Dall’HIV	
  all’AIDS	
  fino	
  alla	
  co-­‐infezione:	
  
una	
  diagnosi	
  difficile	
  ?	
  
	
  Francesco	
  Castelli	
...
Global	
  Burden	
  of	
  Disease	
  2010	
  
h"p://ghdx.healthmetricsandevalua6on.org/global-­‐burden-­‐disease-­‐study-­...
Global	
  Burden	
  of	
  Disease	
  2010	
  
h"p://ghdx.healthmetricsandevalua6on.org/global-­‐burden-­‐disease-­‐study-­...
Abbreviated	
  HIV	
  treatment	
  cascade	
  for	
  
sub-­‐Saharan	
  Africa,	
  2012	
  
	
  
Source: UNAIDS global repo...
GTB:	
  policy	
  on	
  collaboraLve	
  TB/HIV	
  acLviLes	
  
	
  
WHO	
  recommends	
  providing	
  HIV	
  tesLng	
  and...
Percentage	
  of	
  TB	
  paLents	
  with	
  known	
  HIV	
  status	
  by	
  
country,	
  2012	
  (Global	
  TB	
  repot	
...
Number	
  of	
  TB	
  paLents	
  with	
  known	
  HIV	
  status	
  
2004-­‐2012	
  (WHO	
  Global	
  report	
  2013)	
  
Percent	
  of	
  TB	
  paLents	
  with	
  known	
  HIV	
  status	
  
2004-­‐2012	
  (WHO	
  Global	
  report	
  2013)	
  
...
Estimated number
of cases
Estimated number
of deaths
HIV-associated TB 1.1 million (13%)
(range: 1.0–1.2 million)
320,000
...
La co-infezione TB/HIV in Italia
•  Assenza	
  di	
  un	
  registro	
  per	
  la	
  co-­‐infezione	
  
•  S6ma	
  di	
  ≈	...
Treatment outcomes for HIV-positive and
HIV-negative TB patients, 2011.
WHO Global report 2013
GLOBAL TB
PROGRAMME
1.  Reduce	
  sexual	
  transmission	
  of	
  HIV	
  by	
  50%	
  by	
  2015	
  
2.  Halve	
  the	
  transmission	
  of	
 ...
EsLmated	
  number	
  of	
  tuberculosis-­‐related	
  deaths	
  among	
  
people	
  living	
  with	
  HIV,	
  globally	
  ...
GLOBAL TB
PROGRAMME
Ref:	
  Global	
  TB	
  Control	
  Report	
  2013	
  
TB/HIV	
  intervenLons:	
  further	
  progress	
...
Inequity	
  of	
  ART	
  provision	
  to	
  TB	
  paLents	
  	
  
Lab	
  methods	
  for	
  HIV	
  tesLng	
  	
  
The	
  diagnosis	
  of	
  HIV	
  infecLon	
  can	
  reliably	
  be	
  estab...
POC rapid tests for the diagnosis of
HIV infection
Point-­‐of-­‐care	
   rapid	
   tests	
   for	
   HIV	
   anLbody	
   d...
Why	
  Provide	
  Rapid	
  HIV	
  TesLng?	
  
1.	
  A	
  laboratory	
  and	
  lab	
  equipment	
  are	
  not	
  requested....
Timing	
  of	
  tesLng	
  is	
  important	
  because	
  
Lming	
  of	
  ART	
  makes	
  the	
  difference	
  	
  
•  Offer	
...
Effect	
  of	
  AnLretroviral	
  Drugs	
  
during	
  Tuberculosis	
  Therapy:	
  the	
  SAPiT	
  trial	
  
Abdool	
  Karim	...
WHO recommendation
•  Start ART in all HIV infected individuals with active
tuberculosis irrespective of CD4 cell count
(s...
Point-of-care CD4 testing can increase retention
in care prior to starting treatment and can also
reduce time to eligibili...
2013 WHO ART Guidelines in Adults: Summary
Topic 2002 2003 2006 2010 2013
When to start CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200
- Con...
MONITORING ART RESPONSE
Targeted	
  viral	
  load	
  
monitoring	
  (suspected	
  
clinical	
  or	
  immunological	
  
fai...
•  L’importanza dell’integrazione dei servizi
Results: One stop service model in Rwanda
Decentralisation of services and task shifting to nurses
Percent shows out of al...
Health officers and nurses
(Health center)
Physicians
( Hospitals)
Mortality (%) 11 8
Lost to follow up (%) 13 25
Retentio...
Use the decentralized TB services to provide ART
ART services are still too centralized and too few
Number of facilities p...
Early	
  TB	
  diagnosis	
  in	
  PLHIV	
  
The cascade of care
With signs/symptoms
Other diagnostic tests
Treat	
  for	
  TB	
  	
  
if	
  sugges6ve	
  Initial test
...
34 |
WHO	
  guidance	
  documents	
  
GLOBAL TB
PROGRAMME
Xpert	
  MTB/RIF	
  as	
  the	
  iniLal	
  diagnosLc	
  test	
  
Global scale-up of Xpert MTB/RIF
CumulaLve	
  number	
  of	
  GeneXpert	
  instrument	
  modules	
  and	
  
Xpert	
  MTB/R...
Impact	
  of	
  Xpert	
  MTB/RIF	
  in	
  clinical	
  pracLce	
  
The	
  TB-­‐NEAT	
  study	
   	
  is	
  a	
  randomized	...
The end
PPT Castelli "Dall'HIV all'AIDS fino alla coinfezione: una diagnosi difficile?"
PPT Castelli "Dall'HIV all'AIDS fino alla coinfezione: una diagnosi difficile?"
PPT Castelli "Dall'HIV all'AIDS fino alla coinfezione: una diagnosi difficile?"
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PPT Castelli "Dall'HIV all'AIDS fino alla coinfezione: una diagnosi difficile?"

  1. 1. Dall’HIV  all’AIDS  fino  alla  co-­‐infezione:   una  diagnosi  difficile  ?    Francesco  Castelli     Clinica  Mala)e  Infe)ve  e  Tropicali   Università  di  Brescia  e  Spedali  Civili  di  Brescia   Centro  collaboratore  OMS  per  la  co-­‐infezione  TB-­‐HIV   1°  Convegno  Interdisciplinare   Milano,  21-­‐22  Marzo  2014    
  2. 2. Global  Burden  of  Disease  2010   h"p://ghdx.healthmetricsandevalua6on.org/global-­‐burden-­‐disease-­‐study-­‐2010-­‐gbd-­‐2010-­‐data-­‐downloads  
  3. 3. Global  Burden  of  Disease  2010   h"p://ghdx.healthmetricsandevalua6on.org/global-­‐burden-­‐disease-­‐study-­‐2010-­‐gbd-­‐2010-­‐data-­‐downloads  
  4. 4. Abbreviated  HIV  treatment  cascade  for   sub-­‐Saharan  Africa,  2012     Source: UNAIDS global report 2013
  5. 5. GTB:  policy  on  collaboraLve  TB/HIV  acLviLes     WHO  recommends  providing  HIV  tesLng  and  counselling   to  paLents  with  presumpLve  and  diagnosed  TB   HIV:  ART  consolidated  guidelines    
  6. 6. Percentage  of  TB  paLents  with  known  HIV  status  by   country,  2012  (Global  TB  repot  2013)   GLOBAL TB PROGRAMME Ref:  Global  TB  Control  Report  2013  
  7. 7. Number  of  TB  paLents  with  known  HIV  status   2004-­‐2012  (WHO  Global  report  2013)  
  8. 8. Percent  of  TB  paLents  with  known  HIV  status   2004-­‐2012  (WHO  Global  report  2013)   2.8 million of notified TB patients had a documented HIV test result in 2012 (46%) - an increase from 2.5 million and 40% respectively in 2011, and 15 times the level of 3.1% reported in 2004.
  9. 9. Estimated number of cases Estimated number of deaths HIV-associated TB 1.1 million (13%) (range: 1.0–1.2 million) 320,000 (range: 400,000–460,000) 0–24 25–49 50–99 100–299 300 and higher No estimate available The Global Burden of TB, 2012 TB is responsible for one in five AIDS deaths TB  Global  report  2013  
  10. 10. La co-infezione TB/HIV in Italia •  Assenza  di  un  registro  per  la  co-­‐infezione   •  S6ma  di  ≈  4,000  casi  di  TB  /  anno   •  S6ma  di  10%  di  prevalenza  infezione  HIV  in   nuovi  casi  TB   E’  possibile  fare  una  pianificazione  degli   interven6  di  prevenzione  e  cura  in  assenza   di  un  sistema  di  informazione  ?  
  11. 11. Treatment outcomes for HIV-positive and HIV-negative TB patients, 2011. WHO Global report 2013 GLOBAL TB PROGRAMME
  12. 12. 1.  Reduce  sexual  transmission  of  HIV  by  50%  by  2015   2.  Halve  the  transmission  of  HIV  among  people  who  inject  drugs   by  2015   3.  Eliminate  HIV  infec6ons  among  children  and  reduce  maternal   deaths   4.  Reach  15  million  people  living  with  HIV  with  lifesaving   an6retroviral  treatment  by  2015   5.  Halve  tuberculosis  deaths  among  people  living  with  HIV  by   2015   6.  Close  the  global  AIDS  resource  gap   7.  Eliminate  gender  inequali6es  and  gender-­‐based  abuse  and   violence  and  increase  the  capacity  of  women  and  girls  to   protect  themselves  from  HIV   8.  Eliminate  HIV-­‐related  s6gma,  discrimina6on,  puni6ve  laws   and  prac6ces   9.  Eliminate  HIV-­‐related  restric6ons  on  entry,  stay  and  residence   10. Strengthen  HIV  integra6on   2011 UN Political Declaration on HIV and AIDS key targets
  13. 13. EsLmated  number  of  tuberculosis-­‐related  deaths  among   people  living  with  HIV,  globally  and  for  Africa,  2004–2012   GLOBAL TB PROGRAMME Ref:  UNAIDS  Global  Report  2013  
  14. 14. GLOBAL TB PROGRAMME Ref:  Global  TB  Control  Report  2013   TB/HIV  intervenLons:  further  progress   ART  and  CPT  enrolment  among  TB  paLents  
  15. 15. Inequity  of  ART  provision  to  TB  paLents    
  16. 16. Lab  methods  for  HIV  tesLng     The  diagnosis  of  HIV  infecLon  can  reliably  be  established  by  very   sensiLve  ELISA  tests  (detecLng  concomitantly  Abs  and  Ags)  and   confirmed  by  very  specific  immunoblot  tests.   Point  of  Care  (POC)  test  to  detect  HIV  infecLon  are  available  and   are  recommended  by  WHO  since  1997     World  Health  OrganizaQon.  Revised  RecommendaQons  for  the  SelecQon  and   Use  of  HIV  AnQbody  Tests   hUp://www.who.int/docstore/wer/pdf/1997/wer7212.pdf    
  17. 17. POC rapid tests for the diagnosis of HIV infection Point-­‐of-­‐care   rapid   tests   for   HIV   anLbody   detecLon   have   facilitated  the  scale-­‐up  of  HIV  counseling  and  tesLng  throughout   resource  constraint  se_ngs  [1].     The  sensiLvity  of  these  tests  approaches  100%  and  is  equivalent   to  that  of  EIA  [2].  These  tests  cannot  idenLfy  persons  with  acute   HIV  infecLon  who  have  not  yet  developed  specific  anLbodies  [3].     1.  Parekh  Clin  Pathol  2010;134:  537   2.  Van  den  Berk  J  Clin  Microbiol  2003;  41:  3868   3.  Stekler  JD  Clin  Infect  Dis  2009;  49:  444  
  18. 18. Why  Provide  Rapid  HIV  TesLng?   1.  A  laboratory  and  lab  equipment  are  not  requested.   2.  Can  be  performed  by  trained  clinical  personnel   The  negaLve  predicLve  value  of  a  screening  test  is  high     è  A  client  with  a  negaLve  rapid  HIV  test  result  can  be  told  he/she  is  not   infected.       As  with  any  screening  test,  the  posiLve  predicLve  value  of  a  reacLve  rapid  HIV   test  is  low  in  populaLons  with  low  prevalence     è  Every  reacLve  rapid  test  must  be  confirmed  by  a  supplemental  test   3.  Many  persons  do  not  return  for  the  results  of  convenLonal  tests.   Almost  all  clients  receive  their  rapid  HIV  test  results  because  results  can   be  provided  immediately  during  the  tesLng  visit.  
  19. 19. Timing  of  tesLng  is  important  because   Lming  of  ART  makes  the  difference     •  Offer  the  HIV  test  as  soon  as  TB  is  diagnosed   (if  not  done  before)   •  Ensure  rapid  turn-­‐around  6me  for  a  posi6ve   test  (including  confirmatory  test)  
  20. 20. Effect  of  AnLretroviral  Drugs   during  Tuberculosis  Therapy:  the  SAPiT  trial   Abdool  Karim  SS,  N  Engl  J  Med  2010;  362:697-­‐706   •  HR for mortality in arm A = 0.45 (0.26 – 0.79) p=0.005 for any CD4 •  HR = 0.54 for CD<200 •  HR = 0.08 for CD4>200 Trial stopped by the ethical committee
  21. 21. WHO recommendation •  Start ART in all HIV infected individuals with active tuberculosis irrespective of CD4 cell count (strong recommendation – Low quality of evidence) TB/HIV guidelines 2012 and ART consolidated guidelines 2013 Ensure  ART  treatment  during  TB  treatment   •  Anti-TB treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment. •  Those TB/HIV patients with profound immunosuppression (e.g. CD4 counts <50 cells cells/mm3) should receive ART immediately within the first 2 weeks of initiating TB treatment.
  22. 22. Point-of-care CD4 testing can increase retention in care prior to starting treatment and can also reduce time to eligibility assessment, which may result in more eligible patients being initiated on ART.
  23. 23. 2013 WHO ART Guidelines in Adults: Summary Topic 2002 2003 2006 2010 2013 When to start CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200 - Consider 350 - CD4 ≤ 350 for TB CD4 ≤ 350 -Irrespective CD4 for TB and HBV CD4 ≤ 500 -Irrespective CD4 for TB, HBV, PW and SDC - CD4 ≤ 350 as priority 1st Line 8 options - AZT preferred 4 options - AZT preferred 8 options - AZT or TDFpreferred - d4T dose reduction 6 options &FDCs - AZT or TDF preferred - d4T phase out 2 options & FDCs - TDF and EFV preferred across all populations 2nd Line Boosted and non-boosted PIs Boosted PIs -IDV/r LPV/r, SQV/r Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r Boosted PI - Heat stable FDC: ATV/r, LPV/r Boosted PIs - Heat stable FDC: ATV/r, LPV/r 3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Viral Load Testing No No (Desirable) Yes (Tertiary centers) Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) Earlier  ini6a6on   Simpler  treatment   Less  toxic,  more  robust  regimens   Be"er  monitoring   HIV/AIDS DepartmentEvidence-based, but intentionally aspirational…
  24. 24. MONITORING ART RESPONSE Targeted  viral  load   monitoring  (suspected   clinical  or  immunological   failure)   Rou6ne  viral  load   monitoring  (early   detec6on  of     virological  failure)   Switch  to  second-­‐line   therapy   Maintain  first-­‐line   therapy   Viral  load  ≤1000   copies/ml   Viral  load  >1000   copies/ml   Repeat  viral  load   tes6ng  aeer  3–6     months   Evaluate  for   adherence  concerns   Viral  load  >1000   copies/ml   Test  viral  load   70%  greater  resuppression     rate  afer  adherence  intervenLon  
  25. 25. •  L’importanza dell’integrazione dei servizi
  26. 26. Results: One stop service model in Rwanda Decentralisation of services and task shifting to nurses Percent shows out of all identified HIV positive TB patients nationally TB nurse §  Provides HIV testing §  Draws blood for CD4 §  Provides ART and CPT 0 20 40 60 80 100 120 2005 2006 2007 2008 2009 2010 2011 2012 ART for TB patients CPT for TB patients
  27. 27. Health officers and nurses (Health center) Physicians ( Hospitals) Mortality (%) 11 8 Lost to follow up (%) 13 25 Retention rate (%) 76 67 Median CD4 count (IQR) 322 (242, 414) 301 (217,411) Nurses and health officers can initiate ART with better results (Assefa Y et al, 2011) Outcome of patients initiated ART by nurses and physicians after 24 months of follow up, Ethiopia.
  28. 28. Use the decentralized TB services to provide ART ART services are still too centralized and too few Number of facilities providing TB and ART, 2011
  29. 29. Early  TB  diagnosis  in  PLHIV  
  30. 30. The cascade of care With signs/symptoms Other diagnostic tests Treat  for  TB     if  sugges6ve  Initial test Treat  for  TB     if  posi6ve   Clinical decision
  31. 31. 34 | WHO  guidance  documents   GLOBAL TB PROGRAMME
  32. 32. Xpert  MTB/RIF  as  the  iniLal  diagnosLc  test  
  33. 33. Global scale-up of Xpert MTB/RIF CumulaLve  number  of  GeneXpert  instrument  modules  and   Xpert  MTB/RIF  cartridges  procured  under  concessional  pricing   Data  provided  by  FIND   2012   2013  2011  2010   42   524   681   1,441   2,401   2,979   3,602   4,660   5,017   6,181   7,553   9,625   10,561  40.790   86.320   191.900   329.350   591.450   863.790   1.107.330   1.482.550   1.891.970   2.315.380   3.196.920   4.214.990   5.219.960   0   2.000   4.000   6.000   8.000   10.000   12.000   0   1.000.000   2.000.000   3.000.000   4.000.000   5.000.000   Q4   Q1   Q2   Q3   Q4   Q1   Q2   Q3   Q4   Q1   Q2   Q3   Q4   August  2012:  “Buy-­‐down”  with  the   manufacturer  by  PEPFAR,  USAID,   UNITAID  and  Bill  &  Melinda  Gates   Founda6on  -­‐―  the  price  of  the  cartridge   dropped  to  9.98  USD  in  145  eligible   countries   Q4  2012-­‐Q2  2013:  Global  shortage  in   Xpert  MTB/RIF  cartridges  
  34. 34. Impact  of  Xpert  MTB/RIF  in  clinical  pracLce   The  TB-­‐NEAT  study    is  a  randomized  parallel-­‐group  mul6centre  trial  evalua6ng  the   impact  of  Xpert  MTB/RIF  in  five  primary-­‐care  health  facili6es  in  four  African  countries   (South   Africa,   Zimbabwe,   Zambia   and   Tanzania).   Eligible   pa6ents   were   randomly   assigned  to  nurse-­‐performed  Xpert  MTB/RIF  or  microscopy.     The  XTEND  study    is  a  cluster-­‐randomized  trial  evalua6ng  the  impact  of  Xpert  MTB/RIF   in  South  Africa,  involving  20  laboratories  and  2  primary  care  clinics  per  laboratory;  one   clinic  used  Xpert  MTB/RIF  as  the  ini6al  diagnos6c  test  while  the  other  con6nued  using   microscopy.     The   two   studies   confirm   that   to   show   significant   impact   on   clinically   important  outcomes  for  drug-­‐sensiLve  TB  paLents,  adopLon  of  Xpert  MTB/ RIF     needs   to   be   complemented   with   strengthened   health   systems   that   allow  for  the  Lmely  iniLaLon  of  appropriate  treatment  and  a  reducLon  in   the  use  of  empirical  treatment  without  bacteriological  confirmaLon.     Churchyard  G  et  al.  CROI,  Boston  USA,  3-­‐6  March  2014   Theron  G  et  al.  Lancet  Infect  Dis  2014  
  35. 35. The end

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