1. Case Discussion: Complications after ART Weerawat Manosuthi, MD Department of Medicine Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Thailand

2. Case: SW, 55 year-old male 1994- First diagnosed with HIV and CD4 290ZDV+ddI 1994-2001- ARV regimens had been changed due to virologic rebound without resistance test. - He reported fair adherence. - His last VL in 2001 was 4.1 logs. ZDV+ddC+SQV 2 yrs d4T+ddI+IDV/r 3 yrs ZDV+3TC+EFV 1 yr 2002-2006- Lost to follow-up.

3. Case: SW, 55 year-old male 1994- First diagnosed with HIV and CD4 290ZDV+ddI 1994-2001- ARV regimens had been changed due to virologic rebound without resistance test. - He reported fair adherence. - His last VL in 2001 was 4.1 logs. ZDV+ddC+SQV 2 yrs d4T+ddI+IDV/r 3 yrs ZDV+3TC+EFV 1 yr 2002-2006- Lost to follow-up. April 2007- Presented with visual loss. - CD4 28 (3%), VL 5.3 log - HBs Ag - neg, anti-HCV - neg, A1C 9.3% - Cr 0.7 mg/dL, CrCl 101, urine protein 1+ - HIV genotype: No evidence of resistance TDF+3TC+LPV/ r (on 7 May 2007) Q1: Do you agree with this regimen “TDF+3TC+LPV/r” ? 1.I do 2.I do not

4. Case: SW, 55 year-old male 1994- First diagnosed with HIV and CD4 290ZDV+ddI 1994-2001- ARV regimens had been changed due to virologic rebound without resistance test. - He reported fair adherence. - His last VL in 2001 was 4.1 logs. ZDV+ddC+SQV d4T+ddI+IDV/rtv ZDV+3TC+EFV 2002-2006- Lost to follow-up. April 2007- Presented with visual loss. - CD4 28 (3%), VL 5.3 log - HBs Ag - neg, anti-HCV - neg, A1C 9.3% - Cr 0.7 mg/dL, CrCl 101, urine protein 1+ - HIV genotype: No evidence of resistance TDF+3TC+LPV/ rtv (on 7 May 2007) 30 May 2007 - Fever with intra-abdominal lymph node enlargement and necrosis. I, E, Z, Quinolone (Rifabutin was not available)

5. Case: SW, 55 year-old male 1994-First diagnosis with HIV and CD4 290ZDV+ddI 1994-2001- ARV regimens had been changed due to virologic rebound without resistance test. - He reported fair adherence. - His last VL in 2001 was 4.1 logs. ZDV+ddC+SQV 2 yrs d4T+ddI+IDV/rtv 3 yrs ZDV+3TC+EFV 1 yr 2002-2006- Lost to follow-up. April 2007- Presented with visual loss. - CD4 28 (3%), VL 5.3 log, HBs Ag - neg, anti-HCV – neg, CrCL 101 - Cr 0.7 mg/dL, A1C 9.3, urine protein 1+ - HIV genotype: No evidence of resistance TDF+3TC+LPV/rtv (on 7 May 2007) Metformin 30 May 2007- Fever with intraabdominal lymph node enlargement and necrosis.I, E, Z, Quinolone Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, - Na 122 K 6 Cl 97 HCO 3 11 CrCl 6 ml/min - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. Q2: What is the most likely cause of renal impairment? 1.Tenofovir 2.Lopinavir/rtv 3.Anti-TB drugs 4.Diabetes5. Others

6. Rodrı ́guez-No ́voa S, et al. Clin Infect Dis 2009;48:e108-16. Kalyesubula R, et al. AIDS Research and Treatment 2011. Nelson M, et al. AIDS 2008;22,1374-1376. Zimmermann AE, et al. Clin Infect Dis 2006;42,:283-290. Rodrı ́guez-No ́voa S, et al. Expert Opinion 2012;9:545-559.  Older age  Elevated baseline creatinine  Low body weight  Low CD4 nadir  Other comorbidities: diabetes, HCV  Concomitant use of nephrotoxic drugs  Combined therapy with PI  Inhibition of MRP4 by PI/r leads to increased intracellular tenofovir levels  Genetic factors, involving polymorphisms at cellular transporter gene Risk Factors Associated with TDF-Induced Nephrotoxicity Mitochondrial toxicity Interfere tubular cell function

7. Case: SW, 55 year-old male 1994-First diagnosis with HIV and CD4 290ZDV+ddI 1994-2001- ARV regimens had been changed due to virologic rebound without resistance test. - He reported fair adherence. - His last VL in 2001 was 4.1 logs. ZDV+ddC+SQV 2 yrs d4T+ddI+IDV/rtv 3 yrs ZDV+3TC+EFV 1 yr 2002-2006- Lost to follow-up. April 2007- Presented with visual loss. - CD4 28 (3%), VL 5.3 log, HBs Ag - neg, anti-HCV – neg, CrCL 101 - Cr 0.7 mg/dL, A1C 9.3, urine protein 1+ - HIV genotype: No evidence of resistance TDF+3TC+LPV/rtv (on 7 May 2007) Metformin 30 May 2007- Fever with intraabdominal lymph node enlargement and necrosis.I, E, Z, Quinolone Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, Hb 9 - Na 122 K 6 Cl 97 HCO 3 11 CrCl 6 ml/min - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. Q3: Which of the following is the best next regimen? 1.PI/r + integrase inhibitor + 3TC 2.PI/r + etravirine + 3TC 3.PI/r + integrase inhibitor + Etravirine 4.Others

8. Case: SW, 55 year-old male Q4: Which of the following is a next regimen if he is in the resource-limited setting (3 classes available) ? 1.PI/r + 3TC 2.PI/r + AZT + 3TC 3.Others 1994-First diagnosis with HIV and CD4 290ZDV+ddI 1994-2001- ARV regimens had been changed due to virologic rebound without resistance test. - He reported fair adherence. - His last VL in 2001 was 4.1 logs. ZDV+ddC+SQV 2 yrs d4T+ddI+IDV/rtv 3 yrs ZDV+3TC+EFV 1 yr 2002-2006- Lost to follow-up. April 2007- Presented with visual loss. - CD4 28 (3%), VL 5.3 log, HBs Ag - neg, anti-HCV – neg, CrCL 101 - Cr 0.7 mg/dL, A1C 9.3, urine protein 1+ - HIV genotype: No evidence of resistance TDF+3TC+LPV/rtv (on 7 May 2007) Metformin 30 May 2007- Fever with intraabdominal lymph node enlargement and necrosis.I, E, Z, Quinolone Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, Hb 9 - Na 122 K 6 Cl 97 HCO3 11 CrCL 6 ml/min - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage.

9. Case: SW, 55 year-old male Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, - Na 122 K 6 Cl 97 HCO3 11 CrCl 6 ml/min - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. - 3TC+LPV/rtv - Modified dose of anti-TB drugs - Hemodialysis Nov 2007- CD4 23 (8%), VL <50, Cr 7-10 mg/dl Feb 2008- CD4 109 (8%) and VL <50, Cr 3-4 mg/dl - Markedly decreased size of intraabdominal LN Aug 2008CD4 103 (10%), VL <50Off anti-TB drugs

10. Case: SW, 55 year-old male Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, - Na 122 K 6 Cl 97 HCO3 11 - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. - 3TC+LPV/rtv - Modified dose of anti-TB drugs - Hemodialysis Nov 2007- CD4 23 (8%), VL <50, Cr 7-10 mg/dl Feb 2008- CD4 109 (8%) and VL <50, Cr 3-4 mg/dl - Markedly decreased size of intraabdominal LN Aug 2008- CD4 103 (10%), VL <50- Off anti-TB drugs May 2009- CD4 104 (7%), VL <40 - Chest x-ray as - Sputum AFB +ve, PCR TB +ve, DST: pending Q5: What would you manage this episode of TB?

11. Case: SW, 55 year-old male Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, - Na 122 K 6 Cl 97 HCO3 11 CrCL 6 ml/mim - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. - 3TC+LPV/rtv - Modified dose of anti-TB drugs - Hemodialysis Nov 2007- CD4 23 (8%), VL <50, Cr 7-10 mg/dl Feb 2008- CD4 109 (8%) and VL <50, Cr 3-4 mg/dl - Markedly decreased size of intraabdominal LN Aug 2008- CD4 103 (10%), VL <50- Off anti-TB drugs May 2009- CD4 104 (7%), VL <40 - Chest x-ray - Sputum AFB +ve and PCR TB +ve - 3TC+LPV/rtv - I, E, Z, Quinolone Aug 2009- CD4 93 (13%), VL <40 - Sputum culture grew M. TB. - Sense: R, Resist: I, E, S Levoflox, amikacin, cycloserine, PAS, ethionamide Aug 2011- CD4 102 (13%), VL 200, infiltrations cleared- Off anti-TB drugs

12. Case: SW, 55 year-old male Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, - Na 122 K 6 Cl 97 HCO3 11 CrCL 6 ml/mim - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. - 3TC+LPV/rtv - Modified dose of anti-TB drugs - Hemodialysis Nov 2007- CD4 23 (8%), VL <50, Cr 7-10 mg/dl Feb 2008- CD4 109 (8%) and VL <50, Cr 3-4 mg/dl - Markedly decreased size of intraabdominal LN Aug 2008- CD4 103 (10%), VL <50- Off anti-TB drugs May 2009- CD4 104 (7%), VL <40 - Chest x-ray, Sputum AFB +ve and PCR TB +ve Aug 2009- CD4 93 (13%), VL <40 - Sputum culture grew M. TB. Sense: R, Resist: I, E, S - Levoflox, amikacin, cycloserine, PAS, ethionamide Aug 2011- CD4 102 (13%), VL 200, resolved infiltration- Off anti-TB drugs Nov 2011- Lost to follow-up Jan 2012- CD4 135 (15%), VL 61,000 co/ml, Cr 2.6 mg/dl - Genotypic report: M184V, no major PRAM Q6: Which of the following is the best next regimen? 1.PI/r + integrase inhibitor + Etravirine 2.PI/r + integrase inhibitor + 3TC 3.PI/r + 3TC 4.Others

13. Case: SW, 55 year-old male Aug 2007 (Regular visit without symptoms) - CD4 52 (11%), VL 68 (1.8 log), Cr 11.6 mg/dl, - Na 122 K 6 Cl 97 HCO3 11 CrCL 6 ml/mim - Urine protein 1+, U/S of kidney: high normal size - Renal biopsy: diabetic nephropathy, interstitial nephritis and tubular epithelial damage. - 3TC+LPV/rtv - Modified dose of anti-TB drugs - Hemodialysis Nov 2007- CD4 23 (8%), VL <50, Cr 7-10 mg/dl Feb 2008- CD4 109 (8%) and VL <50, Cr 3-4 mg/dl - Markedly decreased size of intraabdominal LN Aug 2008- CD4 103 (10%), VL <50- Off anti-TB drugs May 2009- CD4 104 (7%), VL <40 - Chest x-ray, Sputum AFB +ve and PCR TB +ve Aug 2009- CD4 93 (13%), VL <40 - Sputum culture grew M. TB. Sense: R, Resist: I, E, S - Levoflox, amikacin, cycloserine, PAS, ethionamide Aug 2011- CD4 102 (13%), VL 200, resolved infiltration- Off anti-TB drugs Nov 2011- Lost to follow-up Jan 2012- CD4 135 (15%), VL 61,000 co/ml, Cr 2.6 mg/dl - Genotypic report: M184V, no major PRAM - 3TC+LPV/rtv Apr 2012- CD4 132 (16%), VL <40- 3TC+LPV/rtv Mar 2013- CD4 162 (16%), VL <40- 3TC+LPV/rtv

14. THANK YOU