1. HIV drug resistance in Africa
Prof Tobias Rinke de Wit
PharmAccess Foundation &
Amsterdam Institute for Global Health and Development

2. Moving to 20 million

3. Progress towards the 90–90–90 targets Africa, 2017
59% * 81% * 78% = 37%
Source: UNAIDS Ending AIDS Progress towards the 90–90–90 targets 2017

4. Viral heterogeneity  Resistance
High genetic diversity of HIV-1
Production of 1-10 billion virus particles per day
Reverse transcription prone to error
No proof-reading mechanism
 ~1 (random) mutation per new provirus
Large numbers of mutants  quasispecies
subtypes A-K
sub-subtypes A1-A4, F1-F2*
CRF (>52 circulating recombinant forms)*
HIV drug resistance
* Tatem, AJ, Hemelaar J, Gray RR and Salemi M, AIDS 26, 2012

5. Resistance: a selection process
Viral Load
Time

6. HIV is a swarm

7. When you start ART…

8. The amount of virus is reduced

9. If you do not take ART correctly…
TOOBUSY
TOO LZY
....there will be in-complete suppression of replication

10. Resistant virus will occur
‘Selection pressure’ causes the resistant strains to replicate

11. Pill sharing

12. Adherence is key
Catherine Orrell, personal communication, 2014 12

13. Should we fear a dramatic increase of HIVDR?
Lancet 2001
The malaria disaster
"If compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants…"
Robert C. Gallo and Luc Montagnier. Prospects for the Future. Science 2002
.. As has been predicted by some a decade ago, before ART rollout

14. 2006
Int J Epidem 2012

15. HIV drug resistance

16. PASER cohorts Int J Epidem 2012 6 countries 13 clinical sites
Enrolment Mar 2007 – Sept 2009
PASER M
PASER S
2733 patients initiating 1st line followed up for at least 24 month
208 Nigeria
2 cross sectional cohorts of ART-naive newly infected individuals
81 patients in Mombasa
77 patients in Kampala
250 patients enrolled at second line switch followed up for 24 months
32 Nigeria
Int J Epidem 2012

17. Pre-treatment HIVDR (PDR)

18. PDR doubles (Y1) risk of VF and acquired HIVDR
Odds ratio
% Viral suppression
91%
86%
75%
What is the clinical impact of pretherapy HIVDR?
PDR defined using (1) IAS-USA list and (2) Stanford drug-susceptibility algorithm: fully-active ART 1/2 vs partially-active ART 3/4/5
Viral suppression: No PDR 91%; PDR and fully-active ART 86%; PDR and partially-active ART 75%
Hamers et al. Lancet Inf Dis 2012

19. PDR  Slower recovery CD4

20. PDR  regimen switching
Proportion of patients who switched
N=88/2372=3.7%
N=18/117=15.4%
N=70/2255=3.1%
Cox PH analysis:
switch due to VF+ADR
* adjusted for sex and age
Boender et al., CID 2015

21. Proportion ART re-initiators is increasing
WHO HIVResNet, courtesy S. Bertagnolio

22. Prior ARV use increases risk of VF patients with prior ART have 3x higher risk of VF
Characteristic N
No of events
Unadjusted OR (95%CI)
P-value
**adjusted OR (95%CI)
Prior ARV use No
Yes
1948 83
184 17
1.0
2.47 ( )
<0.001
2.72 ( )
0.002
Type of prior ARV use
None
ART
sdNVP
Others 41 29 13 10 5 2
3.09 ( )
2.00 ( )
1.74 ( )
0.165
0.472
2.99 ( )
3.25 ( )
1.38 ( )
0.014
0.027
0.703
Patients with prior ARV use were nearly 3x more at risk of developing virological failure by 12 months with a higher risk among patients exposed to sdNVP for PMTCT
models were adjusted for pre-treatment drug resistance, pre-treatment CD4 counts, type of first ART initiated, sex, age, calendar year of ART treatment initiation and adherence
*others; non-sdNVP mono-therapy or dual therapy
Inzaule et al., submitted 2017

23. Prior ARV use increases risk of PDR patients with prior ART have 7x higher risk of PDR
Characteristic N
No of events
Unadjusted OR (95%CI)
P-value
**adjusted OR (95%CI)
Prior ARV use No
Yes
2534
119
288 39
1.0
6.82 ( )
<0.001
7.17 ( )
Type of prior ARV use
None
ART
sdNVP
Others* 58 22 20 10 9
8.30 ( )
4.43 ( )
8.09 ( )
0.008
9.07 ( )
3.35 ( )
15.01 ( )
The odds of PDR were 7x higher among persons with prior ARV use, with a higher risk among patients exposed to mono or dual therapies
models were adjusted for age, sex, country, year of treatment initiation, pre-treatment viral-load, CD4 counts and WHO clinical stage
*non-sdNVP mono-therapy or dual therapy
Inzaule et al., submitted 2017

24. Consequences PDR (literature)
Children <12 with PDR are:
15x more likely to have VF at 24m (Kityo et al., JAC 2017)
3-4x more likely for ADR at 24m (Kityo et al., JAC 2017)
Adults with PDR are:
4x More likely to have VF at 12 months (Ávila-Ríos S et al., The Lancet Inf. Dis. 2016)
2x More likely for ADR at 12 months (Hamers et al. The Lancet Inf. Dis. 2011)
3x More likely to discontinue ART by 12m (un-published meta-analysis WHO 2017)
Have slower CD4 recovery (Hamers et al. The Lancet Inf. Dis. 2011)
3-4x More likely to switch to 2nd line (Boender et al., CID 2015)

25. PDR by region and drug class
Pre-ART HIVDR prevalence Yearly increase risk of PDR prevalence:
Overall: 5.6% 38% (p=0.001, multivariate analysis)
Pretoria: 1.1%
Kampala: 12.3% Mostly NNRTI mutations, except Uganda
2436 sequences from 2590 participants
Hamers et al., TLID 11, 750-9, 2011

26. Increasing PDR
Estimated Incremental annual increase: 23% in Southern Africa, 17% in west-central Africa, 29% in Eastern Africa
WHO HIVDR report, July 2017

27. Pre-treatment NNRTI resistance
6 out of 11 national surveys: >10% NNRTI resistance
Source: WHO HIV Drug Resistance Report 2017

28. Transmitted HIVDR (TDR)

29. Early TDR recordings WHO-consecutive sampling approach
Overall
NRTI
NNRTI PI
Kampala
2 VCT, ‘09/’10
D67G, L210W
G190A, G190S, K101E
N88D
Prevalence
6/70 = 8.6% ( )
2.9% (2)
4.3% (3)
1.4% (1)
WHO-TSS*
Moderate (4/47)
Low (2)
Low (1)
Mombasa
4 VCT, ‘09/’10
K70R
K103N (5)
I85V, N88D, L90M
9/68 = 13.2% ( )
1.5% (1)
7.4% (5)
4.4% (3)
Moderate (5/47)
Low (0)
Moderate (3)
WHO-consecutive sampling approach
WHO-recommended proxy criteria for recent infection:
Newly HIV-1 diagnosed and aged ≥18 and <25 years
Lab evidence of recent HIV-1 infection
Ndembi et al. AIDS, 2011
Sigaloff et al. Aids Res Hum Retro 2011

30. Confirming and extending WHO data: TDR surveys
20 moderate level (5-15%)
WHO HIV Drug Resistance Report, S Bertagnolio, IAS Conference July 26, 2012

31. TDR location specific 182 participants; 138 women (76%)
K = 1.1%
M =13.2%
182 participants; 138 women (76%)
Transmitted HIVDR: 2/182 = 1.1% (95% CI, 0.1 – 3.9)
TDR data can vary substantially between geographically close locations (55 km)  limitations to WHO consecutive sampling approach

32. Acquired HIVDR (ADR)

33. Overall PASER ADR mutations in line with WHO studies in 40 countries
WHO, pooled data n=269
S Bertagnolio WHO, IAS
Conference July 26, 2012
Hamers et al. CID 2012
N = 142

34. Five year VF and ADR among 1st line patients Lagos
VF and ADR declines within the first three years but increases thereafter pointing to the need for close treatment monitoring in long-term treated patients
Longer term ADR increase (similar observations in other PASER sites)

35. ADR among adults on failing ART
Source: WHO HIV Drug Resistance Report 2017

36. ADR among children on failing ART
Source: WHO HIV Drug Resistance Report 2017

37. Beyond 2nd line: towards untreatable HIV in Africa?

38. Pediatric HIVDR

39. Pediatric HIV Treatment 2016
First-line treatment
<3 years PI + 2 NRTI
≥ 3 years NNRTI + 2 NRTI
Second-line treatment
<3 years Ral + 2 NRTI
≥3 years PI + 2 NRTI
According to the recent WHO recommendations, all HIV positive infants are to be started on PI treatment if they are less than 3 years. There are no 3rd line treatment for children less than 3 years but provision is given for DRV for children > 3 years and studies are underway for consideration for use of Dolutegravir

41. HIV drug resistance data in children is scarce
Countries showing resistance data in the HIV-1-infected paediatric population selected for the review, including the number of patients (not HIV DR prevalence).
1 out of 3 African countries reporting PDR in children
1 out of 15 worldwide
Rojas Sánchez & Holguín, 2014

42. MARCH-Uganda study
Prospective cohort study of 360 children (≤ 12 years)
Follow-up > 2Y, VL testing every 6 months
HIVDR test when VL>1000
ART initiation
or switch
~310 (85%)
first-line
ARV-naive
PMTCT
~ 50 (15%)
second-line

43. PDR in Ugandan children
Among the children initiating first-line ART, 28 (10.0%) harbored at least one HIVDR mutation. HIVDR per drug class was 5.7% for NRTI and 7.5% for NNRTI; 3.2% had dual-class resistance. PI mutations were not observed. Separate analysis of ARV-naïve and ARV-experienced children revealed at least one HIVDR mutations in 7.7% and 21.7% of samples, respectively.
10% Pre-treatment HIVDR in children of average age 5 Y (8% in naive children, 22% in PMTCT-experienced children)
C. Kityo et al., ARHR, 2016

44. Alarming pediatric PDR
Meta-analysis including 2,617 children in 13 African countries
Pooled PDR prevalence is 12.7% in PMTCT-unexposed and 42.7% in PMTCT-exposed children
PDR prevalence increased in PMTCT-unexposed children from 0% (2004) to 26.8% (2013)
PI-based first-line ART should be initiated in children (<3 Y) and possibly also in older children
Boerma et al, Journal of Antimicrobial Chemotherapy, 2016

45. VF at 2nd line ART in children: adolescents at high risk
16.4% VF after 54 months overall
26.3% among adolescents
9.1% among young children
adjusted hazard ratio ~4 for VF among adolescents
Figure: cumulative incidence of virologic failure among children and adolescents on second-line treatment. Virologic failure is defined as two consecutive viral load results>1000 copies/ml after at least 6 months of second-line treatment. T0 is set at 6 months after treatment switch, total follow-up time is 60 months.
After 24 months, 9.1% (95%CI ) of younger children and 26.3% (95%CI ) of adolescents had experienced VF, p<0.001 (figure 3a).
Including 12 cohorts, 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa
Boerma et al, JIAS 2017

46. Pediatric HIVDR survey Nigeria
participating EID labs
Adamawa
Abia
Oyo
Ogun
Lagos
Osun
Ekiti
Ondo
Kwara
Edo
Delta
Bayelsa
Rivers
Akwa
Ibom
Cross
River
Imo
Anambra
Enugu
Ebonyi
Kogi
Benue
Nasarawa
Niger
Plateau
Taraba
Gombe
Bauchi
Yobe
Borno
Kaduna
Kebbi
Zamfara
Sokoto
Katsina
Jigawa
FCT
Kano 1 14 15 2 3 4 5 6 7 8 9 16 10 11 12 13
1.ALTC, Abuja
2.UUTH, Akwa Ibom
3.AKTH, Kano
4.FMC, Jalingo, Taraba
5. JUTH, Plateau
6.NAUTH, Anambra
7. LUTH, Lagos
8.UMTH, Borno
9.PLASVIREC, Plateau
10.OAUTH, Osun
11.UBTH, Edo
12.FMC-Makurdi, Benue
13.FTC-Gombe
14.ABUTH, Kaduna
15.UDUTH, Sokoto
16.OLA, Jos Plateau
Non-Participating sites
Lab-based survey: mention that they collected samples from diff clinical sites.
EID sites participating in the pediatric pretreatment HIVDR survey. Labs are numbered based on declining throughput, participating sites are highlighted in brown, regions in grey while non-participating labs are marked grey
Inzaule et al, AIDS 2017

47. For 430 children with HIVDR results
RT = RTI? RTI is: combination of both NNRTI and NRTI HIVDR mutations in the same genome?
Analyses ongoing with Beth Chaplin / Phyllis Kanki
Inzaule et al, AIDS 2017

48. WHO HIVResNet confirms
PDR in ART naive children <18 M, National surveys: Mozambique, Swaziland, Uganda, Zimbabwe, South Africa
Jordan MR et al. CID in press

49. Capacity building remains important

50. Capacity building: workshops & on-site training
2006, Johannesburg: PASER Network meeting
2007, Dar es Salaam: Advanced Medical Training
2008, Kampala: PASER Network meeting
2008, Nairobi: PASER/ARTA* Network meeting
2009, Lusaka: PASER/ARTA Network meeting
2010, Entebbe: PASER/ARTA Network meeting
2012, Kampala: ARTA/PASER Policy workshop
2013, Bloemfontein: PASER/SATuRN Medical Training

51. Advocacy: keep HIVDR on the map
 STAR, South Africa March 7, 2011
The Nation, Kenya
August 1, 2011 
 Daily Monitor, Uganda April 25,2012

52. New class of ARVs

53. Low integrase inhibitor resistance in SSA
424 patients with VL>400 after 1 year 1st line ART
major INSTI mutations <5%: only as minority variants.
We had a total of 424 patients, Of these 21% were from Kenya, 26% Uganda, 7% Nigeria, 23% South Africa and 23 from Zambia. The sampling distribution was similar to that of the original cohort (Kenya 16.2%, Uganda 23.4%, Nigeria 7.6%, South Africa 23.3% and Zambia 21.2%).
Major INSTI mutations were rare <5% and only occurred as minority variants. Accessory mutations however occurred at higher thresholds and with higher frequencies especially in Kenya, Uganda and Nigeria due to subtype differences
Integrase inhibitors (like DTG!) are predicted to be effective in SSA
Inzaule et al, submitted 2017

54. DTG as ‘anti HIVDR drug’
Advantages
Superior in 1st line to EFV, atazanavir, darunavir
Better in 2nd line than LPV/r and better in 3rd line than raltegravir
Affordable in FDC with 3TC and TDF (TLD at $75/year)
Minimal drug interactions, long half-life
Good safety profile, minimal toxicities
High HIVDR threshold and large fitness cost if HIVDR
Disadvantages
Neuropsychiatric side-effects, little experience in Africa
Higher IRIS risk for low CD4 patients starting on DTG
Interaction with some tuberculosis drugs (rifampetine)
Insufficient data during pregnancy and in young children
Supply issues (only 2 generic companies produce DTG)
Pending DTG registration and accommodation in National ART guidelines
Logistical challenges, training, information provision
If positioned as ‘the solution’  decreased funding for HIVDR monitoring

55. Monitoring VL at the population level

56. Background
Viral load (VL) is the most reliable indicator of treatment failure during antiretroviral therapy (ART)
Since 2013, the World Health Organization recommends using VL to monitor patients on ART and support appropriate regimen switches.
Start antiretroviral therapy
First-line treatment failure
Second-line treatment
VL result
Lack of access to VL testing: <40% of those in need

57. VL suppression in LMICs in adults
Suppression rates:
70-80% for the first two years
In adults >85%
High income countries: >90%
PI-based treatment still <80%
Meta-analysis of 165 studies
>85% <1,000 cps/ml
Boender et al. CID 2015.

58. VL suppression in LMICs in children
Meta-analysis of 72 studies,
Including 51,347 children
After 12 months
65-73% VL <1,000 cps/ml
72 studies, reporting on 51,347 children and adolescents (<18 years), were included.
After 12 months on first-line ART, viral suppression was achieved by
64.7% (95%CI ) in the early,
74.2% (95%CI ) in the intermediate,
and 72.7% (95% ) in the current time period.
Rates were similar after 6 and 24 months of ART.
Using an intention-to-treat analysis, 42.7% (95%CI ) in the early,
45.7% (95%CI ) in the intermediate, and
62.5% (95%CI ) in the current period were suppressed.
Long-term follow-up data were scarce.
Boerma et al. CID, in press

59. VL monitoring: 4x less unnecessary switches
Clinical + CD4 count + targeted VL (n=186)
Clinical + CD4 count (n=64)
Sigaloff et al., J.Acquir.Immune Defic. Syndr. 58, 23-31, 2011

60. No VL monitoring  more HIVDR
Cohort 1 (n=100)
Virological failure by routine pVL test, 12 mo ART
Cohort 2 (n=161)
Clinico-immunological failure, 26 mo ART
Hamers CID12; Sigaloff JAIDS12

61. Misclassification of first-line failure
False-positive
False-negative
Unneccessary switch
Accumulation of mutations
Clinical failure
Virologic failure
Immunologic failure
The absence of viral load monitoring leads to delayed switching
Prolonged viremia on first-line regimens lead to mutation accumulation
Limited knowledge of drug resistance patterns after first-line failure and their clinical impact on response to standard second-line (boosted PI-based) therapy
Viral Load 61

62. Monitoring HIVDR at the population level

63. WHO monitoring and surveillance of HIVDR
EWI: monitored annually at all/representative national ART clinics:
On-time pill pick-up
Retention on ART at 12 months
Drug stock-out
Viral load suppression
Viral load testing completion
Appropriate switch to second-line ART
Surveillance of pre-treatment HIV drug resistance in adults initiating first-line ART
Surveillance of acquired HIV drug resistance in adults and children on treatment
Surveillance of HIV drug resistance in infants >18 months of age
WHO (2017) Tackling HIV drug resistance: trends, guidelines and global action

64. Worrying EWI results 59 countries, 12,000 clinics, 2004-2014
Overall 99.1% of patients are prescribed correct drugs (92.7% in Americas; 95.9% in Western Africa)
Overall 20% LTFU after 1 year (exceeding recommended 15%); increasing from 11.9% in 2004 to 24.5% in 2012; highest in Africa (20%- 30%)
1 year retention in ART program: 73.5% (falling short of recommended 85%); lowest in West and Central Africa
Overall 85.5% on time pill pickup (lower than recommended 90%); 69.9% in Africa versus 91.4% in South-East Asia
Overall 63.3% on-time appointment keeping (short of 80%); 40.7% in Western Africa!
Overall 35.7% drug stock-outs amongst 1,703 clinics; highest in Africa
WHO EWI report 2016

65. Incremental impact HIVDR over the coming 3 years
Adapted from: Phillips et al; JID 2017

66. Overall HIVDR concerns
T&T programs provide ART in earlier phase (higher CD4)  healthy people have lower adherence  more HIVDR?
Reaching implies 27% not virally suppressed, likely key populations at higher risk (adolescents,  HIVDR
Doubling target population for ART (to 37 million) increases risk of insufficient ARVs, stock-outs, drug sharing  HIVDR
Patients in Africa switch too late to 2nd line  longer ARV exposure during a failing 1st line  increase HIVDR
Increased VL testing  increased detection of viral failure, increased switching  increased HIVDR testing costs ($)
ARVs used in Africa are low-barrier drugs (expired patents)  higher HIVDR
Overall: more HIVDR  more ART failures  higher population viral load  no incidence reduction

67. WHO: Global Action Plan on HIVDR
WHO (2017) Tackling HIV drug resistance: trends, guidelines and global action

68. Challenges ahead

69. PEPFAR: 2004 - 2015 funding (US$ millions)
June 2014

70. Challenges for the years to come
Target population of people qualifying for ART has doubled since WHO recommendation 2015
Generic drug producers are struggling to keep up with drug consumption, given low margins
Stagnating ART supply can result in pill sharing, etc.  increased HIVDR
International funding for HIV treatment is stagnating/declining and alternative funding by LMIC is hardly taking off
HIVDR is present, increasing over time and makes 3% of Africa patients already ‘untreatable’; no access to 3rd line ART
Children are particularly vulnerable (adolescents even more)
More than ever HIVDR monitoring is needed to protect and sustain ART impact in LMIC

71. “Be creative and think big to tackle the real problems”
This film was produced by Ron van der Lugt and was shown during the 20th Anatomische Les in Amsterdam, the Netherlands.

72. Acknowledgments PharmAccess Foundation WHO HIVResNet
Amsterdam Institute for Global
Health and Development
Sonia Boender
Seth Inzaule
Ragna Boerma
Raph Hamers
Kim Sigaloff
Stefanie Kroeze
Ferdinand Wit
Pascale Ondoa
Joep Lange †
Michèle van Vugt
Tobias Rinke de Wit (PI)
UMCU Virology
Rob Schuurman
Annemarie Wensing
Erasmus MC
David van de Vijver
Brooke Nichols
Study participants and staff
PASER
MARCH
WHO HIVResNet
Silvia Bertagnolio
Michael Jordan
Joseph Perriens
Neil Parkin
TreatAsia/amfAR
Kevin Frost
Jeffery Smith
Annette Sohn
TASER sites
UNSW/Kirby Institute
Matthew Law
Sally Land
AidsFonds
Ton Coenen
Uganda
Pontiano Kaleebu
Cissy Kityo
Peter Mugyenyi
Immaculate Nankya
South Africa
Wendy Stevens
Carole Wallis
Kim Steegen
Ian Sanne
Francesca Conradie
Prudence Ive
Mariette Botes †
Zimbabwe
Ruedy Luthy
Maureen Wellington
Zambia
Margaret Siwale
Moheb Labib
Kenya
Stanley Luchters
Saade Abdallah
Kishor Mandaliya
Nigeria
Akin Osibogun
Sulaimon Akanmu
Nicaise Ndembi