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A Phase IIB four arm randomized trial to reduce HIV infection in

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					       Session 4:
CAPRISA Epidemiology &
  Prevention Research
  HIV Epidemiology in Vulindlela:
                        .


Rationale CAPRISA 006 – RHIVA Trial
   (Reducing HIV in Adolescents)
          Quarraisha Abdool Karim, PhD
      on behalf of the CAPRISA - MiET Team

    CAPRISA Scientific Advisory Board Meeting,
                  6 April 2009
          HIV Epidemiology & Prevention

                                                                                         Behavioural
HIV epidemiology                          Microbicides                                   interventions

     Focus:                                             Focus:                              Focus:
 Young women               Trials in young women                                          Schoolgirls


  HIV incidence                          Tenofovir gel trial                              RHIVA trial
Sexual behaviour                              HPTN 035 / MTN


                                    10
                                               Male
                                    8          Female
                   Prevalence (%)




                                    6

                                    4

                                    2

                                    0

                                         <9    10-14 15-19 20-24 25-29 30-39 40-49 >49
                   Overview

•   HIV infection in Africa
•   HIV infection in Vulindlela – importance of
    young women
•   Reducing HIV infection in young women -
    What have we learnt to date?
•   The RHIVA trial
                                                       HIV by age and sex in Africa

                                  Kenya                                                                                               25           Malawi                                                               Men
                     15
                                                                                                 Men                                                                                                                    Women
                                                                                                 Women                                20




                                                                                                                 HIV prevalence (%)
HIV prevalence (%)




                     10                                                                                                               15



                                                                                                                                      10

                      5

                                                                                                                                       5



                      0                                                                                                                0
                          15-19    20-24   25-29   30-34    35-39    40-44    45-49    50-54      55-59                                     15-19       20-24           25-29     30-34      35-39           40-44      45-49




                                                                                                                                            Lesotho
                                                                                                                                      50
                                                                                                                                                                                                                        Men
                     15
                                  Cameroon                                                        Men
                                                                                                  Women                               40
                                                                                                                                                                                                                        Women




                                                                                                               HIV prevalence (%)
HIV prevalence (%)




                     10
                                                                                                                                      30



                                                                                                                                      20
                      5


                                                                                                                                      10

                      0
                          15-19    20-24   25-29    30-34    35-39    40-44    45-49     50-54         55-59
                                                                                                                                       0
                                                                                                                                           15-19    20-24       25-29     30-34   35-39   40-44      45-49      50-54    55-59
      HIV incidence and HIV prevalence by
         age and sex, South Africa 2005
                                          30
                                                                                   Prevalence (females)
                                                                                   Prevalence (males)
       HIV prevalence and incidence (%)




                                          25
                                                                                    Incidence (females)
                                                                                    Incidence (males)
                                          20


                                          15


                                          10


                                          5


                                          0
                                               <20   20-29         30-39         40-49          50+
                                                             Age group (years)



Source: Rehle T, Shisana O, Pillay V, Zuma K, Puren A, Parker W. National HIV incidence measures:
    new insights into the South African epidemic. South African Medical Journal 2007 (in press)
             CAPRISA Vulindlela CRS




CAPRISA
Vulindlela
Clinical
Research
Site, near
Howick in
KwaZulu-
Natal
Temporal trends in HIV prevalence in
   ANC attendees : 2001-2008
  Year          N          Prev (%)
  2001         349           32.4

  2002         403           34.8

  2003         225           40.8

  2004         552           42.6

  2005         361           37.4

  2006         333           37.6

  2007         361           34.4

  2008         389           40.9
Age specific HIV prevalence in Vulindlela
       ANC attendees:2004-2008

                 2004              2005              2006               2007                 2008
<20              26.7               22.0             17.2               13.7                 20.8

20-24            54.7               37.5             48.0               37.5                 39.2

25-29            66.3               50.0             52.1               61.4                 60.8

30-34            53.8               56.8             51.4               55.6                 59.6

> 35               9.8              34.3             33.3               42.1



Q Abdool Karim, MH Latka, JA Frohlich, G Makhaye, ABM Kharsany, M Zuma, SS Abdool Karim
 Temporal trends in HIV infection in prenatal women: impact of increasing mortality in a mature
              HIV epidemic in rural KwaZulu-Natal, South Africa.. Submitted.
 Proportion of Pregnancies and HIV
 prevalence in <20 year age group in
Vulindlela ANC attendees : 2004-2008
 Year     Proportion of all   HIV Prev (%)
            Pregnancies
 2004           36.6              26.7

 2005           30.2              22.0

 2006           29.2              17.2

 2007           36.3              13.7

 2008           38.4              20.8
HIV infection in young pregnant women
          in Vulindlela in 2008
    Age category       HIV Prevalence (%)
      15-16yrs                 4
      17-18yrs                 22

      19-20yrs                 35
      21-22yrs                 35

      23-24yrs                 44


 • 97 adolescents of 5600 patients in care
 • 15% on ARV treatment
                   Mortality Rates in Vulindlela

• Overall mortality rate in 2006:
   2.9 deaths/100 p-yrs ( 2.5 - 3.3/100 p-yrs).
   The highest mortality in:
     • women in the 30 - 34-year age group – 3.1/100wy
     • men in the 35 - 39 and > 60-year age groups -
       6.7/100my

• Of the 185 verbal autopsies reported:
   42% were attributable to AIDS.
   20 - 24 year old women and 35 - 39 year old men are
     bearing a disproportionately large burden of AIDS-
     related mortality in this community
   Pulmonary TB most common cause of death
   M Mashego, D Johnson, J Frohlich, H Carrara, Q Abdool Karim, S Afr Med J 2007; 97: 589-594.
     CAPRISA HIV Seroincidence Study:
      Select Baseline Characteristics

• HIV prevalence                     37%
• Monthly Coital frequency           3-8
• Self reported baseline condom use 26%
• Self reported month 6 condom use   51%
• Incidence rate              6.8%/100py
    CAPRISA 050 – Vulindlela
 Age-Specific STI Incidence Rates

Age Group   N     Incidence/100pyrs [95% CI]
  (years)
  16-17     43           7.0 (0-14.9)

  18-24     180         13.9 (8.4-19.3)

  25-3O     39          10.3 (0.2-20.3)
      Temporal trends in HIV incidence rates
      over time at 12 months and 24 months
                      (n=839)
Age group     First 12 months   Second 12 months
(years)        HIV incidence      HIV incidence
              (per 100pys)[n]    (per 100pys)[n]

All             7.4 [47/839]       5.7 [20/486]

14-19           6.2 [12/270]       6.6 [6/153]

20-24           7.9 [17/280]       8.7 [8/145]

≥25             7.8 [18/289]       3.6 [6/188]
                Interventions Piloted

• Stepping Stones & SIBAHLE
    Multilevel
    Beyond HIV/AIDS – gender, GBV, future, masculine
     and feminine identity and expectations
    Skills and Self-Esteem
    Changing values and norms
    Individual responsibility
    Parental and community responsibility
    Leadership responsibility
    Method for Adapting Interventions tested elsewhere
    Relevance and acceptability of content and process
     beyond target group
    Social Cognitive and Gender Empowerment Theory
     Based
                   HIV Prevention
                                                                                          Behavioural
HIV epidemiology                           Microbicides                                   interventions

     Focus:                                              Focus:                              Focus:
 Young women                Trials in young women                                          Schoolgirls


  HIV incidence                           Tenofovir gel trial                              RHIVA trial
Sexual behaviour                               HPTN 035 / MTN


                                     10
                                                Male
                                     8          Female
                    Prevalence (%)




                                     6

                                     4

                                     2

                                     0

                                          <9    10-14 15-19 20-24 25-29 30-39 40-49 >49
   Challenges to HIV prevention in young
                  women
• Current interventions: Lifeskills programs, IEC –
  information-education-counselling, gender-based
  violence, stepping stones, abstinence programs,
  “just-say-no”…
• Not a single intervention program in adolescents
  anywhere in the world has been shown to reduce HIV
  infection ! Why?
    HIV/AIDS is more than a behavioural problem, but it is
     embedded in socio-economic & political context.
    Failure to address gender power relations
    Failure to consider survival and coping strategies
    Imposed advice to change vs Facilitate self-imposed change
    Failure to link prevention & treatment
       School-based HIV/AIDS prevention
            programmes to date…
• Several AIDS prevention programmes are implemented across
  the world by governments, academia, NGOs and CBOs, and
  private sector
• Most, by design, focus on increasing AIDS knowledge & are
  rarely evaluated
• When done, evaluations are poorly conducted
    Inadequate measurement of impact eg. condoms distributed,
      schoolchlidren educated, intentional behaviour not meaningful
    Reduction in HIV infection is goal but seldom measured
    No control groups – cannot assess direct impact
• Some show increased HIV knowledge & awareness,
• Few demonstrate self-reported behaviour change,
• None show success in preventing HIV infection
        Use of cash incentives shown to be
         successful in drug rehabilitation
• Cash incentives in cocaine users (Lewis & Petry 2005)
    159 cocaine abusers randomized to cash incentives for 3 or more
     family related activities during the 12 week treatment period
    Those who joined family related activities remained abstinent longer
• Lower vs higher cash incentive for cocaine abuse
  (Sindelar et al. 2007)
    120 cocaine abusers randomized to $80 vs $240 vs control
    Larger amount more effective - longest duration of abstinence &
     higher treatment completion
• Weekly $5 gift certificates increase treatment
  completion rates in African American women (Bride
  and Humble 2008)
    7 fold higher treatment completion compared to controls (total value
     of incentives of $175)
        Cash Incentives to Quit Smoking

• Cash incentives used to motivate GE employees to quit
  smoking in the USA
• 878 employees randomly assigned to:
    receive information about smoking-cessation programs (n=442) or to
    receive information about programs plus financial incentives
     (n=436).
• Incentivised group had significantly higher rates of
  smoking cessation than did the information-only group:
    9-12 months after enrollment (14.7% vs. 5.0%, P<0.001)
    15-18 months after enrollment (9.4% vs. 3.6%, P<0.001).
    higher rates of enrollment in a smoking-cessation program (15.4%
     vs. 5.4%, P<0.001),
    completion of a smoking-cessation program (10.8% vs. 2.5%,
     P<0.001),
    smoking cessation within the first 6 months after enrollment (20.9%
     vs. 11.8%, P<0.001)
            Volpp et al A randomized, controlled trial of financial incentives for smoking
                              cessation. NEJM 2009 360(7):699-709.
        Combining Cash Incentives and
          Microfinance - PROGRESA
• Mexican anti-poverty programme that combines a
  traditional cash transfer program with financial
  incentives for families to invest in human capital of
  children (health, education and nutrition)
    Conditionalities - families must obtain preventive health care,
     participate in growth monitoring and nutrition supplements
     programs, and attend education programs about health and
     hygiene.
    significant increased utilization of public health clinics for
     preventive care.
    lowered the number of inpatient hospitalizations and visits to
     private providers.
    significant improvements in the health of both children and adults.
    Children - 23% reduction in the incidence of illness, 1- 4%
     increase in height, & 18% reduction in anemia.
    Adults - significant reduction in the number of days of difficulty with
     daily activities due to illness and in the number of days in bed due
     to illness.
                     Gertler et al Health economics. 2008 Jul 15
     Key lessons in the conduct of HIV
             prevention trials

• Effect size in individual prevention interventions are
  small
    Fidelity of delivery of intervention
    Saturation and coverage of target population
    Maximise adherence

• Site Selection & Populations critically important
    High incidence rates
    substantial difference to be made and measured
       Key lessons in the conduct of HIV
               prevention trials

• Measure HIV incidence rates
   Poor correlation between behavioural markers and
    HIV risk

• Evaluate with most rigorous study design - RCTs

• Minimise Design effects
   minimise too much variability within and between
    clusters/ populations/unit of randomisation
      Study Schema - CAPRISA 006
   RHIVA (Reducing HIV in Adolescents)
• Phase III placebo controlled, cluster randomised,
  trial to assess the impact of a school-based
  incentivised HIV prevention intervention on HIV
• Study Population: All grade 9 and 10 learners (> 14
  years) attending 12 secondary schools in Vulindlela
• Study Size:         2400 learners (~ 200 per school)
• Study Duration:    36 months
• Primary outcome: HIV incidence rates
• Secondary outcomes: School attendance, academic
  performance, sexual behaviour & pregnancy rates
                RHIVA Trial Intervention
• Control and Intervention Schools: Standardized DoE
  Essential Package comprises:
    Seven modules incl. DoE Essential Package & Life Skills
    Info on local sites for condoms, VCT, circumcision & AIDS
     care
    Information incl. posters, pamphlets and AIDS hotline details

• Intervention Schools: Cash incentives paid on
  achievement of the following milestones:
      School attendance (Quarterly)
      Library books read (Quarterly)
      Participation in a hobby / sport / community project (Quarterly)
      Academic performance (Half-yearly)
      Self-initiated testing for HIV infection (Annually)
            RHIVA Trial Intervention

• Additional Support in Intervention schools:
    On-site teacher support, textbooks and library books
    Financial management training through the Life Skills
     curriculum
    Structured, supervised after-school extra-curricular
     activities
    Family support and counselling services
           Partnership with MiET

• MiET in partnership with DoE has developed and
  implemented innovative school models:
    CSTL programme in all provinces
    MiET is an implementing partner with the SADC
     Secretariat in the CSTL programme
• MiET’s experience and well developed partnership
  with KZN Department of Education makes this
  intervention and evaluation possible with the DoE’s
  support and participation
    Care and support for students testing
                HIV positive
• Strong link between school intervention and AIDS
  care & treatment
• International standards of pre- and post-test
  counselling will be provided for all HIV testing
• HIV positive students will be cared for by CAPRISA
  & where preferred by accredited referral centres
• Teachers will be trained to provide support
• MiET & CAPRISA school nurses to provide on-site
  comprehensive prevention, care & support
                Study Milestones

• 2009:
    Design & pilot-test intervention and trial
     measurements
    Consultation with key stakeholders, site
     preparation, assembly & training of study teams
    Complete protocol

• 2010: Initiate intervention & baseline assessments

• 2013: Complete follow-up & data collection

• 2013: Data analysis completed & Final report
         Summary of Proposed RHIVA
          approach - 4 key concepts

• Target: Young women - group most at HIV risk
• Intervention Design: Based on facilitating &
  incentivising young women to choose a better
  future through healthier choices & better
  educational opportunities
• End-product: Intrinsic (and self-imposed)
  behaviour change – greater prospect of
  sustainability
• Rigorous evaluation: Based on the highest
  standards of scientific evidence and ethics for
  global impact
                                   Acknowledgements
•   The RHIVA trial is a collaborative effort with Media Education Trust – Africa and the Department
    of Education.
•   We acknowledge with gratitude financial support of the RHIVA trial from the Royal Netherlands
    Embassy
•    CARE- CDC and LifeLab for financial support of the Studies to understand HIV acquisition in
    young women
•   HIV Prevention Trials Network for financial support for the validation and adaptation of SIHLE
•   KwaZulu-Natal Provincial Department of Health & Department of Education
•   Financial support for CAPRISA from the National Institute of Allergy and infectious Disease (NIAID), National
    Institutes of Health (NIH) (grant# AI51794) is gratefully acknowledged. The US President's Emergency Plan for
    AIDS Relief (PEPfAR) funded the care of patients in the study. The Global Fund to fight AIDS, Tuberculosis and
    Malaria, via the Enhancing Care Initiative, funded drugs used in the studies.

•   Several of the senior clinicians, and medical students were supported by the Columbia University-Southern
    African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International
    Center, National Institutes of Health (grant # D43TW00231) or the Fogarty International Center Clinical Research
    Scholars Programme as well as a training grant from LifeLab


                                            Salim S Abdool Karim; Quarraisha Abdool Karim, Janet
                                            Frohlich; Ayesha Kharsany; Fanele Ntombela; Gethwana
                                            Mahlase; Silvia Maarschalk; Muke Mlotswa; Nonhlanhla
                                            Yende; Irene van Middelkoop; Natasha Samsunder; Hilton
                                            Humphries; Nancy Hancock

               Lynn van der Elst, Thuli Dlamini and Chris Ramdass

				
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