1. Declines in adult HIV mortality in Botswana, 2003-5: evidence for an impact of antiretroviral therapy programs Rand Stoneburner, Dominic Montagu, Cyril Pervilhac*, Boga Fidzani**, Wayne Gill***, Gail Kennedy, Hilary Spindler, George Rutherford. HIV/AIDS Programme, World Health Organization*, National AIDS Co-ordinating Agency Botswana**, Joint United Nations Programme on HIV/AIDS***, Institute for Global Health, University of California San Francisco.

2. Background/purpose  Antiretroviral therapies (ART) reverse immunodeficiency and mortality risk among patients with severe HIV disease  ART program indicators provide evidence of therapeutic benefits in an increasing population of severely ill HIV/AIDS patients  However, impacts of ART programs in reducing HIV mortality at the population level have yet to be documented in Africa and are of strategic importance in assessing the ultimate intervention effectiveness  Botswana MOH and National AIDS coordinating agency asked the simple question. Is there an impact of ART on HIV- mortality at the population level and can it be measured using available data sources?

3. Aim and approach:  To assess ARV impact on adult mortality  Hypothesis: increasing ARV use among HIV ill will reduce mortality  Approach: analyze trends in adult mortality and ARV uptake over time and place  First, do mortality trends reasonably reflect HIV dynamics over time?  Are there declines in suspected HIV deaths?  Are declines in suspected deaths related to:  The general temporal distribution of ARV uptake  The population coverage rate of ARV uptake by district  The timing or initiation date of ARV coverage by district.

4. Methods  Analyses of mortality data from vital registration Ministry of Health (MOH)  Reported deaths by age sex and district from 1991-June 2005. Deaths in 2005 were annualized based on deaths occurring through June 2005 and reported by November 2005.  Analyses of ART program monitoring data-- ( MOH)  Numbers of patients enrolled and receiving ART by district site and year from 2002 through June 2005

5. Methods (cont.)  Mortality:  Vital registration (1)  Institutional discharges (dead alive) from district hospitals reported to Central Statistical Office (routinely available early 1990s -2003) but 2 year lag in collation and public release. This required rapid review of deaths reports from 2004 to June 2005  Non-institutional deaths reported from district health adm.  Validation: 95 - 98% mortality capture compared to census 1991 and 2001  Hospital midnight census (2)  Nightly record of institutional occupancy, admissions discharges (alive/dead), births, neonatal deaths ( through 2004)

6. Crude mortality and deaths by age in institutional settings Botswana 1991-2003  Crude mortality rates increase 3 fold  % of non-institutional deaths decreased from 26% to 15 %  “AIDS” as cause of death increased from 4% to 27%,1992-2003.  Age-specific institutional deaths increased 8 fold in ages 25-54; 3 fold in 0-4  Trends in institutional deaths mirror trends in HIV mortality.

7. ARV programme indicators, 2002 to February 2006. Eligible patients registered 60,478 Patients alive on ARV61,981 ( incl, private sector) Median baseline CD484/mm3 ( range 1-849) Median CD4 increase 12 mo 166/mm3 Patient follow-up90% Adherence85% Toxicity requiring med. Switch <7% Viral load <400 copies at 6 mo. 86% Deaths on treatment8% Survival at 12 mo83% ( CI 80-85%)

8. Association of increasing ART uptake and declines in adult mortality overall and by age 2003-2005*  Coincident with increasing patients on ARV between 2002 June 2005:  Institutional deaths declined 8% & 20% between 2003-4 and 2004-5, respectively.  Declines were greatest in 25-54 year olds; remained relatively stable in older and younger ages.  Similar declines not evident in 0- 4 year olds between 2003-4 (? 05).  Recent mortality declines are temporally associated with increasing ARV uptake *annualize based on deaths through June, reported by November 2005.

9. Geographic association between: ARV coverage rates and initiation dates by district, Botswana, 2003-05  Districts with early initiation and highest ARV coverage rates by 2003:  Francistown  Gaborone  Swerowe  Maun (Ngami)

10. Association of district level declines in deaths ages 20-49 between 2003-04 and ARV treatment rates by July 2003  Gaborone and Francistown: earliest opening dates, highest ARV coverage rates and 27 % and 17% mortality declines, respectively.  After weighting for population size declines in district level mortality were significantly correlated with district:  date of initiation of ART coverage (P<.05); level ART coverage (P<.05)

11. Comparing institutional mortality using vital registration and mortality derived from the midnight bed census in Gaborone and Francistown districts,1994-2004  Trends in mortality through 2004 from the midnight bed census data are similar to those from vital registration providing independent corroboration of observed declines.

12. Conclusions:  Our preliminary analysis provides evidence of any early association between ART uptake and declines in adult mortality in Botswana.  These findings must be interpreted with caution until further verified by updated and validated 2005 and 2006 mortality statistics and results from cohort based studies.  Alternative hypotheses? :  Natural dynamics, effects of other interventions; surveillance artifacts or other biases are less plausible.  The absent of similar declines in children is disturbing and needs to be explained urgently.  Mortality registration systems like that in Botswana can be an important adjunct to routine ART monitoring systems in informing questions related to population impact of ART as well as other health interventions.

13. Thank you Cyril Pervilhac*, HIV/AIDS Programme, World Health Organization*, Boga Fidzani**, National AIDS Co-ordinating Agency Botswana**, Wayne Gill***, Joint United Nations Programme on HIV/AIDS***, Dominic Montagu Gail Kennedy, Hilary Spindler, George Rutherford. Institute for Global Health, University of California San Francisco.