Current Status of Antiretroviral Therapy in Taiwan
50
Current Status of Antiretroviral Therapy in Taiwan Chien-Ching Hung, MD, PhD Department of Internal Medicine National Taiwan University Hospital
Transcript of Current Status of Antiretroviral Therapy in Taiwan
STR perspectives in HIV-1 treatment in Taiwan: from now to the
futureChien-Ching Hung, MD, PhD Department of Internal
Medicine
National Taiwan University Hospital
Disclosures
• I have received honoraria for speaking at educational events or consulting from: – AbbVie, Bristol-Myers Squibb, Gilead Sciences,
Janssen, and ViiV
• I have received research funding from – Bristol-Myers Squibb, Janssen, Merck, and ViiV
Outline • Brief introduction to HIV epidemiology in Taiwan • Introduction to development of antiretroviral
therapy • Evolution of treatment guidelines in Taiwan • Short-term experience with the cost-based
regulations on antiretroviral regimens • Update on the current guidelines • Challenges ahead
HIV epidemiology in Taiwan, 1984-2017
0
500
1000
1500
2000
2500
3000
3500
4000
Gandhi M and Gandhi RT. N Engl J Med 2014;371:248-59.
HIV replication and treatment targets
The development of antiretroviral therapy (ART)
1985 1990 2000 2005 2010 2015
ZDV, 1987 ddI, 1991
2018
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. April 8, 2015, & other years as noted.. Available at: http://www.aidsinfo.nih.gov/Guideline
Evolution of “When to Start ART?”
1987 1998 2001 2002 2004 2008 2009/2011/2015
FACTOR RECOMMENDATION FOR TREATMENT
AIDS Treat Treat Treat Treat Treat Treat Treat Treat
CD4 All <500 • Recommended at <200 • Offer at <350 • Individualize decision at >350
• Recommended <350
• Risks/Benefits >350
• Recommended <500
• Favor/Optional >500
Viral Load
>20,00 0 >55,000 >100,000 No specific viral load No specific viral load
Other Factors
HIV-infected individuals for the prevention of HIV
transmission
Class DHHS IAS-USA EACS INSTI DTG/ABC/3TC
DTG + (TAF or TDF)/FTC EVG/c/(TAF or
TDF)/FTC RAL + (TDF or
DTG/ABC/3TC DTG, EVG/c, or RAL
plus (TAF or TDF)/FTC
NNRTI RPV/(TAF or TDF)/FTC
DHHS Guidelines. Oct 2017 Günthard HF, et al. JAMA. 2016;316:191-210
ECS v9 2017
CD4, <200 cells/mm3 ZDV/3TC ABC/3TC
EFV KLA;
ATV/r
NVP
2010 Pregnant women HIVAN Chronic HBV infection AIDS-related illness; CD4, <350 cells/mm3
ZDV/3TC ABC/3TC
EFV KLA;
ATV (400 mg)
2012 Pregnant women HIVAN Chronic HBV infection AIDS-related illness; CD4, <350 cells/mm3
• 4 categories of regimens based on cost • Application for approval • Revision made based on pricing
negotiation
Year When to start Recommended Alternative
2013 Pregnant women HIVAN Serodiscordant partners Chronic HBV infection AIDS-related illness CD4 <500 cells/mm3
• 4 categories of regimens based on cost
• Application for approval • Revisions made based on
pricing negotiation
† By following the regulations, many individuals commence thymidine analogue (TA)-based regimens.
† Prior authorization is needed for the regimens containing PIs, INSTIs, or RPV plus non-thymidine analogue backbones.
7-Feb-18
I: AZT/3TC +NNRTI
IV: 20,500/17,500 NT$ Non-AZT/3TC + RPV, PIs, or IIs
Time to regimens modification during the first 24 weeks after starting antiretroviral treatment according to the regimen
MS 7-Feb-18
Thymidine analogue (TA) backbones: 67.6% (64.2% to 70.1%)
Non-TA backbone: 48.9% (44.4% to 53.1%)
Hazard Ratio, 1.82 [95% CI, 1.55 to 2.14]
Lipoatrophy (left) and “buffalo hump” (right)
HAART: the good, the bad, the ugly
Evolution of regulations on combination antiretroviral therapy in Taiwan-3
Year When to start Recommended Alternative
2016 Any CD4 TDF/FTC/EFV (Atripla)
TDF/FTC/RPV (Complera)
ABC/3TC/DTG (Triumeq)
Cost-based regimens • Total cost <15500 NT$
• Application for approval is required 1. non-AZT/3TC-based 2. 2-drug regimens 3. Regimens with cost>15500 NT$
2017 Any CD4 TDF/FTC/EFV (Atripla) TDF/FTC/RPV (Complera)* ABC/3TC/DTG (Triumeq)** TAF/FTC/Cob/EVG (Genvoya)
*PVL<100,000 copies/ml and CD4>200 cells/mm3
** HLA B*5701
• Late diagnosis • Administrative and NHI reimbursement issues • Concerns about antiretroviral resistance
– No pre-treatment resistance testing • Concerns about issues that may affect adherence
– convenience – tolerability – safety – long-term complications – comorbidities
Trends of CD4 counts at cART initiation in Taiwan
Lin KY, et al. PLoS One 2017
Treatment outcomes: all-cause mortality
All-cause mortality, n (%) 22 (1.7) 6 (0.3) 6.86 (2.78-16.91) <0.001
Lin KY, et al. PLoS One 2017
Improved survival of HIV-positive patients in Taiwan 0.
85 0.
90 0.
95 1.
group = 1 group = 2 group = 3
Kaplan-Meier survival estimates
Median CD4, 260 cells/mm3
CD4 <200 cells/mm3, 41.1% 27.9% with any OI; 46.7% with PVL >5 log10 copies/ml
Samji H, et al. PLoS ONE 2013
Changing patterns of the causes of death in a Swiss Cohort (SHCS)
• SHCS is a prospective observational cohort • Characteristics of participants that died from 2005-2009 • 459 deaths/9,053 participants (5.1%)
Ruppik M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 789.
Causes of Death in Participants in the Swiss HIV Cohort Study in 3 different Time Periods, and in the Swiss Population in 2007
0%
Pr op
or tio
Diagramm1
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
11.5
8.5
5.5
0.5
2
0
0
0
0
42
0
2
28
0
100
To resize chart data range, drag lower right corner of range.
Due to greatly increased life expectancy, management of co-morbidities is now an important part of routine care
• Individuals with HIV are more susceptible to developing cardiovascular disease, bone fractures, and renal failure than HIV-negative people1
• HIV infection and ART can have long-term effects on numerous aspects of health2–7
• ART, antiretroviral therapy • 1. Guaraldi G, et al. Clin Infect Dis 2011;53:1120–6; 2. McArthur JC, et al. Ann Neurol 2010;67:699–714; 3. Nguyen ML, et al. Curr Infect Dis Rep 2010;12(1)46-55; 4. Freiberg MS, et al. JAMA Intern Med 2013;173:614–22; 5. Brown TT, et al. AIDS 2006;20:2165–74; 6. Towner WJ, et al. J Acquir Immune Defic Syndr 2012;60:321–7; 7. Lucas GM, et al. Clin Infect Dis 2014;59:e96–138.
Cancer3
• Single-center, case-control study
HIV-Infected Pts (n = 2854) HIV-uninfected Controls (n = 8562)
*Comorbidites: bone fractures, CVD, diabetes, HTN, hypothyroidism.
0
20
40
60
80
100
Wu PY, et al. PLoS One 2014;9:e104945.
A Taiwan study in 920 HIV+ patients aged 40 years or
older in 2013
cardiovascular and renal complications
Pa tie
nt s (
40–49 years 50+ years (n = 610) (n = 310)
Address issues of polypharmacy in aging
patients to ensure adherence and minimise drug-drug
interactions
Duration of exposure to antiretroviral therapy and prevalence of hyperlipidemia
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
TG250 T-CHO240 TG250 T-CHO240 TG250 T-CHO240 TG250 T-CHO240
HAART PI NRTI NNRTI
Diabetes mellitus incidence is increased in HIV-positive patients on HAART
Brown TT et al., Arch Int Med 2005;165:1179–1184
Diabetes Mellitus is more than 4 times higher in HIV-infected patients on HAART as compared to the general population
Pa tie
nt s
Fr ee
Study Time, years No. of Patients
HIV Seronegative HIV Infected Using HAART
361 229
265 204
177 145
89 62
DM incidence and duration of cumulative exposure to cART
ART duration Wu PY, et al. HIV Drug therapy, Glasgow, 2016
Chart1
0‰
2.7‰
4‰
3.9‰
NNRTI duration
AZT duration
ddI,d4T duration
TDF duration
A RR 1.75
Age Group (Years)
* Adjusted for age, gender, race, hypertension, diabetes and dyslipidaemia. Proportion of patients with hypertension, diabetes and dyslipidaemia significantly higher in HIV-positive vs HIV- negative cohort
n = 1,044,589
n = 3,851
en ts
P er
1 00
0 PY
HIV-infected patients have a higher incidence of myocardial infarction
40-75 years, N=926 40-44 years (n=326); 45-49 years (249); 50-54 years (173); 55-59 years (78); 60years (100)
CVD risk estimation using 3 different equations
3.56
FRS risk D:A:D(R) risk ASCVD risk
Wu PY, et al. EACS 2017
≥60 years
40-75 years, N=926 40-44 years (n=326); 45-49 years (249); 50-54 years (173); 55-59 years (78); 60years (100)
CVD risk estimation using 3 different equations
5.8%
FRS group>=10% D:A:D (R) group>=10% ASCVD group>=10%
Wu PY, et al. EACS 2017
≥60 years
HIV-positive patients with reduced bone mineral density
Brown TT & Qaqish RB. AIDS 2006;20:2165-74. Tsai MS, et al. J Microbiol Immunol Infect 2014;47:109-15.
A meta-analysis1 including studies from USA, Europe, Latin America and Asia revealed:
67% of HIV patients had reduced bone mineral density (BMD)
Compared with HIV- controls, HIV+ patients had:
6.4-fold increased odds of reduced BMD
3.7-fold increased odds of osteoporosis
BMI Decreasing BMILonger duration on ARTIncreasing age
Prevalence and associated factors of reduced BMD in Taiwanese HIV+ patients2
Study (n = 320) conducted before the introduction of TDF in Taiwan Osteopenia (BMD T-score between -1.0 and -2.5) prevalence: 35.6% Osteoporosis (BMD T-score ≤-2.5) prevalence: 3.8% Factors associated with reduced BMD:
BMD of HIV-positive patients aged >45 years
37.8% 56%
48.2% 38.5%
14% 5.5%
Normal, n Osteopenia, n Osteoporosis, n
NTUH, unpublished data
Renal safety of tenofovir disoproxil fumerate (TDF)
Cooper RD, et al. Clin Infect Dis 2010;51:496-505. Laprise C, et al. Clin Infect Dis 2013;56:567-75.
Systematic review and meta-analysis of 17 studies1
revealed:
Change in GFR for TDF vs no treatment
From a long-term perspective, loss in eGFR attributable to TDF is relatively mild2
• “…findings do not support the need to restrict TDF use in jurisdictions where regular monitoring of renal function and serum phosphate levels is difficult or impractical.” 1
Greater risk of acute renal failure Risk difference, 0.7%; 95% CI: 0.2–1.2
Significantly greater loss of kidney function among TDF recipients compared with control subjects
Nephrotoxicity more likely Nephrotoxicity less likely
MD [95% CL], mL/min
0 10 20-20 -10
Total -3.9 (-5.7, -2.1)
The decline in eGFR for each additional one year of TDF exposure was 4.32 ml/min/1.73 m2
eGFR of HIV-infected patient with different durations of TDF exposure
Huang YS, et al. J Microbiol Immunol Infect 2017
Renal tubular cell TFV concentrations: TDF vs. TAF
OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir Stein DK. ASM 2016. Boston. MA. Oral
TAF/FTC/cob/EVG (Genvoya)
E/C/F/TAF (Genvoya®) 19.0 mm x 8.5 mm ~1100 mg
RPV/FTC/TAF 15.4 mm x 7.3 mm ~700 mg
E/C/F/TDF 20.0 mm x 10.0 mm ~1400 mg
RPV/FTC/TDF (Complera®) 19.0 mm x 8.5 mm ~1200 mg
FTC/TDF (Truvada®) 19.0 mm x 8.5 mm ~1000 mg
Gilead Sciences Inc. Data on File
Pill size is not intended to compare clinical efficacy and safety, indications, dosing regimens, or treatment adherence.
FTC/TAF 12.5 mm x 6 mm ~225 mg
EFV/FTC/TDF (Atripla®) 20 mm x 10.4 mm ~1600 mg
TDF-based TAF-based
* E/C/F/TDF, R/F/TAF, F/TAF are not approved in Taiwan
Prevalence of chronic HBV infection among HIV- positive patients in Taiwan
20.3
7.8
3.7
0
5
10
15
20
25
Prevalence, %
Before 1984 1984-1986 after 1986
1. 39.2% of those born after 1986 have lost seroprotection against HBV
2. Incident HBV infection rate was 9.2 per 1000 PYFU among the non- responders after revaccination
Sun HY, et al. Am J Gastroenterol 2009;104:877-884. Sun HY, et al. PLoS One 2014;9:e90194 Huang YC, et al. Liver Int (revised)
HCV seroprevalence among HIV-positive patients in Taiwan
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
<=20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 >60
Overall
MSM
Heterosexual
IDU
Years
0
2.29
in ci
de nc
e ra
te (p
er 1
00 0y
r)
Year
Incidence rate of recent HCV infection among HIV- positive patients at NTUH
Sun HY, et al. J Clin Microbiol 2012 Sun HY, et al. EACS 2017
Generic velpatasvir plus sofosbuvir for the treatment of HCV among HIV-positive patients
97.10% 98.11%
Liu CH, et al. Aliment Pharmacol Ther (revised)
Why do we need to expedite the initiation of cART? “Undetectable=Untransmittable”
Gutierrez-Valencia A, et al. Clin Infect Dis 2017;65:551-6.
In 2012, an estimate of 70% of 41,000 patients with newly
diagnosed HIV infection in the US acquired HIV from those
who did not known their HIV serostatus or those who had not received antiretroviral therapy
since diagnosis
Max: 1138
Max: 847
Max: 382
Max: 47
Mean, 127 Mean, 61
Du ra
tio n
of c
O om
bo o
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
16.9%
34.7%
41.4%
55.6%
7 Days
Group 1: 7 days; Group 2: 8-30 days; Group 3: 31 days
Door-to-cART interval and viral suppression Pr
ob ab
ili ty
% of
e
N= 550 101 187 1166 740 645 532 495 N(II)= 161 26 118 581 102 39 87 243
Lai CC, et al. J Antimicrob Chemother 2012;67:1254-60. Lai CC, et al. J Antimicrob Chemother 2016;71:226-34. Chang, SY (Unpublished data, updated on 20171207)
0
2
4
6
8
10
12
14
16
18
20
PI
NRTI
NNRTI
II
MDR
Any
Prevalence of genotypic resistance mutations to integrase inhibitors in Taiwan
0.6 1.7
Resistance, %
ARV-naïve (n=948)
ARV-naïve, InSTI-naïve (359)
Summary
• The case number of newly diagnosed HIV infection continues to increase at an annual rate of 8-9%
• A substantial proportion of patients initiating AZT/3TC-based cART have to switch regimens because of tolerance and safety issues
• 4 STRs are available as the first-line ART regimens in Taiwan
• Barriers to rapid initiation of cART need to be tackled and removed
• Managing comorbidities has become a pressing issue of HIV care
Acknowledgements
• Taiwan CDC for research funding • Dr. Chang SY for the resistance data • Dr. Liu CH (Hepatologist) for providing care to
patients with chronic HCV infection • Taiwan HIV Study Group • Case managers for patient care
Current Status of Antiretroviral Therapy in Taiwan
Disclosures
Outline
5
DHHS, IAS-USA Guidelines: Recommended Regimens for the First-line ART
Evolution of regulations on combination antiretroviral therapy in Taiwan-1
Evolution of regulations on combination antiretroviral therapy in Taiwan-2
Cost-based Regulations on Antiretroviral Therapy since 2012
Time to regimens modification during the first 24 weeks after starting antiretroviral treatment according to the regimen
Lipoatrophy (left) and “buffalo hump” (right)
Evolution of regulations on combination antiretroviral therapy in Taiwan-3
Barriers to early initiation of cART
Trends of CD4 counts at cART initiation in Taiwan
Treatment outcomes: all-cause mortality
24
Changing patterns of the causes of death in a Swiss Cohort (SHCS)
Due to greatly increased life expectancy, management of co-morbidities is now an important part of routine care
Comorbidities Increase With Age and With HIV Infection
Key Issues in Comorbidity Management in HIV+ Patients: Aged Patient Population
Duration of exposure to antiretroviral therapy and prevalence of hyperlipidemia
Diabetes mellitus incidence is increased in HIV-positive patients on HAART
DM incidence and duration of cumulative exposure to cART
32
eGFR of HIV-infected patient with different durationsof TDF exposure
Renal tubular cell TFV concentrations: TDF vs. TAF
Novel TAF Backbone: TDF vs TAF-based STR
Prevalence of chronic HBV infection among HIV-positive patients in Taiwan
HCV seroprevalence among HIV-positive patients in Taiwan
Incidence rate of recent HCV infection among HIV-positive patients at NTUH
Generic velpatasvir plus sofosbuvir for the treatment of HCV among HIV-positive patients
47
48
Why do we need to expedite the initiation of cART?“Undetectable=Untransmittable”
50
53
Prevalence of genotypic resistance among treatment-naïve patients in Northern Taiwan
Prevalence of genotypic resistance mutations to integrase inhibitors in Taiwan
Summary
Acknowledgements
National Taiwan University Hospital
Disclosures
• I have received honoraria for speaking at educational events or consulting from: – AbbVie, Bristol-Myers Squibb, Gilead Sciences,
Janssen, and ViiV
• I have received research funding from – Bristol-Myers Squibb, Janssen, Merck, and ViiV
Outline • Brief introduction to HIV epidemiology in Taiwan • Introduction to development of antiretroviral
therapy • Evolution of treatment guidelines in Taiwan • Short-term experience with the cost-based
regulations on antiretroviral regimens • Update on the current guidelines • Challenges ahead
HIV epidemiology in Taiwan, 1984-2017
0
500
1000
1500
2000
2500
3000
3500
4000
Gandhi M and Gandhi RT. N Engl J Med 2014;371:248-59.
HIV replication and treatment targets
The development of antiretroviral therapy (ART)
1985 1990 2000 2005 2010 2015
ZDV, 1987 ddI, 1991
2018
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. April 8, 2015, & other years as noted.. Available at: http://www.aidsinfo.nih.gov/Guideline
Evolution of “When to Start ART?”
1987 1998 2001 2002 2004 2008 2009/2011/2015
FACTOR RECOMMENDATION FOR TREATMENT
AIDS Treat Treat Treat Treat Treat Treat Treat Treat
CD4 All <500 • Recommended at <200 • Offer at <350 • Individualize decision at >350
• Recommended <350
• Risks/Benefits >350
• Recommended <500
• Favor/Optional >500
Viral Load
>20,00 0 >55,000 >100,000 No specific viral load No specific viral load
Other Factors
HIV-infected individuals for the prevention of HIV
transmission
Class DHHS IAS-USA EACS INSTI DTG/ABC/3TC
DTG + (TAF or TDF)/FTC EVG/c/(TAF or
TDF)/FTC RAL + (TDF or
DTG/ABC/3TC DTG, EVG/c, or RAL
plus (TAF or TDF)/FTC
NNRTI RPV/(TAF or TDF)/FTC
DHHS Guidelines. Oct 2017 Günthard HF, et al. JAMA. 2016;316:191-210
ECS v9 2017
CD4, <200 cells/mm3 ZDV/3TC ABC/3TC
EFV KLA;
ATV/r
NVP
2010 Pregnant women HIVAN Chronic HBV infection AIDS-related illness; CD4, <350 cells/mm3
ZDV/3TC ABC/3TC
EFV KLA;
ATV (400 mg)
2012 Pregnant women HIVAN Chronic HBV infection AIDS-related illness; CD4, <350 cells/mm3
• 4 categories of regimens based on cost • Application for approval • Revision made based on pricing
negotiation
Year When to start Recommended Alternative
2013 Pregnant women HIVAN Serodiscordant partners Chronic HBV infection AIDS-related illness CD4 <500 cells/mm3
• 4 categories of regimens based on cost
• Application for approval • Revisions made based on
pricing negotiation
† By following the regulations, many individuals commence thymidine analogue (TA)-based regimens.
† Prior authorization is needed for the regimens containing PIs, INSTIs, or RPV plus non-thymidine analogue backbones.
7-Feb-18
I: AZT/3TC +NNRTI
IV: 20,500/17,500 NT$ Non-AZT/3TC + RPV, PIs, or IIs
Time to regimens modification during the first 24 weeks after starting antiretroviral treatment according to the regimen
MS 7-Feb-18
Thymidine analogue (TA) backbones: 67.6% (64.2% to 70.1%)
Non-TA backbone: 48.9% (44.4% to 53.1%)
Hazard Ratio, 1.82 [95% CI, 1.55 to 2.14]
Lipoatrophy (left) and “buffalo hump” (right)
HAART: the good, the bad, the ugly
Evolution of regulations on combination antiretroviral therapy in Taiwan-3
Year When to start Recommended Alternative
2016 Any CD4 TDF/FTC/EFV (Atripla)
TDF/FTC/RPV (Complera)
ABC/3TC/DTG (Triumeq)
Cost-based regimens • Total cost <15500 NT$
• Application for approval is required 1. non-AZT/3TC-based 2. 2-drug regimens 3. Regimens with cost>15500 NT$
2017 Any CD4 TDF/FTC/EFV (Atripla) TDF/FTC/RPV (Complera)* ABC/3TC/DTG (Triumeq)** TAF/FTC/Cob/EVG (Genvoya)
*PVL<100,000 copies/ml and CD4>200 cells/mm3
** HLA B*5701
• Late diagnosis • Administrative and NHI reimbursement issues • Concerns about antiretroviral resistance
– No pre-treatment resistance testing • Concerns about issues that may affect adherence
– convenience – tolerability – safety – long-term complications – comorbidities
Trends of CD4 counts at cART initiation in Taiwan
Lin KY, et al. PLoS One 2017
Treatment outcomes: all-cause mortality
All-cause mortality, n (%) 22 (1.7) 6 (0.3) 6.86 (2.78-16.91) <0.001
Lin KY, et al. PLoS One 2017
Improved survival of HIV-positive patients in Taiwan 0.
85 0.
90 0.
95 1.
group = 1 group = 2 group = 3
Kaplan-Meier survival estimates
Median CD4, 260 cells/mm3
CD4 <200 cells/mm3, 41.1% 27.9% with any OI; 46.7% with PVL >5 log10 copies/ml
Samji H, et al. PLoS ONE 2013
Changing patterns of the causes of death in a Swiss Cohort (SHCS)
• SHCS is a prospective observational cohort • Characteristics of participants that died from 2005-2009 • 459 deaths/9,053 participants (5.1%)
Ruppik M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 789.
Causes of Death in Participants in the Swiss HIV Cohort Study in 3 different Time Periods, and in the Swiss Population in 2007
0%
Pr op
or tio
Diagramm1
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1984-1995
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
1996-2004
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
2005-2009
11.5
8.5
5.5
0.5
2
0
0
0
0
42
0
2
28
0
100
To resize chart data range, drag lower right corner of range.
Due to greatly increased life expectancy, management of co-morbidities is now an important part of routine care
• Individuals with HIV are more susceptible to developing cardiovascular disease, bone fractures, and renal failure than HIV-negative people1
• HIV infection and ART can have long-term effects on numerous aspects of health2–7
• ART, antiretroviral therapy • 1. Guaraldi G, et al. Clin Infect Dis 2011;53:1120–6; 2. McArthur JC, et al. Ann Neurol 2010;67:699–714; 3. Nguyen ML, et al. Curr Infect Dis Rep 2010;12(1)46-55; 4. Freiberg MS, et al. JAMA Intern Med 2013;173:614–22; 5. Brown TT, et al. AIDS 2006;20:2165–74; 6. Towner WJ, et al. J Acquir Immune Defic Syndr 2012;60:321–7; 7. Lucas GM, et al. Clin Infect Dis 2014;59:e96–138.
Cancer3
• Single-center, case-control study
HIV-Infected Pts (n = 2854) HIV-uninfected Controls (n = 8562)
*Comorbidites: bone fractures, CVD, diabetes, HTN, hypothyroidism.
0
20
40
60
80
100
Wu PY, et al. PLoS One 2014;9:e104945.
A Taiwan study in 920 HIV+ patients aged 40 years or
older in 2013
cardiovascular and renal complications
Pa tie
nt s (
40–49 years 50+ years (n = 610) (n = 310)
Address issues of polypharmacy in aging
patients to ensure adherence and minimise drug-drug
interactions
Duration of exposure to antiretroviral therapy and prevalence of hyperlipidemia
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
TG250 T-CHO240 TG250 T-CHO240 TG250 T-CHO240 TG250 T-CHO240
HAART PI NRTI NNRTI
Diabetes mellitus incidence is increased in HIV-positive patients on HAART
Brown TT et al., Arch Int Med 2005;165:1179–1184
Diabetes Mellitus is more than 4 times higher in HIV-infected patients on HAART as compared to the general population
Pa tie
nt s
Fr ee
Study Time, years No. of Patients
HIV Seronegative HIV Infected Using HAART
361 229
265 204
177 145
89 62
DM incidence and duration of cumulative exposure to cART
ART duration Wu PY, et al. HIV Drug therapy, Glasgow, 2016
Chart1
0‰
2.7‰
4‰
3.9‰
NNRTI duration
AZT duration
ddI,d4T duration
TDF duration
A RR 1.75
Age Group (Years)
* Adjusted for age, gender, race, hypertension, diabetes and dyslipidaemia. Proportion of patients with hypertension, diabetes and dyslipidaemia significantly higher in HIV-positive vs HIV- negative cohort
n = 1,044,589
n = 3,851
en ts
P er
1 00
0 PY
HIV-infected patients have a higher incidence of myocardial infarction
40-75 years, N=926 40-44 years (n=326); 45-49 years (249); 50-54 years (173); 55-59 years (78); 60years (100)
CVD risk estimation using 3 different equations
3.56
FRS risk D:A:D(R) risk ASCVD risk
Wu PY, et al. EACS 2017
≥60 years
40-75 years, N=926 40-44 years (n=326); 45-49 years (249); 50-54 years (173); 55-59 years (78); 60years (100)
CVD risk estimation using 3 different equations
5.8%
FRS group>=10% D:A:D (R) group>=10% ASCVD group>=10%
Wu PY, et al. EACS 2017
≥60 years
HIV-positive patients with reduced bone mineral density
Brown TT & Qaqish RB. AIDS 2006;20:2165-74. Tsai MS, et al. J Microbiol Immunol Infect 2014;47:109-15.
A meta-analysis1 including studies from USA, Europe, Latin America and Asia revealed:
67% of HIV patients had reduced bone mineral density (BMD)
Compared with HIV- controls, HIV+ patients had:
6.4-fold increased odds of reduced BMD
3.7-fold increased odds of osteoporosis
BMI Decreasing BMILonger duration on ARTIncreasing age
Prevalence and associated factors of reduced BMD in Taiwanese HIV+ patients2
Study (n = 320) conducted before the introduction of TDF in Taiwan Osteopenia (BMD T-score between -1.0 and -2.5) prevalence: 35.6% Osteoporosis (BMD T-score ≤-2.5) prevalence: 3.8% Factors associated with reduced BMD:
BMD of HIV-positive patients aged >45 years
37.8% 56%
48.2% 38.5%
14% 5.5%
Normal, n Osteopenia, n Osteoporosis, n
NTUH, unpublished data
Renal safety of tenofovir disoproxil fumerate (TDF)
Cooper RD, et al. Clin Infect Dis 2010;51:496-505. Laprise C, et al. Clin Infect Dis 2013;56:567-75.
Systematic review and meta-analysis of 17 studies1
revealed:
Change in GFR for TDF vs no treatment
From a long-term perspective, loss in eGFR attributable to TDF is relatively mild2
• “…findings do not support the need to restrict TDF use in jurisdictions where regular monitoring of renal function and serum phosphate levels is difficult or impractical.” 1
Greater risk of acute renal failure Risk difference, 0.7%; 95% CI: 0.2–1.2
Significantly greater loss of kidney function among TDF recipients compared with control subjects
Nephrotoxicity more likely Nephrotoxicity less likely
MD [95% CL], mL/min
0 10 20-20 -10
Total -3.9 (-5.7, -2.1)
The decline in eGFR for each additional one year of TDF exposure was 4.32 ml/min/1.73 m2
eGFR of HIV-infected patient with different durations of TDF exposure
Huang YS, et al. J Microbiol Immunol Infect 2017
Renal tubular cell TFV concentrations: TDF vs. TAF
OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir Stein DK. ASM 2016. Boston. MA. Oral
TAF/FTC/cob/EVG (Genvoya)
E/C/F/TAF (Genvoya®) 19.0 mm x 8.5 mm ~1100 mg
RPV/FTC/TAF 15.4 mm x 7.3 mm ~700 mg
E/C/F/TDF 20.0 mm x 10.0 mm ~1400 mg
RPV/FTC/TDF (Complera®) 19.0 mm x 8.5 mm ~1200 mg
FTC/TDF (Truvada®) 19.0 mm x 8.5 mm ~1000 mg
Gilead Sciences Inc. Data on File
Pill size is not intended to compare clinical efficacy and safety, indications, dosing regimens, or treatment adherence.
FTC/TAF 12.5 mm x 6 mm ~225 mg
EFV/FTC/TDF (Atripla®) 20 mm x 10.4 mm ~1600 mg
TDF-based TAF-based
* E/C/F/TDF, R/F/TAF, F/TAF are not approved in Taiwan
Prevalence of chronic HBV infection among HIV- positive patients in Taiwan
20.3
7.8
3.7
0
5
10
15
20
25
Prevalence, %
Before 1984 1984-1986 after 1986
1. 39.2% of those born after 1986 have lost seroprotection against HBV
2. Incident HBV infection rate was 9.2 per 1000 PYFU among the non- responders after revaccination
Sun HY, et al. Am J Gastroenterol 2009;104:877-884. Sun HY, et al. PLoS One 2014;9:e90194 Huang YC, et al. Liver Int (revised)
HCV seroprevalence among HIV-positive patients in Taiwan
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
<=20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 >60
Overall
MSM
Heterosexual
IDU
Years
0
2.29
in ci
de nc
e ra
te (p
er 1
00 0y
r)
Year
Incidence rate of recent HCV infection among HIV- positive patients at NTUH
Sun HY, et al. J Clin Microbiol 2012 Sun HY, et al. EACS 2017
Generic velpatasvir plus sofosbuvir for the treatment of HCV among HIV-positive patients
97.10% 98.11%
Liu CH, et al. Aliment Pharmacol Ther (revised)
Why do we need to expedite the initiation of cART? “Undetectable=Untransmittable”
Gutierrez-Valencia A, et al. Clin Infect Dis 2017;65:551-6.
In 2012, an estimate of 70% of 41,000 patients with newly
diagnosed HIV infection in the US acquired HIV from those
who did not known their HIV serostatus or those who had not received antiretroviral therapy
since diagnosis
Max: 1138
Max: 847
Max: 382
Max: 47
Mean, 127 Mean, 61
Du ra
tio n
of c
O om
bo o
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
16.9%
34.7%
41.4%
55.6%
7 Days
Group 1: 7 days; Group 2: 8-30 days; Group 3: 31 days
Door-to-cART interval and viral suppression Pr
ob ab
ili ty
% of
e
N= 550 101 187 1166 740 645 532 495 N(II)= 161 26 118 581 102 39 87 243
Lai CC, et al. J Antimicrob Chemother 2012;67:1254-60. Lai CC, et al. J Antimicrob Chemother 2016;71:226-34. Chang, SY (Unpublished data, updated on 20171207)
0
2
4
6
8
10
12
14
16
18
20
PI
NRTI
NNRTI
II
MDR
Any
Prevalence of genotypic resistance mutations to integrase inhibitors in Taiwan
0.6 1.7
Resistance, %
ARV-naïve (n=948)
ARV-naïve, InSTI-naïve (359)
Summary
• The case number of newly diagnosed HIV infection continues to increase at an annual rate of 8-9%
• A substantial proportion of patients initiating AZT/3TC-based cART have to switch regimens because of tolerance and safety issues
• 4 STRs are available as the first-line ART regimens in Taiwan
• Barriers to rapid initiation of cART need to be tackled and removed
• Managing comorbidities has become a pressing issue of HIV care
Acknowledgements
• Taiwan CDC for research funding • Dr. Chang SY for the resistance data • Dr. Liu CH (Hepatologist) for providing care to
patients with chronic HCV infection • Taiwan HIV Study Group • Case managers for patient care
Current Status of Antiretroviral Therapy in Taiwan
Disclosures
Outline
5
DHHS, IAS-USA Guidelines: Recommended Regimens for the First-line ART
Evolution of regulations on combination antiretroviral therapy in Taiwan-1
Evolution of regulations on combination antiretroviral therapy in Taiwan-2
Cost-based Regulations on Antiretroviral Therapy since 2012
Time to regimens modification during the first 24 weeks after starting antiretroviral treatment according to the regimen
Lipoatrophy (left) and “buffalo hump” (right)
Evolution of regulations on combination antiretroviral therapy in Taiwan-3
Barriers to early initiation of cART
Trends of CD4 counts at cART initiation in Taiwan
Treatment outcomes: all-cause mortality
24
Changing patterns of the causes of death in a Swiss Cohort (SHCS)
Due to greatly increased life expectancy, management of co-morbidities is now an important part of routine care
Comorbidities Increase With Age and With HIV Infection
Key Issues in Comorbidity Management in HIV+ Patients: Aged Patient Population
Duration of exposure to antiretroviral therapy and prevalence of hyperlipidemia
Diabetes mellitus incidence is increased in HIV-positive patients on HAART
DM incidence and duration of cumulative exposure to cART
32
eGFR of HIV-infected patient with different durationsof TDF exposure
Renal tubular cell TFV concentrations: TDF vs. TAF
Novel TAF Backbone: TDF vs TAF-based STR
Prevalence of chronic HBV infection among HIV-positive patients in Taiwan
HCV seroprevalence among HIV-positive patients in Taiwan
Incidence rate of recent HCV infection among HIV-positive patients at NTUH
Generic velpatasvir plus sofosbuvir for the treatment of HCV among HIV-positive patients
47
48
Why do we need to expedite the initiation of cART?“Undetectable=Untransmittable”
50
53
Prevalence of genotypic resistance among treatment-naïve patients in Northern Taiwan
Prevalence of genotypic resistance mutations to integrase inhibitors in Taiwan
Summary
Acknowledgements
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