The public health approach to reduce the burden of advanced HIV disease:

WHO recommendations

Po-Lin Chan/Nathan FordWorld Health Organisation

Background and rationale

• A significant proportion of patients continue to present with advanced HIV disease

• People starting ART with advanced HIV disease have high mortality particularly in first six months following ART initiation

• Major causes of death include co-infections such as TB, severe bacterial infections, cryptococcal meningitis

• WHO guidelines include individual recommendations for diagnosis, prophylaxis and treatment

• Recent studies have assessed the potential for an enhanced package of interventions to reduce mortality/morbidity

Why are people still dying from HIV?

7,5

19,5

1,91

0

5

10

15

20

25

2011 2012 2013 2014 2015 2016

Number on ART

Number of deaths

For adults and adolescents, and children older than five years, advanced HIV disease is defined as CD4 cell count <200cells/mm3 or WHO stage 3 or 4 event.

Includes both ART naïve individuals and those who interrupt treatment and return to care

All children younger than five years old with HIV are considered as having advanced HIV disease.

WHO definition of advanced HIV disease

IeDEA-COHERE: Results based on 951 855 adults from 55 countries after imputation of missing dataDoes not include “re-starters” after interruption

In 2015,37% of people

starting ART did so at CD4 cell count <200 cells/mm3

Carmona S et al, CID 2018

IeDEA and COHERE, CID 2017

Proportion presenting with low CD4 cell count has not changed

Persistent challenge of advanced HIV disease

Causes of mortality

Ford et al, Lancet HIV 2016

Need to target the right OI..

Osler et al, CID 2018

Packaged interventions for reducing mortality among patients with advanced

HIV disease

Key study characteristics

REALITY(enhanced prophylaxis)

REMSTART(enhanced OI screening &

adherence)

Study countries Kenya, Malawi, Uganda, Zimbabwe Tanzania, Zambia

Sample size and design study 1805 individuals (open label) 1999 individuals (open label)

Eligibility criteria and population CD4 < 100 ( PLHIV ≥ 5 yrs old) CD4 < 200 (PLHIV ≥ 18 yrs old)

Main outcome Mortality reduction at 6 and 12 mo Mortality reduction at 12 mo

Rapid ART initiation✓

CrAg screening test✓

Adherence support visits x 4 weeks✓

CTX/isoniazid/B6 daily x 12 weeks ✓ ✓

Fluconazole 100mg daily x 12 weeks✓ ✓

Azithromycin 500 mg daily x 5 days✓ ✓

Albendazole 400 mg x single dose ✓ ✓

Costing analysis✓ ✓

Cost effectiveness analysis✓

1 TB screening with GenXpert at baseline included in both arms of the study , re-screening at 6 weeks in intervention arm :TB cases only asssessed in interventiongroup2 ART intensification (RAL) x 4 weeks and food supplementation x 12 weeks, not included a s part of the PICO question but assessed in the factorial analysis and discounted.

Outcomes

• 28% reduced death• Improved adherence

at 6 months• 27% reduced death• Reductions in

incident morbidity• Reductions in

hospitalization

BEN

EFIT

S &

HA

RM

S

BENEFITS HARMS• Reduced all-cause mortality • Potential for antimicrobial resistance

-azithromycin

• Reduced incident morbidity• New TB disease• New cryptococcal disease

• Potential for antifungal resistance -fluconazole 100mg

• Reduced (or unchanged) new hospitalisations

• Potential increased absolute cost to health services

• Simplified package consistent with public health approach

• Simplified package may reduce attention to other important comorbidities/co-infections

• Promotes increased attention to advanced disease

A package of interventions including screening, treatment and/or prophylaxis for major opportunistic infections, rapid ART initiation* and intensified adherence support interventions should be offered to everyone presenting with advanced HIV disease.

Strong recommendation, moderate-quality evidence

WHO Recommendation

* linked recommendation

WHO, 2017

Package of care for people with advanced HIV disease

Diagnosis Prophylaxis ART initiation Adapted adherence support

XPERT MTB/RIF as first test for TB

Cotrimoxazoleprophylaxis

Rapid ART initiation

Tailoredcounselling to support adherence

LF-LAM for TB diagnosis among peoplewith signs and symptoms

TB preventive treatment

Defer if clinicalsymptomssuggest TB or cryptoccalmeningitis

Cryptococcalantigen screening

Fluconazolepre-emptive therapy

WHO, 2017

INH/B6/CTX scored FDC, Half doses if <12 years

Diagnosis Prophylaxis ART initiation Adapted adherence support

XPERT MTB/RIF as first test for TB

Cotrimoxazoleprophylaxis

Rapid ART initiation

Tailoredcounselling to support adherence

LF-LAM for TB diagnosis among people with signs and symptoms

TB preventive treatment

Defer if clinicalsymptomssuggest TB or cryptoccalmeningitis

Cryptococcalantigen screening

Fluconazolepre-emptive therapy

- Diagnosis- Prevention and screening- Treatment (1 week Ampho B + Flucytosine)- (non) use of corticosteroids- Timing of ART

Shorter induction treatment = better outcomes

WHO guidelines for cryptococcal disease

WHO 2018; Molloy et al, NEJM 15 March 2018

• The role of presumptive treatment in managing TB, Pneumocystis jirovecii pneumonia, severe bacterial infections and cryptococcal disease should be considered in settings in which access to diagnostic tests is limited and people present with typical signs and symptoms (especially when accompanied by clinical signs indicating severe illness)

• The WHO algorithm for managing people with HIV who are suspected of having TB and are seriously ill incorporates presumptive treatment of TB, bacterial infections and Pneumocystis jirovecii pneumonia into the care pathway

Considerations

Advanced HIV disease: a renewed focus

https://academic.oup.com/cid/issue/66/suppl_2

Guideline Development Group

Co-chairs: Alexandra Calmy (Hôpitaux Universitaires de Genève, Switzerland) and Graeme Meintjes (University of Cape Town, South Africa).

Eduardo Arathoon (Asociacion de Salud Integral, Guatemala), Patricia Asero (International Community of Women Living with HIV, Kenya), Rosa Bologna (Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Argentina), Mohamed Chakroun(Fattouma Bourguiba Teaching Hospital, Tunisia), Lucia Chambal (Ministry of Health, Mozambique), Tom Chiller (MycoticDisease Branch, United States Centers for Disease Control and Prevention, USA), Francesca Conradie (University of the Witwatersrand, South Africa), Serge Eholie (Centre Hospitalier Universitaire de Treichville, Côte d’Ivoire), Lisa Frigati(Tygerberg Hospital and Stellenbosch University, South Africa), Diana Gibb (Medical Research Council, United Kingdom), Eric Goemaere (Médecins Sans Frontières, South Africa), Nelesh Govender (University of the Witwatersrand and National Institute for Communicable Diseases, South Africa), Alison Grant (London School of Hygiene and Tropical Medicine, United Kingdom), Nagalingeswaran Kumarasamy (YRGCARE, India), David Lalloo (Liverpool School of Tropical Medicine, United Kingdom), Thuy Le (Oxford University Clinical Research Unit, Viet Nam), Emilio Letang (Barcelona Institute for Global Health and Ifakara Health Institute, Spain), Dorothy Mbori-Ngacha (UNICEF, Kenya), Sayoki Mfinanga (Muhimbili Medical Research Centre, National Institute for Medical Research, United Republic of Tanzania), Mathieu Nacher (Université de Guyane, French Guiana), Muhayimpundu Ribakare (Rwanda Biomedical Centre, Rwanda), Kenly Sikwese (African Community Advisory Board, Zambia), Nini Tun (Medical Action Myanmar, Myanmar), Jose E. Vidal (Instituto de Infectologia Emílio Ribas and Universidade de São Paulo, Brazil)

External Review Group

Xavier Anglaret (Inserm – French National Institute of Health and Medical Research, France), Moherndran Archary (King Edward VIII Hospital, South Africa) Moses Bateganya (United States Centers for Disease Control and Prevention, USA), David Boulware (University of Minnesota, Uganda), Sergio Carmona (National Health Laboratory Services, South Africa) Marcelo Freitas (ICAP, Mozambique), Beatriz Grinstejn (Fundação Oswaldo Cruz, Brazil), Joseph Jarvis (London School of Hygiene and Tropical Medicine, United Kingdom and Botswana Harvard AIDS Institute Partnership, Botswana), David Meya(Makerere University, Kampala, Uganda), Eyerusalem Negussie (Ministry of Health, Ethiopia), Daniel O’Brien (BarwonHealth, Australia), Heather Paulin (United States Centers for Disease Control and Prevention, USA), Andy Prendergast (Queen Mary University of London, United Kingdom), George Siberry (Office for the US Global AIDS Coordinator, USA), and Evy Yunihastuti (Faculty of Medicine, Universitas Indonesia, Indonesia)

WHO

Nathan Ford and Marco Vitoria (HIV Department, WHO) coordinated the overall guideline development process with support from Chantal Migone (HIV Department, WHO), under the leadership of Meg Doherty and Gottfried Hirnschall(HIV Department, WHO). Helen Bygrave (independent consultant, United Kingdom) wrote the guideline document withNathan Ford

Acknowledgements