1. Managing Emerging complications of HIV Treatment

2. Background  ARV has become more available in our settings –Currently >65,000 Kenyans are estimated to be on ARV treatment  Antiretroviral therapy (ART) alters the nature of HIV disease, transforming an almost uniformly fatal illness into a chronic but stable condition.  However its use may be complicated by a number of factors, including side effects, drug interactions and treatment failure.

3. Toxicity  Adverse drug reactions (ADRs) are the most common reason for treatment change or discontinuation –All classes of ARV drugs associated with ADRs  Rate of toxicity is high –45% have clinical adverse events and 27% have laboratory adverse events  9% of clinical and 16% of laboratory are serious or severe

4. 14% 20% 8% 58% Toxicity Failure Nonadherence Other n = 25 n = 61 n = 44 n = 182 ICONA Study: Reasons for Failure of Initial HAART d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.

5. Common side effects  Which side effects are you seeing in your patients?

6. ARV Drug Class Adverse Effects NRTIs  Peripheral neuropathy  Pancreatitis  Lipoatrophy  Hepatitis  Lactic acidosis  Mitochondrial toxicity NNRTIs  Rash  Fever  Nausea  Diarrhea  Hepatoxicity, CNS PIs  Lipodystrophy  GI Intolerance  Hyperglycaemia  Lipid abnormalities Common Adverse Effects  Peripheral Neuropathy – d4T,ddI  Hematotoxicity - AZT  Hepatotoxicity - NVP  Diarrhea – NFV  Skin rash – NVP  Lipodystrophy – PIs, NRTIs  CNS disturbance – EFV  Hypersensitivity – ABC  Hyperlipidemia-PIs, d4T

7. Common toxicity in our setting  There is little information on tolerability to these medications in African populations. –Severe rash /Steven Johnson's syndrome –Hepatotoxicity –Peripheral neuropathy –Hematological –Metabolic and morphologic complications. –Others  pancreatitis

8. Distribution and Frequency of Clinical Adverse Events among HIV- Infected Patients Receiving ARV Therapy, Kibera ARV Program Adverse Event Any(n=283) Grade 3-4 (n=283) Any adverse event 184 (65%) 18 (6%) Neuropathy 65 (23%) 7 (3%) Rash 58 (20%) 4 (1%) Nausea 46 (16%) 1 (0.4%) Asthenia11(3.9%)0 Diarrhea 5 (1.8%) 1 (0.4%) Clinical hepatitis 4 (1%) Lipodystrophy 6 (2)

9. Time to First Adverse Event among HIV- Infected Patients Receiving ARV Therapy, Kibera ARV Program Time to First Adverse Event among HIV- Infected Patients Receiving ARV Therapy, Kibera ARV Program No adverse event at Probability 6 months 0.47 12 months 0.26 18 months 0.17 n=283 n=92 n=19 n=14

10. Rash  Most commonly due to Nevirapine, Also sometimes due to Efavirenz, Abacavir and Cotrimoxazole  Rash seen in up to 20% of patients, usually in the first 2-8 weeks of use  Associated with: –Gender (female > male; RR 4.85-8.31) –CD4 count/disease stage –previous sulphur allergy (RR 5)  Often mild to moderate, can be managed symptomatically  Can progress to severe rash or even Stevens Johnson syndrome, in 5 -7%

11. Rash continued…..  Dose- escalation decreases incidence –Do not dose escalate if rash  Pretreatment with steroids increases risk of severe rash  Stop NVP for grade 3 rash or higher

12. Stevens-Johnsons syndrome

13. Abacavir Hypersensitivity Reaction  Occurs in approximately 5-8% of ABC-treated patients  Associated with: –female gender –higher CD4 count –Genetically linked to haplotype HLA-B*5701  Multiorgan clinical syndrome including 2 or more of the following: –Fever, rash, GI complaints (nausea, emesis, diarrhea), malaise, and respiratory symptoms (pharyngitis, cough, dyspnea)  Usually occurs within first 6 weeks of starting ABC

14. Abacavir hypersensitivity Reaction cont…… Management  Discontinue drug (if diagnosis strongly suspected)  NEVER re-challenge- Continued ABC in face of HSR or reintroduction after HSR can result in death

15. Hepatotoxicity  Nevirapine is most likely to cause hepatotoxicity( other NRTI and PIs) –Occurs in up to 10% of patients on NVP –Most common in first weeks to months –12 x more likely in women than in men –More likely at CD4 >250 in women and CD4>400 in men  Often mild to moderate but can be severe ( potentially fatal)  More common if underling liver disease –Consider other causes  Infectious hepatitis, other infections  Other drugs (e.g. anti-TB)  Check ALT/SGPT routinely at baseline, 4-6 weeks and at 3 months (as available)  Check ALT/SGPT if any hepatic symptoms/signs  Discontinue NVP for grade 3 toxicity or higher –(transaminases> 5x normal)

16. Laboratory Toxicity Highest Toxicity Grade on ARVs Normal n (%) 1 n (%) n (%)2 3 n (%) 4 Anemia (n=182) 174 (96%) 7 (4%) 0 (0%) 1 (<1%) 0 (0%) Transamin ase elevation (n=182) 54 (30%) 83 (46%) 42(23%) 2 (1%) 1 (<1%) Among patients with >= 1 lab test after ARV initiation

17. HAART and Liver Enzyme Elevations  Meta-analysis of 20 publications of HIV-infected patients ± HCV coinfection  Grade 2 or higher liver elevations noted Drug Class Patients With LEE,% NNRTI 0 10 32.00 18.44 15.96 20 30 40 13.62 5.26 14.67 PIMixedBPI NRTI Overall P =.004 P =.025 P =.009 % LEE in HCV-Coinfected Patients by Drug Class Benhamou Y, et al. CROI 2006. Abstract 88.

18. 2NN: Hepatic Events With NVP QD or BID vs EFV  Initial data from 2NN suggested ↑ incidence of hepatotoxicity with NVP QD or BID vs EFV Storfer S, et al. EACS 2005. Abstract PE9.6-2. 0 1 2 3 4 5 6 7 8 NVP QD NVP BID EFV Hepatic Events (%) 6.7 8.6 4.8 5.6 3.7 2.1 n = 210 n = 379n = 378 P =.0004 P =.0135 Asymptomatic grade 3/4 ALT/AST elevations Symptomatic hepatic event All 2NN Patients 9 10

19. 2NN: Hepatic Events With NVP QD or BID vs EFV Storfer S, et al. EACS 2005. Abstract PE9.6/2. 0 1 2 3 4 5 6 7 8 NVP QD NVP BID EFV Hepatic Events (%) 5.6 6.2 4.2 6.3 3.2 2.6 n = 161 n = 310n = 334 P =.055 P =.0233 Asymptomatic grade 3/4 ALT/AST elevations Symptomatic hepatic event Non-Thai Centers 9 10  Initial data from 2NN suggested ↑ incidence of hepatotoxicity with NVP QD or BID vs EFV  Result later found to be primarily due to 1 Thai study center –Difference NVP QD vs BID lost

20. HCV-3 Coinfection Associated With Greater Risk of Hepatotoxicity  N = 388 HIV/HCV-coinfected patients in Italian cohort – 132 had HCV genotype 3  Factors associated with ↑ risk of grade ≥ 3 hepatotoxicity – Male sex – HBsAg positivity – Baseline ALT – HCV genotype 3 0.9 1.0 0.8 0.7 0.6 0.00.51.01.52.02.53.0 0.5 0.4 Time Since Entry (Years) Cumulative Proportion of Patients Free of ≥ Grade 3 Hepatotoxicity P <.001 HCV ≠ 3 HCV-3 Torti C, et al. ICAAC 2005. Abstract H-1484.

21.  Management?

22. Hematological Toxicity  AZT by far the most common cause –Most likely in women, those with pre-existing anemia and low baseline CD4 count –Peaks at 4-12 weeks after treatment initiation –AZT can also cause neutropenia, thrombocytopenia  Check Hb at baseline, 4-6 weeks at 3 months, thereafter 6 monthly routinely  Check Hb if clinical symptoms/signs of anemia  Remember other possible causes of bone marrow suppression –Cotrimoxazole

23. Peripheral Neuropathy  Associated with: –NRTI therapy –“d” drugs especially D4t, ddI, –Duration of therapy  Other associations: –Lower CD4 count –Other drugs –Alcohol  Incidence: 5-10%  Can be disabling and irreversible

24. Peripheral neuropathy Continued…..  Management include: –Prompt withdraw of these drugs enables gradual resolution of symptoms –Avoid use of neurotoxic drugs –Simple analgesics, with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe –Patient education

25. Metabolic and morphologic complications associated with HIV infection and ART  Lipodystrophy –Lipohypertropy( adipose accumulation)  Abdominal adiposity  Dorsocervical fat enlargement –Lipoatrophy  Extremities  Face  Buttocks

26. Metabolic and morphologic disturbances continued…..  Lactic acidosis  Glucose metabolism –Insulin resistance – impaired glucose metabolism –DM  Dyslipidemias –Increased triglycerides –Decreased HDL –Increased LDL  Bone disease –Osteonecrosis –osteoporosis

27. Case  35 year old male HIV positive since 1995  Started on D4T/3TC/NFV in 1998  CD4: 201, Wt: 62 kg  Clinically doing well, CD4 400, VL undetectable 2002: Noticed change in facial features 2003: “Popping out” of veins on all extremities

29. Case  Patient is very bothered by his changed appearance and resulting stigmatization –Friends recognize his facial wasting as HIV related –He thinks people in the street are looking at him –Feels he is being turned down for jobs  Considering stopping his ART  What do you do?

30. Lipodystrophy  First described in 1998 after introduction of PIs  Common in patients on long term ART( 30-50% in several large, prospective studies)  Distressing to patients and may increase stigma  Lipoatrophy –Associated fat loss in the face and limbs with central fat accumulation –associated with thymidine analogs (d4T >> AZT) –Very common after long periods on stavudine containing regimen  Lipohypertrophy –Fat accumulation centrally with large belly and buffalo hump –Breast enlargement – associated with PIs

31. Diagnosis  Primarily on Clinical grounds  Clinical Diagnosis may be hampered by several factors –Fat depletion in the periphery may be associated with AIDS wasting syndrome –Visceral fat accumulation may be associated with wait gain that occurs shortly after starting ART  In individuals with stable weight, assessment of lipodystrophy relies on demonstration of maldistribution of fat following use of ART and therefore, by necessity, requires knowledge of premorbid fat content and distribution. May be reasonable to document fat distribution prior to the initiation of ART by –Weight, height, and circumferences of the arms, thighs, waist, hips and neck –Photographs

32. Late Toxicity Management difficult; maybe irreversible  Lipodystrophy –Lipoatrophy (LA) associated with thymidine analogs (d4T > AZT) –Common after long periods on stavudine containing regimen –Associated fat loss in the face and limbs with central fat accumulation –Distressing to patients and may increase stigma

33. The Face (and Body) of Lipodystrophy

35. Diagnosis Continued….. –Abdominal MRI or CT scan especially for visceral fat –Dual energy x ray absorptiometry( Dexa scan) for peripheral fat loss. Cannot distinguish abdominal subcutaneous and visceral fat

36. n = 41 A5005s: Thymidine Analogues Associated With Limb Fat Loss  Subjects given ZDV/3TC or d4T/ddI + EFV, NFV, or both  Both NRTI combinations associated with early fat ↑ –Likely restoration of HIV-related fat loss  By Week 48 and on, subjects on d4T/ddI had significantly more limb fat loss than those taking ZDV/3TC -20 -15 -10 -5 0 5 10 15 16324864 Median Change in Limb Fat (%) ddI/d4TZDV/3TC P <.001 n = 61 Dubé MP, et al. AIDS. 2005;19:1807-1818.

37. ACTG 384/5005S: Limb Fat Changes  Peripheral limb fat declined below baseline level with both ZDV/3TC and ddI/d4T  Lipoatrophy delayed with ZDV/3TC compared with ddI/d4T Dubé MP, et al. Antivir Ther. 2002;7:L18. Abstract 27 1632486480 -20 -15 -10 -5 0 5 10 15 Weeks Zidovudine/lamivudine Stavudine/didanosine % Change in Limb Fat

38. Treatment  No clear standard-  Goal of therapy –Target metabolic derangement –Purely cosmetic

39. Treatment continued….. Treatment continued…..  Withdrawal or substitution  Potential switching options –Switch d4T or AZT to ABC (MITOX study) [1]  Significant and continued increase in limb fat in patients with moderate or severe lipodystrophy during prior d4T or AZT –Switch d4T to TDF  Studies ongoing  GS 903 showed very low prevalence of lipodystrophy with TDF vs d4T and maintenance of normal limb fat with TDF at 144 weeks [2] 1. Carr A, et al. JAMA. 2002;288:207-215. 2. Gallant JE, et al. XV IAC, Bangkok, 2004. Abstract TuPeB4538.

40. Mean total limb fat (kg): 7.9 * 5.0 8.7 * 4.4 1 4 1 12 3 19 0 2 4 6 8 10 12 14 16 18 20 Patients with lipodystrophy (%) Week 48Week 96Week 144 *P <.001 TDF, 3TC, EFV d4T, 3TC, EFV Staszewski S, et al. 10th CROI, Boston, 2003. Abstract 564b. Gallant JE, et al. XV IAC, Bangkok, 2004. Abstract TuPeB4538. GS 903: Lipodystrophy With TDF vs d4T

41. Impact of Switching From d4T on Lipids and Limb Fat  96-week open-label extension phase of 903 study –Data from subgroup of patients given d4T for 144 weeks who switched to open-label TDF for 48 weeks Zhong L, et al. EACS 2005. Abstract PE9.3/5. Mean Change in Fasting Lipids at Week 48 (mg/dL) TGsTCLDLHDL -80 -60 -40 -20 0 -72 -38 -16 Mean Total Limb Fat (kg) 0 4.2 4.4 Wk 96Wk 144 Wk 48 post-switch P <.001 4.6 4.8 5.0 5.02 (n = 74) 4.60 (n = 74) d4TTDF

42. RAVE: Switch Thymidine Analogue to ABC or TDF  Suppressed patients with self-defined lipoatrophy on thymidine analogue NRTI  105 patients randomized to replace TA with –Tenofovir, or –Abacavir  Total limb fat increased to similar extent in both arms over 48 weeks Moyle G, et al. CROI 2005. Abstract 44LB. Change in Fat Mass by DEXA at Week 48 (g) 393 522 1061 316 791 1046 0 200 400 600 800 1000 1200 LimbTrunkTotal Fat TDF ABC Within-group change in limb fat from baseline: TDF (P =.01), ABC (P =.001)

43. Pharmacological interventions for lipodystrophy  Testosterone –Decreased levels found in HIV infected men –Placebo controlled trial evaluating role of testosterone is ongoing within the AACTG –Currently only recommended for HIV –infected men with lipodystrophy who also have hypogonadism  Human growth hormone –Open label trail of 30 American patients led to signifacant decraese in VAT but is associated with severe advere events, hyperglycemia,athragias and fluid retention  Metformin  Decarese in VAT that was not statistically significant  Thiazolidinediones-Troglitazone –Decreases VAT in diabetics, however no consistent VAT deacrese in HIV infected

44. Non pharmacological interventions  May offer some benefit  Exercise can be pursued at a moderate intensity without adverse effect on HIV control –Exercise and diet  Useful for fat accumulation, insulin resistance and cardiovascular disease; less so for LA –Reduces central adiposity –Improves glycemic control and lipid profile –May lead to loss of peripheral subcutaneous fat –Smoking cessation (cardiovascular risk)

45. Case  46 year old male  Presents with thrush and 12 kg weight loss  HIV positive, CD4: 112, Wt: 52 kg January 05: Started on D4T/3TC/NVP (30) March 05: Feeling much better; weight 59 kg September 05: Malaise for several weeks, no fever or any other specific symptoms  What to do?

46. Case  Physical exam: slight hepatomegaly  CXR normal, Hb normal  CD4 210 (from 112) October 05: Worsening malaise, now with nausea, vomiting, abdominal pain, weight loss (56 kg)  ALT 388  What to do?

47. Hyperlactataemia and Lactic Acidosis  Over all incidence 8-18% in HIV pts on NRTI’s –Mostly asymptomatic –Elevations lactate in first 6-9 months after start NRTI –Median 9 months, range 3-20 months  Highest risk: –D4T>DDI>>ZDV –DDI/D4T (pregnancy)  Lowest risk 3TC (TDF, ABC)  Can progress to Lactic Acidosis Syndrome Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

48. Lactic Acidosis Syndrome  Clinical definition –Hepatic steatosis –Liver failure –Profound lactic acidosis  Biochemical definition –Lactic acid >5.0 –Bicarbonate <20 –(pH<7.3) Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

49. Hyperlactataemia and Lactic Acidosis  Associated with NRTI administration  NRTI’s have some affinity for human DNA polymerase gamma in mitochondria –impairing mitochondrial DNA synthesis –resulting in mitochondrial toxicity  Accumulation of lactate causing acidosis

50. Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37 Hyperlactataemia and Lactic Acidosis

51. Compensated or asymptomatic hyperlactatemia –Chronic –Normal Anion Gap –Common Decompensated or symptomatic lactic acidosis –Rapidly progressive –Increased anion gap –Life-threatening, rare 153 Lactate (mmol/L) 426 Symptoms Acidosis Normal Range Hyperlactatemia: Clinical Syndromes

52. When to suspect hyperlactataemia or lactic acidosis?  High index of suspicion  Gastro-intestinal complaints (onset months after starting ART)  Unexplained weight loss while CD4 stable  Nausea, vomiting, abdominal pain  Liver abnormalities  Altered mental status  Profound metabolic acidosis Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

53. Management of Hyperlactataemia and Lactic Acidosis  Stop all NRTI’s  Consider carefully restarting 3TC with ZDV (or TDF or ABC) under close supervision when patient improved  Supportive management

54. Management of Adverse Drug Effects  Try and establish the ARV drug responsible for the adverse effect  Consider duration of ARV use, other disease processes (e.g. hepatitis), other treatments (including self administered)  If it is necessary to stop ART, discontinue all ARV drugs simultaneously*  Grade 1 or 2 reactions: continue ART under observation. – Single drug substitution may be necessary  Grade 3 or 4- Stop ART; manage Adverse Event and re-introduce ART.

55. Minimizing adverse events  Appropriate drug and regimen selection  Dose titration  Monitoring and reassuring for effects that are transient  Appropriate timing of administration  Pharmacological interventions  Withdrawal of the offending drug(s)