HAARTHAART--副作用副作用及并发症及并发症

Chloe Chloe OrkinOrkin医师医师

主治医师主治医师 艾滋病专业艾滋病专业

Barts and the London NHS Trust

HAARTHAART的疗效的疗效艾滋病及死亡发生率艾滋病及死亡发生率19941994--2000 2000

EuroSIDA Cohort 2000

抗抗逆转录逆转录病毒药物病毒药物(ARV)(ARV)的的副作用副作用

切记！切记！::总总的来说的来说ARVARV疗效极佳而且极易被疗效极佳而且极易被患者耐受患者耐受!!然而然而

有些并发症很常见有些并发症很常见

它们它们可能可能成为成为成功治疗的障碍成功治疗的障碍

可能影响生活质量可能影响生活质量

可能导致用药难以坚持可能导致用药难以坚持（患者顺应性不佳）（患者顺应性不佳）

HIVHIV被被抑制抑制的的过程过程

成熟病毒

转录酶抑制剂

蛋白酶抑制剂

Maraviroc（一种新药）

融合抑制剂

整合酶抑制剂

成熟病毒抑制剂

进入抑制剂

核苷类核苷类//核苷酸类核苷酸类逆转录酶抑制剂逆转录酶抑制剂((NRTINRTI’’ss))

以下药物阻塞酶进行以下药物阻塞酶进行““逆转录逆转录””

齐多夫定齐多夫定 AZTAZT拉米夫定拉米夫定 3TC3TC

去羟肌苷去羟肌苷 DDIDDI斯坦夫定斯坦夫定 D4TD4T

阿巴卡韦阿巴卡韦 ABCABCTenofovirTenofovir TDFTDF

齐多夫定齐多夫定 ( AZT) ( AZT) 副作用副作用 ((胶囊胶囊1 1 粒粒 bdbd--对饮食无对饮食无限制限制))

常见常见::---- 恶心恶心, , 呕吐及头疼呕吐及头疼

常见常见::---- 贫血及嗜中性贫血及嗜中性粒细胞粒细胞减少症减少症

其他其他::---- 皮肤及粘膜皮肤及粘膜色泽加深色泽加深，指甲色素沉着，指甲色素沉着

严重严重::---- 肌炎肌炎(CPK(CPK升高升高))

ZDV ZDV 和贫血和贫血

贫血在贫血在进展期进展期HIVHIV感染感染中极其常见中极其常见

如果如果 HbHb <7 <7 应禁用应禁用 ZDVZDV–– 可换可换用用斯坦夫定斯坦夫定或或去羟肌苷去羟肌苷

如果如果 HbHb 77--10 10 可使用可使用ZDVZDV，但应提醒患者可能的贫血，但应提醒患者可能的贫血若症状持续则建议用若症状持续则建议用FBCFBC早至早至治疗的治疗的22--44周周，，ZDVZDV引致的贫血即引致的贫血即可可产生产生,,但一般于但一般于治疗治疗44--66周后产生周后产生

若若出现出现明显明显HbHb下降下降 (<25% or (<25% or HbHb <6.5)<6.5)，，应停用应停用ZDVZDV一些患者可能需要输血一些患者可能需要输血

不再使用不再使用ZDVZDV

拉米夫定拉米夫定 (3TC(3TC))的的副作用副作用((剂量剂量 150mg150mg，， 无无饮食饮食限制限制))

常见常见::---- 无无 ((极易极易耐受耐受))

较较少见少见::---- 偶偶发性发性恶心恶心, , 头疼头疼,,呕吐呕吐, , 腹泻腹泻

严重严重::---- 胰腺炎胰腺炎((极少见极少见))

本药具有抗本药具有抗乙肝乙肝病毒作用病毒作用

斯坦夫定斯坦夫定 (D4T) (D4T) ((剂量剂量 40mg > 60kg, 30mg < 60kg, 40mg > 60kg, 30mg < 60kg, 无无饮饮

食食限制限制))

由于作用机制相同，由于作用机制相同，不能与不能与ZDVZDV合用合用

常见常见副作用副作用::周围周围神经病神经病((可可达达20%)20%)

不常见不常见::虚弱虚弱,,肌痛肌痛, , 头痛头痛

严重严重::肝中毒肝中毒, , 胰腺炎胰腺炎 ((少见少见))

慢性慢性::脂代谢脂代谢异常异常综合综合征征((脂肪脂肪丢失丢失))

去羟肌苷去羟肌苷(DDI) (DDI) ((剂量剂量> 60kg 400mg, < 60kg 250mg, > 60kg 400mg, < 60kg 250mg, 空腹空腹服服用用))

常见常见::恶心恶心肿胀肿胀腹泻腹泻外外周周神经病神经病((可上至可上至20%)20%)

严重严重::胰腺炎胰腺炎酗酒酗酒者慎用者慎用胰腺炎时勿用胰腺炎时勿用

阿巴卡韦阿巴卡韦 (ABC)(ABC) ((剂量剂量 300mg 300mg bdbd or 600mg or 600mg odod 无无

饮食限制饮食限制))

重要毒性重要毒性 = = 过敏过敏反应反应

若若考虑使用考虑使用ABCABC，需注意，需注意患者患者是否有是否有身体不适身体不适

发热发热

胃肠不适胃肠不适

皮疹皮疹

昏睡昏睡

如怀疑如怀疑出现以上不良反应出现以上不良反应，，应摇应摇且不再使用且不再使用

再次使用可能致死再次使用可能致死

在在英国英国用药者需做用药者需做HLA B HLA B * 57015701检测检测

TenofovirTenofovir (TDF) (TDF) ((剂量剂量 245mg 245mg qdqd, , 无无饮食饮食限制限制))

肾脏肾脏: : – Fanconi 综合征综合征

–– 若若患者存在肾功能损害患者存在肾功能损害，，用药用药会加会加重重肾损害肾损害

–– 避免避免使用肾脏使用肾脏毒性毒性药物药物

–– 出现出现全身性感染应全身性感染应停用停用

可能可能导致导致成骨矿物质成骨矿物质丢失丢失

肿胀，恶心，腹泻，肿胀，恶心，腹泻，

对于对于ARVARV药物所药物所致外致外周周神经炎的神经炎的鉴别鉴别

有关的有关的ARV : ARV : 斯坦夫定斯坦夫定 和和 去羟肌苷去羟肌苷

症状症状: : 疼痛，麻木或疼痛，麻木或感感觉改变觉改变

分布分布–– 对称对称性性–– 由脚趾由脚趾上行上行–– 较晚较晚出现出现手部手部感觉改变感觉改变

检查检查: : 感官知觉变化感官知觉变化 +/+/-- 反射反射减弱减弱

必须重视评估必须重视评估周围周围神经炎神经炎对对日常生活日常生活的影响的影响((行走，睡眠，工作等行走，睡眠，工作等))

对于ARV药物所致周围神经炎的管理

轻度轻度PN–– 安抚安抚患者患者，监测，复查看是否，监测，复查看是否继续进展继续进展

中度中度PNPN–– 换药换药–– 加加用镇用镇痛剂痛剂((单用单用,,阿片类阿片类 或阿密曲替林或阿密曲替林))

重度重度外围神经炎–– 停用引起炎症的药停用引起炎症的药物物，换，换药药–– 切切记记：：症状可能停药症状可能停药后后几个月后继续恶化几个月后继续恶化–– 症状通常症状通常可以可以稳定或稳定或得到改善得到改善

乳酸乳酸酸中酸中毒综合毒综合征征

涉及全部涉及全部NRTI :NRTI :---- 少见少见

---- 表现十分不易识别表现十分不易识别 ((疲劳疲劳, , 恶心恶心, , 呕吐呕吐,,腹疼，体重减少腹疼，体重减少, , 不适不适, , 呼吸困难呼吸困难, , 以及近以及近似晕车似晕车, , 胰腺炎胰腺炎, , 脂肪肝脂肪肝).).实验现象实验现象::----阴离子间隙增大阴离子间隙增大,,乳酸增多乳酸增多, ALT/AST, ALT/AST稍微升高稍微升高, HCO3, HCO3 降低降低

诊断诊断::---- 前述症状及前述症状及血血乳酸水平乳酸水平升高升高 (> 5.0 (> 5.0 mmolmmol/L /L 成人成人) + ) + 酸酸中毒中毒

管理管理::致死率致死率高高(60%)(60%)停用所有停用所有ARVARV，，请有关请有关专家专家会诊会诊

以后不再用以后不再用NRTIsNRTIs

非核苷非核苷类类逆转录逆转录病毒病毒抑制剂抑制剂 ((NNRTINNRTI’’ss))

乃韦拉平乃韦拉平 NVPNVP依法韦仑依法韦仑 EFVEFV

乃韦拉平乃韦拉平 (NVP(NVP))--((剂量剂量 200mg 200mg bdbd 无食物限制无食物限制))

黑匣警戒线黑匣警戒线: : 女女< CD4 250 (< CD4 250 (安全安全) ) 男男 < CD4 400 (< CD4 400 (安全安全))

通常通常:: ( ( 文献文献报道报道可高达可高达20%)20%)皮疹皮疹

(1(1--2%2%发展至发展至SJS)SJS)

不常见不常见::肝炎以及肝衰竭肝炎以及肝衰竭（罕见）（罕见）

处理处理 NVP NVP 皮疹皮疹

建议患者留心任何皮疹建议患者留心任何皮疹

中中-- 重重度度皮疹皮疹

大约大约2% 2% 患者会患者会发生发生严重皮疹严重皮疹/ / Stevens Johnson综合征

严重皮疹导致严重皮疹导致::--–– 潮湿脱皮潮湿脱皮

–– 累及累及粘膜粘膜

–– 并发发热并发发热

–– 并发并发LFTLFT升高升高

NevirapineNevirapine 的的过过敏反应敏反应

严重的严重的过过敏反应可能会表现为敏反应可能会表现为::

---- 嘴唇肿胀嘴唇肿胀

----结膜炎结膜炎

---- 重重度度踝关节疼痛踝关节疼痛

---- 开始有或无皮疹开始有或无皮疹

NVPNVP--相关相关SJSSJS

对对NVPNVP引致的严重皮肤反应的处理引致的严重皮肤反应的处理

永久性停用永久性停用NevirapineNevirapine治疗方案治疗方案::

----静脉静脉补液补液

---- 扑尔敏扑尔敏

---- 布洛芬布洛芬

---- 扑热息痛扑热息痛

----若感染使用抗生素若感染使用抗生素

---- 密切观察，密切观察，切记患者的病情切记患者的病情可能在可能在随后的随后的7272--9696小时内恶化小时内恶化..

NevirapineNevirapine肝肝毒性毒性

恶心，发热，呕吐恶心，发热，呕吐

ALT/AST ALT/AST 上升，上升， +/+/-- 胆红素水平上升胆红素水平上升

若若上升不超过上升不超过 33倍倍正常值正常值 观察观察

若若达到或超过达到或超过33倍倍正常值或更高正常值或更高 停用停用 NVPNVP

EfavirenzEfavirenz 副作用副作用((剂量剂量 600mg , 600mg , 无饮食限制无饮食限制))

避免怀孕避免怀孕CNS CNS 作用较为常见作用较为常见(50%)(50%)–– 睡梦变化睡梦变化–– 晕眩晕眩–– 睡眠障碍睡眠障碍–– 头痛头痛–– 情绪改变情绪改变

皮疹皮疹(10%)(10%)–– 一般轻微到中一般轻微到中度度–– 11--2% Stevens Johnson2% Stevens Johnson综合症综合症(SJS)(SJS)肝肝功能功能异常异常 (< 3%)(< 3%)–– 比使用比使用NVPNVP少见少见

EfavirenzEfavirenz (EFV)(EFV)

不多见不多见::肝肝毒性毒性::

---- 文献报告文献报告ALT/AST <3%ALT/AST <3%---- 更多见于更多见于同时同时合并合并乙肝及丙肝感染乙肝及丙肝感染者者

---- 比比NVPNVP少少

蛋白酶抑制剂蛋白酶抑制剂((PIPI’’ss))

NelfinavirNelfinavirRitonavirRitonavirSaquinavirSaquinavirIndinavirIndinavirLopinavirLopinavirFosamprenavirFosamprenavirAtazanavirAtazanavirTipranavirTipranavirDarunavirDarunavir

药物毒性 –蛋白酶抑制剂

蛋白酶抑制剂(PI’s)共通毒性 腹泻，恶心, 脂肪增生(脂肪堆积)

糖尿病, 血胆固醇升高, 胰岛素抵抗，干性坏疽

药物特异性毒性

Nelfinavir 腹泻,皮疹Indinavir 肾结石,皮肤干燥,指甲变化

高胆红素血症

Lopinavir/r 腹泻

Saquinavir/r 腹泻

Ritonavir 腹泻，恶心，呕吐，脸红，肝炎，嘴唇麻木，肿胀，异常不适 Fosamprenavir/r 腹泻

Atazanavir/r 高胆红素血症(胆红素升高 –黄疸)

蛋白酶抑制剂的长期代谢并发症长期代谢并发症

胰岛素抵抗胰岛素抵抗 //糖尿病糖尿病

((血糖升高血糖升高))

脂代谢脂代谢异常异常综合症综合症

((体体态态变化变化))

血血脂肪异常脂肪异常

((胆固醇升高胆固醇升高//甘油三酯降低甘油三酯降低))

骨质疏松症骨质疏松症 //干性干性坏疽坏疽

((骨质钙化异常骨质钙化异常))

Hyperlipidaemia – leading to MI/CVA

HAARTHAART患者患者的的脂脂代谢代谢监测监测

若若采用采用含含PIPI或或EFVEFV的的HAARTHAART方案方案，病人应，病人应进行基线进行基线脂代谢检测脂代谢检测，随后，随后每每66个个月进行月进行查一次脂代谢查一次脂代谢 ((胆固醇胆固醇, , 甘油甘油三三酯酯) ) * * 抽血前抽血前 好好

禁食禁食

若若怀疑存在怀疑存在糖尿病则糖尿病则应应查血糖查血糖

脂肪代谢障碍脂肪代谢障碍::体体态态改变改变

脂肪堆积脂肪堆积::

颈部脂肪肉垫堆积颈部脂肪肉垫堆积

胸部增大胸部增大/ / 男子乳房女性男子乳房女性化化

内脏内脏 / / 向心性向心性肥胖肥胖

脂肪瘤脂肪瘤

脂肪减少脂肪减少((萎缩症萎缩症):):

脸部脂肪减少脸部脂肪减少

皮下脂肪减少皮下脂肪减少

臀部脂肪减少臀部脂肪减少

LIPODYSTROPHY

LIPODYSTROPHY

总结总结 / / 要点要点

创造良好的创造良好的HIVHIV医疗护理医疗护理应具备与应具备与药物使用，副作用药物使用，副作用以及相关管理以及相关管理知识知识

轻至中度副作用以及随时间减轻的副作用可以轻至中度副作用以及随时间减轻的副作用可以对对症症治治疗疗..

若出现若出现严重或严重或可可致残副作用，致残副作用，应立即应立即停用引起此类反停用引起此类反映的药物映的药物-- 有时有时应作急诊处理应作急诊处理

总结总结 / / 要点要点(2)(2)

教育病人了解可能出现的药物反作用十分关键教育病人了解可能出现的药物反作用十分关键

开始疗法及随后对反作用保持警惕十分重要开始疗法及随后对反作用保持警惕十分重要

开展仔细的综合基线评估，对于观察何种副作开展仔细的综合基线评估，对于观察何种副作用提前存在十分重要用提前存在十分重要..

HAARTHAART--Adverse Events and Adverse Events and ComplicationsComplications

Dr Chloe OrkinDr Chloe OrkinConsultant in HIV MedicineConsultant in HIV MedicineBartsBarts and the London NHS Trustand the London NHS Trust

Durability of clinical effect of HAARTDurability of clinical effect of HAARTIncidence of AIDS and Death 1994Incidence of AIDS and Death 1994--20002000

0

5

10

15

20

25

30

35

9/94-3/953/95-9/959/95-3/963/96-9/969/96-3/973/97-9/979/97-3/983/98-9/989/98-3/993/99-9/99>9/99

Calendar period

Inci

denc

e (p

er 1

00 P

YFU

)

0

20

40

60

80

100DeathsAIDS% on HAART

EuroSIDA Cohort 2000

Adverse Effects of Antiretroviral DrugsAdverse Effects of Antiretroviral Drugs

REMEMBER: Overall experience is that ARV REMEMBER: Overall experience is that ARV medications work exceptionally well and are very medications work exceptionally well and are very well tolerated!well tolerated!HoweverHowever

Some occur commonly Some occur commonly

They may be a barrier to successful therapyThey may be a barrier to successful therapy

May affect quality of lifeMay affect quality of life

May contribute to nonMay contribute to non--adherenceadherence

HIV InhibitionHIV Inhibition

Maturevirus

Reverse transcriptase

inhibitors

Proteaseinhibitors

Enfuvirtide

Integraseinhibitors

Maturationinhibitors

Entryinhibitors

Maraviroc

Nucleoside/Nucleotide reverse Nucleoside/Nucleotide reverse transcriptase inhibitors (transcriptase inhibitors (NRTINRTI’’ss))

These drugs block the enzyme These drugs block the enzyme ““reverse transcriptasereverse transcriptase””

ZidovudineZidovudine AZTAZTLamuvidineLamuvidine 3TC3TC

DidanosineDidanosine DDIDDIStavudineStavudine D4TD4T

AbacavirAbacavir ABCABCTenofovirTenofovir TDFTDF

ZidovudineZidovudine ( AZT) adverse effects( AZT) adverse effects (1 cap (1 cap bdbd--no food restrictions)no food restrictions)

Most common:Most common:---- Nausea, Vomiting, and Headaches Nausea, Vomiting, and Headaches

Common:Common:---- Anaemia and neutropeniaAnaemia and neutropenia

Other:Other:---- Darkening of skin and mucous Darkening of skin and mucous

membranes, nail pigmentationmembranes, nail pigmentationSerious:Serious:

---- Myositis (elevated CPK)Myositis (elevated CPK)

ZDV and ZDV and AnaemiaAnaemia

Baseline anaemia is very common in advanced HIVBaseline anaemia is very common in advanced HIVIf Hb <7 avoid ZDVIf Hb <7 avoid ZDV–– Use Stavudine or Didanosine insteadUse Stavudine or Didanosine instead

If Hb 7If Hb 7--10 can use ZDV but warn patients of possible 10 can use ZDV but warn patients of possible anaemia advising FBC if symptoms developanaemia advising FBC if symptoms developZDVZDV--induced induced anaemiaanaemia can occur as early as 2can occur as early as 2--4 4 weeks, but typically occurs after 4weeks, but typically occurs after 4--6 weeks6 weeksIf there is a significant If there is a significant HbHb drop (<25% or drop (<25% or HbHb <6.5) <6.5) ZDV should be discontinuedZDV should be discontinuedSome patients may need transfusionSome patients may need transfusion

Do not treat with ZDV againDo not treat with ZDV again

LamivudineLamivudine (3TC) side effects (3TC) side effects (dose 150mg (dose 150mg bdbdno food restriction)no food restriction)

Common:Common:---- None None (very well(very well--tolerated)tolerated)

Less common:Less common:---- Occasional nausea, headaches, Occasional nausea, headaches,

vomiting, and diarrhoeavomiting, and diarrhoeaSerious:Serious:

---- Pancreatitis (very rare)Pancreatitis (very rare)

Also has Hepatitis B activityAlso has Hepatitis B activity

Stavudine (D4T) Stavudine (D4T) (dose 40mg > 60kg, 30mg < 60kg, no (dose 40mg > 60kg, 30mg < 60kg, no food restriction)food restriction)

Contraindicated with ZDV as works by Contraindicated with ZDV as works by same mechanism same mechanism

Common side effects:Common side effects:Peripheral neuropathy (up to 20%)Peripheral neuropathy (up to 20%)

Uncommon:Uncommon:Lethargy, myalgia, headacheLethargy, myalgia, headache

Serious:Serious:Liver toxicity, pancreatitis (rare)Liver toxicity, pancreatitis (rare)

Chronic:Chronic:Lipodystrophy syndrome (fat loss)Lipodystrophy syndrome (fat loss)

Didanosine (DDI) Didanosine (DDI) (Dose > 60kg 400mg, < 60kg 250mg, (Dose > 60kg 400mg, < 60kg 250mg, ttakenaken on empty stomach)on empty stomach)

Common:Common:NauseaNauseaBloatingBloatingDiarrhoeaDiarrhoeaPeripheral neuropathy (up to 20%) Peripheral neuropathy (up to 20%)

Serious:Serious:PancreatitisPancreatitisUse with caution in heavy alcohol usersUse with caution in heavy alcohol usersDo not reDo not re--use if use if pancreatitispancreatitis occursoccurs

Abacavir (ABC)Abacavir (ABC) (dose 300mg (dose 300mg bdbd or 600mg or 600mg odod no no food restriction)food restriction)

Important toxicity = Important toxicity = Hypersensitivity reactionHypersensitivity reaction

Consider if a patient on ABC presents withConsider if a patient on ABC presents withMalaiseMalaiseFeverFeverGI upsetGI upsetRashRashLethargyLethargy

If suspected; discontinue ABC and do not reIf suspected; discontinue ABC and do not re--challengechallengeRechallenge could KILLRechallenge could KILLIn UK HLA B*5701 testIn UK HLA B*5701 test

TenofovirTenofovir (TDF) (TDF) (Dose 245mg (Dose 245mg qdqd, no food , no food restriction)restriction)

Renal: Renal: –– FanconiFanconi SyndromeSyndrome–– Worsening renal impairment if already impaired Worsening renal impairment if already impaired –– Avoid with Avoid with nephrotoxicnephrotoxic drugsdrugs–– Avoid if septicAvoid if septic

Possible bone demineralisationPossible bone demineralisation

Bloating, nausea, diarrhoeaBloating, nausea, diarrhoea

Recognition of ARV drug inducedRecognition of ARV drug inducedPeripheral NeuropathyPeripheral Neuropathy

ARV drugs implicated: stavudine and didanosineARV drugs implicated: stavudine and didanosine

Symptoms: pain, numbness or change in sensationSymptoms: pain, numbness or change in sensation

DistributionDistribution–– SymmetricalSymmetrical–– Ascends from toes upwardsAscends from toes upwards–– Hand involvement very lateHand involvement very late

Examination: changes in sensory perception +/Examination: changes in sensory perception +/-- loss of reflexesloss of reflexes

Important to assess how PN affects activities of daily living Important to assess how PN affects activities of daily living (walking, sleeping, working, etc.)(walking, sleeping, working, etc.)

Management of ARV drug inducedManagement of ARV drug inducedPeripheral NeuropathyPeripheral Neuropathy

Mild PNMild PN–– Reassure patient, monitor, review if progressionReassure patient, monitor, review if progression

Moderate PNModerate PN–– Consider switch of causative agentConsider switch of causative agent–– Add in analgesia (simple, opiate or amitryptyline)Add in analgesia (simple, opiate or amitryptyline)

Severe PNSevere PN–– Discontinue causative ARV drugs and substitute for others Discontinue causative ARV drugs and substitute for others

(if possible other options)(if possible other options)–– Remember symptoms may continue to worsen for several Remember symptoms may continue to worsen for several

months after stopping the causative ARVmonths after stopping the causative ARV–– Symptoms usually stabilize or improveSymptoms usually stabilize or improve

Lactic Acidosis SyndromeLactic Acidosis Syndrome

Entire NRTI class implicated:Entire NRTI class implicated:---- RareRare---- Presentation is very vague (fatigue, nausea, vomiting, abdominaPresentation is very vague (fatigue, nausea, vomiting, abdominal pain, weight l pain, weight loss, malaise, dyspneoa, and proximal motor weakness, loss, malaise, dyspneoa, and proximal motor weakness, pancreatitispancreatitis, fatty liver)., fatty liver).Laboratory clues:Laboratory clues:---- Increased anion gap, increased lactic acid, modest elevation inIncreased anion gap, increased lactic acid, modest elevation in ALT/AST, and ALT/AST, and low HCO3low HCO3

Diagnosis:Diagnosis:---- Former symptoms with elevated Former symptoms with elevated

lactate level (> 5.0 lactate level (> 5.0 mmolmmol/L in adults) + acidosis/L in adults) + acidosisManagement:Management:

High mortality rate (60%)High mortality rate (60%)Discontinue all Discontinue all ARVsARVs, seek expert advice, seek expert advice

Do not use Do not use NRTIsNRTIs in futurein future

Non nucleoside reverse Non nucleoside reverse transcriptase inhibitors (transcriptase inhibitors (NNRTINNRTI’’ss))

NevirapineNevirapine NVPNVPEfavirenzEfavirenz EFVEFV

Nevirapine (NVPNevirapine (NVP))--(dose 200mg (dose 200mg bdbd no food restriction)no food restriction)

Black box warning: Women < CD4 250 (safe) Black box warning: Women < CD4 250 (safe) Men < CD4 400 (safe)Men < CD4 400 (safe)

Common:Common: (reported up to 20%)(reported up to 20%)Cutaneous rashCutaneous rash

(progresses to SJS in 1(progresses to SJS in 1--2%)2%)

Less Common:Less Common:Hepatitis and very rarely hepatic failureHepatitis and very rarely hepatic failure

Managing NVP Rash Managing NVP Rash

Advise patient to attend with any rashAdvise patient to attend with any rashModerateModerate-- Severe rashSevere rashApprox 2% of patients will get a severe Approx 2% of patients will get a severe rash/ Stevens Johnson Syndromerash/ Stevens Johnson SyndromeA severe rash may:A severe rash may:--–– be moist and desquamatingbe moist and desquamating–– involve mucous membranesinvolve mucous membranes–– be associated with feverbe associated with fever–– be associated with raised LFTsbe associated with raised LFTs

Nevirapine HypersensitivityNevirapine Hypersensitivity

Serious hypersensitivity reactions may present Serious hypersensitivity reactions may present as follows:as follows:

---- Lip swellingLip swelling---- ConjunctivitisConjunctivitis---- Severe foot arthralgiasSevere foot arthralgias---- With or without skin rash initiallyWith or without skin rash initially

NVPNVP--Related SJSRelated SJS

Management of NVPManagement of NVP--induced Severe induced Severe Skin ReactionSkin Reaction

Permanently Discontinue NevirapinePermanently Discontinue NevirapineTreatment:Treatment:

----IV fluidsIV fluids---- ChlorpheniramineChlorpheniramine---- BrufenBrufen---- ParacetamolParacetamol----Antibiotics if infectedAntibiotics if infected---- Close observation, realizing that patient may Close observation, realizing that patient may

get much worse over next 72get much worse over next 72--96 hours96 hours

Nevirapine Liver Toxicity Nevirapine Liver Toxicity

Nausea, fever, vomitingNausea, fever, vomitingALT/AST elevations +/ALT/AST elevations +/-- bilirubin level elevations reportedbilirubin level elevations reported

If up to 3x normal valuesIf up to 3x normal values WATCHWATCHIf 3x normal or higherIf 3x normal or higher STOP NVPSTOP NVP

Efavirenz side effects Efavirenz side effects (dose 600mg , no food (dose 600mg , no food restrictions)restrictions)

Avoid in pregnancyAvoid in pregnancyCNS effects are common (50%)CNS effects are common (50%)–– Change in dreamsChange in dreams–– DizzinessDizziness–– Sleep disturbanceSleep disturbance–– HeadacheHeadache–– Mood changeMood change

RashRash(10%)(10%)–– Usually mild to moderateUsually mild to moderate–– 11--2% Stevens Johnson2% Stevens Johnson

Liver Abnormalities (< 3%)Liver Abnormalities (< 3%)–– Less common than with NVPLess common than with NVP

Efavirenz (EFV)Efavirenz (EFV)

Less Common:Less Common:Liver toxicity:Liver toxicity:

---- Elevations in ALT/AST less Elevations in ALT/AST less than 3% of patientsthan 3% of patients

---- Higher in patients with coHigher in patients with co--existingexistingHepatitis B and C infections Hepatitis B and C infections

---- Less common than with NVPLess common than with NVP

Protease inhibitors (Protease inhibitors (PIPI’’ss))

NelfinavirNelfinavirRitonavirRitonavirSaquinavirSaquinavirIndinavirIndinavirLopinavirLopinavirFosamprenavirFosamprenavirAtazanavirAtazanavirTipranavirTipranavirDarunavirDarunavir

Drug Toxicities – Protease Inhibitors

Protease Inhibitors (PI’s)Class specific diarrhoea, nausea, lipohypertrophy (fat accumulation)

diabetes, hypercholesterolaemia, insulin resistance,avascular necrosis

Drug specific

Nelfinavir diarrhoea, rashIndinavir kidney stones, dry skin, nail changes

hyperbilirubinaemia

Lopinavir/r diarrhoea

Saquinavir/r diarrhoea

Ritonavir diarrhoea, nausea, vomiting, flushinghepatitis, numb lips, bloating, abdominal discomfort

Fosamprenavir/r diarrhoeaAtazanavir/r hyperbilirubinaemia (elevated bilirubin – jaundice)

LongLong--Term Metabolic Complications Term Metabolic Complications of PIof PI’’ss

Insulin Resistance /Diabetes Mellitus Insulin Resistance /Diabetes Mellitus (elevated blood glucose)(elevated blood glucose)

Lipodystrophy Syndrome Lipodystrophy Syndrome (body habitus changes)(body habitus changes)

Lipid Abnormalities Lipid Abnormalities (increased cholesterol/triglyceride levels)(increased cholesterol/triglyceride levels)

Osteoporosis / Avascular Necrosis Osteoporosis / Avascular Necrosis (bone mineralization abnormalities)(bone mineralization abnormalities)

Lipid Monitoring of Patients Lipid Monitoring of Patients on HAARTon HAART

Patients should have Patients should have baseline baseline and and thenthen 66--monthlymonthly lipid assessments if on lipid assessments if on PIPI--containing or EFVcontaining or EFV--containing HAART containing HAART (cholesterol, triglycerides) (cholesterol, triglycerides) * preferably fasting* preferably fasting

Check glucose if suspect diabetesCheck glucose if suspect diabetes

Lipodystrophy: Body Habitus ChangesLipodystrophy: Body Habitus Changes

Fat accumulation:Fat accumulation:

Neck fat padNeck fat pad

Breast enlargement/ Breast enlargement/ gynaecomastia gynaecomastia

Visceral / central obesityVisceral / central obesity

LipomasLipomas

Fat loss (atrophy):Fat loss (atrophy):

Facial fat lossFacial fat loss

Subcutaneous fat loss in Subcutaneous fat loss in the extremitiesthe extremities

Fat loss in buttocksFat loss in buttocks

LIPODYSTROPHY

LIPODYSTROPHY

Summary / ConclusionsSummary / Conclusions

Knowledge of medication, side effects and Knowledge of medication, side effects and management is essential for good HIV caremanagement is essential for good HIV care

Mild to moderate side effects, and those that Mild to moderate side effects, and those that resolved with time, may be managed with resolved with time, may be managed with symptomatic therapy.symptomatic therapy.

Serious or disabling effects may necessitate Serious or disabling effects may necessitate discontinuation of the offending drugdiscontinuation of the offending drug-- sometimes sometimes urgentlyurgently

Summary / Conclusions (2)Summary / Conclusions (2)

It is important to It is important to EDUCATEEDUCATE patients about patients about the potential adverse effects of these the potential adverse effects of these medications.medications.

It is important to be vigilant to these adverse It is important to be vigilant to these adverse effects when initiating therapy and also effects when initiating therapy and also during followduring follow--up. up.

It is important to perform careful, It is important to perform careful, comprehensive evaluations at baseline to see comprehensive evaluations at baseline to see what side effects are prewhat side effects are pre--existingexisting