Rubin_MDS218_final1 Managing Adverse Effects of HAART David Rubin, MD Clinical Assistant Professor of Medicine Weill Cornell Medical College Medical Director, AIDS Center New York Hospital Queens

Rubin_MDS218_final2 Introduction n Despite the “revolution” of HAART transforming natural history of HIV infection, issues related to side effects confront patients and providers in “doing it right” n Focused management of these issues maximizes patients’ ultimate adherence to a given HAART regimen

Rubin_MDS218_final3 Understanding the Scope of the Problem n Broad treatment-related AEs —Lipodystrophy —Metabolic abnormalities —Bone disease n Drug-specific AEs —NRTIs —NNRTIs —PIs

Rubin_MDS218_final4 Importance of Adverse Effect Management n Increasing complexity of HAART —Increasing number of agents —Drug-drug interactions n Value of close monitoring to help patients ultimately tolerate difficult effects of certain agents —ie, ABC, NVP, EFV n Helping patients to tolerate the maximum number of agents preserves options for the future for that particular patient

Rubin_MDS218_final5 General Considerations n Many questions regarding effects of using antiretrovirals in current combinations remain unanswered, are there associations with —Cardiovascular disease —Diabetes mellitus —Chronic metabolic and morphologic changes ( a.k.a. Lipodystrophy)

Rubin_MDS218_final6 “Pro-Active” Approach to Initiating HAART n Important to discuss potential adverse effects with patient n Important to support the patient on starting meds, ie, inform patient on ways to contact you for “hand holding” n Adherence issues clearly are associated with this initial patient-provider interaction n Must frequently follow laboratory parameters, CBC, SMAC (chemistries including LFTs)

Rubin_MDS218_final7 Nucleoside Analogs (NRTIs) n Emerging data on “class” adverse rxns —Lactic acid level (lactic acidemia) —Rare lactic acidosis —Steatosis —Association of lactic acidemia with common NRTI side effects (?) —Theories of mitochondrial toxicity of agents explaining all AEs including lipodystrophy —Peripheral neuropathy: rapid/progressive Sx = discontinuation vs mild/intermittent

Rubin_MDS218_final8 Zidovudine (Retrovir, AZT) n Primary side effects: short term —Initial nausea —Initial headache —Ongoing nausea —Ongoing “dysphoria” n Primary side effects: long term —Anemia: usually noticed by 6 weeks —Leukopenia

Rubin_MDS218_final9 D-Drugs n d4T (Zerit ®, stavudine) —Peripheral neuropathy —Hepatitis —Pancreatitis n ddI (Videx ®, didanosine): new “EC” vs tablets, with better tolerability, issue for adherence —Pancreatitis —Peripheral neuropathy n ddC (Hivid ®, zalcitabine) —Peripheral neuropathy —Pancreatitis

Rubin_MDS218_final10 Abacavir Hypersensitivity n Initial discussion with patient —“the card” —Warning—not scaring, re: reintroduction n Description of syndrome —“Clinical diagnosis” only with varied presentation —Important to alert patient to contact you before stopping it, otherwise high likelihood of “losing it”

Rubin_MDS218_final11 Non-Nucleoside RTI (NNRTI) n Nevirapine —Rash l Management takes frequent monitoring to assess whether patient may continue or must stop, rash in up to 1/3 of patients l Keep in mind concern of “Stevens-Johnson” with desquamation of cutaneous and mucus membranes (<1%) —Hepatitis l May develop relatively quickly after start l Pay particular attention to co-infected patients with Hepatitis C in women

Rubin_MDS218_final12 NNRTIs n Efavirenz —CNS Side Effects l Dizziness: reason for QHS dosing l Vivid dreams l Depression –Think twice in patients with Hx of serious mental illness —Rash l Generally mild and self-limited n Delavirdine —Rash similar to NVP

Rubin_MDS218_final13 Protease Inhibitors (PIs) n General —GI side effects —Size and number of pills n But never forget: they first revolutionized HAART and currently clearly change progression rates to AIDS and death in the sickest patients, ie, CD4 <100

Rubin_MDS218_final14 Indinavir n Dosing —Crix q8 vs IDV/RTV —Hydration! —3 periods of food restriction vs none n Nephrolithiasis n “Retinoid Syndrome” n Hyperlipidemia (particularly with RTV) n Other renal issues n Hyperbilirubinemia

Rubin_MDS218_final15 Nelfinavir n Diarrhea! —Usual course: after initial dosing, presents in intermittent pattern —Best advice is to take after a substantial meal —Usually not accompanied with any other complaint —Responds to loperamide well, some use calcium carbonate

Rubin_MDS218_final16 Saquinavir n GI complaints: nausea, gas, bloating, cramps, and diarrhea —Symptomatic treatment —If occurs, becomes more tolerable over time —Amount of food prior to Rx n Size of pill issue —“GERD-type” symptoms may occur —Responds to Rx for GERD n Must be refrigerated

Rubin_MDS218_final17 Amprenavir n Size of pills —“GERD” and “mechanical” issues n GI Complaints — nausea, cramps, bloating, gas, and diarrhea n Rash (small but important)

Rubin_MDS218_final18 Ritonavir n Full dose is rarely used due to intolerable taste issues along with GI Sx n Combination with IDV, SQV, and LPV —Allows for BID dosing of all above with food n Hyperlipidemia & hyperglycemia n Must be refrigerated n Drug-drug interactions—many!

Rubin_MDS218_final19 Kaletra ® n First “fixed-dose” PI containing RTV, ie, LPV gets boosted to very high blood levels n GI side effects relatively mild, mostly “bloating and gas” n Taken with food n Must be refrigerated

Rubin_MDS218_final20 Conclusion n Side effect management clearly key element for maintaining high rate of adherence, thus frequent monitoring, including laboratory, is necessary n By maximizing support for patient to tolerate each potentially troublesome agent, you maximize the patient’s long-term options n Knowledge and “wisdom” play a large role in helping patients reach their goals as to managing AEs

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