirals, by country Conclusions For the 51 low and middle income countries in this analysis, the mean percentage of HIV-infected people receiving antiretroviral treatment was 30% (range 0.6% in Madagascar to 62% in Botswana). Countries with higher ART coverage had significantly lower rates of new HIV infection and lower HIV-related death rates. According to this analysis, 65% of the new HIV infections and 70% of the HIV-related deaths in 2012 could have been prevented, if all 51 countries had antiretroviral coverage rates as high as Botswana (62%). Some low and middle-income countries have rates of antiretroviral treatment coverage higher than certain high-income countries – for example the United States (33% coverage, ranked 30th out of 58 countries). These results provide a compelling argument for continuing to improve antiretroviral treatment coverage worldwide Presented at the World AIDS Conference, Melbourne, Australia, July 2014 [abstract LBPE29]

15. HIV treatment, the most effective biomedical intervention for the prevention of HIV transmission

16. 103 centers; 16,597 patients, 12,069 on HAART. Median FU time. 5.43 years; Median time on HAART: 4.42 years Crudeincidence of all cause mortality decreasedwithlongerexposuretocART. Rates of non-AIDS deathsremainedconstant

17. NNT for success • Universal access and TasP: Modelling shows that if 72% of the population has undetectable VL, AIDS could be no longer a public health threat • PreP: ???? • Treatment is efficacious (it works) and effective • PreP is efficacious (in some trials) but not effective*, so far. (Might be considered for special populations) * It requires test and periodic monitoring of target populations, adherence in healthy individuals, etc NNT: Numbers needed to treat

18. Key challenges • Societal: Stigma, discrimination, criminalization • Diversity of facility costs • Gaps in the treatment cascade • Delivery challenges • Financing • Addressing the epidemic in adolescents, children and other left behind populations • To control a epidemic without a vaccine, nor a cure

19. Why are we behind our needs? • Insufficient funding • Low testing rate, missed opportunities • Stigma, discrimination, criminalization • Retention in care, adherence • Less community mobilization • Logistical issues (Procurement, stockouts) • Lack of political will (“I invest, the benefits will came when I am no longer in office”) • Mixed messagges from the scientific community (“Waiting for the results of RCTs”)

20. The way forward • Set aspirational new targets • Promote a renewed alliance including international organizations, funders, countries, academia, pharma • Increase countries’ ownership • Integrate HIV with NCD care • Generate new activism • Each day we miss, thousands of lives are lost