This document discusses long term effects of antiretroviral therapy (ART) for HIV, opportunistic infections, and medication adherence. It provides guidelines for diagnosing AIDS, benefits of ART, treatment for treatment-naïve patients, mechanisms of action and side effects of drug classes. Long term effects of ART include increased risk of cardiovascular disease, malignancies, and neurological complications. Strict adherence to ART is important to achieve viral suppression and prevent resistance.

1. HIV
Medications, Long Term
Effects, Opportunistic
Infections and Adherence
Danielle Gill, PharmD, MPH

2. Objectives
 Diagnosis of AIDS
 Benefits of ART
 HIV guidelines for treatment naïve
 Mechanism of action of drug classes
 Side effects and dosages of ART
 Medication adherence
 Opportunistic infections and prophylaxis
 Long term effects of ART

3. Diagnosis of AIDS: CDC
definition Less then 200 CD4 cells/mm3 of blood
 One or more of following:
 Candidiasis of bronchi, esophagus, trachea or lungs
 Cervical cancer that is invasive
 Coccidioidomycosis that has spread
 Cryptococcosis that is affecting the body outside the lungs
 Cryptosporidiosis affecting the intestines and lasting more than a month
 Cytomegalovirus (CMV) disease outside of the liver, spleen or lymph nodes
 Cytomegalovirus retinitis that occurs with vision loss
 Encephalopathy that is HIV-related
 Herpes simplex including ulcers lasting more than a month or bronchitis, pneumonitis or
esophagitis
 Histoplasmosis that has spread
 Isosporiasis affecting the intestines and lasting more than a month

4. Diagnosis of AIDS: CDC
 Kaposi's sarcoma
 Lymphoma that is Burkitt type, immunoblastic or that is primary and affects the brain
or central nervous system
 Mycobacterium avium complex (MAC) or disease caused by M kansasii
 Mycobacterium tuberculosis in or outside the lungs
 Other species of mycobacterium that has spread
 Pneumocystis jiroveci (PJP or PCP)
 Pneumonia that is recurrent
 Progressive multifocal leukoencephalopathy (PML)
 Salmonella septicemia that is recurrent
 Toxoplasmosis of the brain, also called encephalitis
 Wasting syndrome caused by HIV infection

5. Clinical Question: �
What is the thought to be the most
important lab test to determine immune
function and predict disease
progression?
A. Viral load (HIV RNA)
B. CD4
C. CD8
D. transaminases

6. Lab tests in newly diagnosed
 HIV antibody testing (if prior documentation is not available or if HIV
RNA is below the assay’s limit of detection) (AI);
 CD4 T-cell count (CD4 count) (AI);
 Plasma HIV RNA (viral load) (AI);
 Complete blood count, chemistry profile, transaminase levels, blood
urea nitrogen (BUN), and creatinine, urinalysis, and serologies for
hepatitis A, B, and C viruses (AIII);
 Fasting blood glucose and serum lipids (AIII)
 Genotypic resistance testing at entry into care, regardless of whether
ART will be initiated immediately (AII).
 For patients who have HIV RNA levels <500 to 1,000 copies/mL, viral amplification
for resistance testing may not always be successful (BII).

7. Why use ART (Antiretroviral
Therapy)?
 Effective ART with virologic suppression improves and preserves
immune function (regardless of baseline CD4 count)
 Earlier ART initiation may result in better responses and clinical
outcomes
 Reduction in AIDS- and non-AIDS-associated morbidity and
mortality
 Reduction in HIV-associated inflammation and associated
complications
 ART strongly indicated for all patients with low CD4 count or
symptoms
 ART can significantly reduce risk of HIV transmission
 Recommended ARV combinations are effective and
well tolerated

8. HIV ART in
Treatment Naïve Patients
Treatment naive patients
2 NRTIs (TDF/FTC)+ 1 NNRTI (EFV)
2 NRTIs (TDF/FTC) + 1 PI/r (ATV/r or DRV/r)
2 NRTIs (TDF/FTC) + 1 INSTI (DTG or RAL)
Or
2 NRTIs (ABC/3TC)* + 1 INSTI (DTG)
*patients must be HLA-B*5701 negative*
NRTI: nucleoside/nucleotide reverse transcriptase inhibitors)
NNRTI: non-nucleoside reverse transcriptase inhibitor
PI: protease inhibitor
INSTI: integrase strand transfer inhibitor
Other classes not recommended for initial treatment
CCR5 antagonist (Maraviroc)
Fusion inhibitor (Enfuvirtide, Fuzeon)

9. Ritonavir

10. Clinical Question: �
 What class or classes of ART work to
prevent insertion of the virus into the
host cell?
A. NRTI
B. Entry Inhibitor
C. Fusion Inhibitor
D. B and C

11. Mechanism of Action
 CCR5 antagonist (Maraviroc)
 Binds to CCR5 (a co-receptor for most HIV strains) and inhibits entry of
the virus into the host cell
 Fusion inhibitor (Enfuvirtide or Fuzeon)
 Binding of the inhibitor to the HR1 region prevents the HR2 region from
access to HR1 and inhibits the fusion process
 NRTI: nucleoside/nucleotide reverse transcriptase inhibitors)
 Block activity of reverse transcriptase (replicates HIV)
 NNRTI: non-nucleoside reverse transcriptase inhibitor
 Blocks activity of reverse transcriptase (replicates HIV)
 INSTI: integrase strand transfer inhibitor
 Prevent the binding of the pre-integration complex to host cell DNA, thus
terminating the integration step of HIV replication
 PI: protease inhibitor
 block the protease enzyme and prevent the cell from producing new
viruses

12. Antiretrovirals and Dosages
Nucleoside/nucleotide Reverse Transcriptase Inhibitors
Micromedex.com

13. Antiretrovirals and Side Effects
Nucleoside Reverse Transcriptase Inhibitors
Emtricitabine lactic acidosis, hepatomegaly

14. Antiretrovirals and Dosage
Non-nucleoside reverse transcriptase inhibitors

15. Antiretrovirals and Side Effects
Non-nucleoside reverse transcriptase inhibitors
Etravirine severe skin rash, nausea

16. Antiretrovirals and Dosage
Protease Inhibitors

17. Clinical Question: �
An HIV patient is noticing increased fat
around their stomach region. Which
class of drugs is likely the cause?
A. NNRTI
B. PI
C. INSTI
D. CCR5

18. Antiretrovirals and Side Effects
Protease Inhibitors

19. Antiretrovirals, Dosage, and Side Effects
Entry Inhibitor
CCR5: Chemokine co-receptor antagonist
Drug
Maraviroc (MCV)

20. Antiretrovirals, Dosage, and Side Effects
Fusion Inhibitors
Drug
Enfuvirtide (Fuzeon)

21. Anteretrovirals and Dosage
Integrase Inhibitors

22. Antiretrovirals and Side Effects
Integrase Inhibitors

23. Antiretrovirals, Dosage, and Side Effects
PK Boosters

24. Question: �
Which ART requires HLA-B*5701 testing
before prescribing?
A. Zidovudine
B. Lamivudine
C. Tenofovir
D. Abacavir

25. Overlapping ART Toxicity
• Peripheral neuropathy
didanosine, isoniazid, ddc
• Bone marrow suppression
ZDV, dapson, hydroxyurea, ribavirin, TMP-SMZ
• Hepatotoxicity
Nevirapine, Efavirenz, maraviroc, NRTIs, Pis, macrolide,
isoniazid
• Pancreatitis
didanosine, ritonavir, stavudine, TMP-SMZ, pentamidine

26. Renal and Hepatic Dosed ART
 Zidovudine
 CrCl <15 or HD: 100mg TID or 300mg daily
 Truvada
 CrCl 30-49: 1 tab Q48h
 CrCl <30 or HD: Contraindicated
 Stavudine
CrCl 25-50: <60kg 20mgQ12h; >60kg 15mgQ12h
CrCl <10-24 or HD: 20mgQ24h; 15mgQ24h
 Abacavir
Child/Pugh Score 5-6: 200mg BID
>6 contraindicated
 Didanosine EC
CrCl 30-49: >60kg 200mg daily, >60kg125mg daily
CrCl <10-29: 125mg daily 125mg daily
 Zidovudine
 CrCl <15 or HD: 100mg TID or 300mg daily
 Truvada
 CrCl 30-49: 1 tab Q48h
 CrCl <30 or HD: Contraindicated
 Stavudine
CrCl 25-50: <60kg 20mgQ12h; >60kg 15mgQ12h
CrCl <10-24 or HD: 20mgQ24h; 15mgQ24h
 Abacavir
Child/Pugh Score 5-6: 200mg BID
>6 contraindicated
 Didanosine EC
CrCl 30-49: >60kg 200mg daily, >60kg125mg daily
CrCl <10-29: 125mg daily 125mg daily

27. Renal and Hepatic Dosed ART

28. Renal and Hepatic Dosed ART

29. Combonation Product Names

30. Medication Adherence
 Strict Adherence is important to lower viral load, reduce resistance,
increase QOL, improve patient survival, and reducing risk of HIV
transmission
 Achieving >=90% to 95% adherence significantly reduces the
likelihood of virologic failure and drug resistance*
 ART regimens have improved but suboptimal adherence is common
over time
 It is important to assess patients readiness for ART therapy prior to
initiating it and assess adherence at each appointment
 Patient engagement and retention in care is important to increase
and maintain medication adherence
 Medication adherence is second only to CD4 count in accurately
predicting progression to AIDS and death*

31. Measuring Adherence
 No Gold Standard
 HIV RNA suppression (most reliable)
 Pharmacy records and pill counts
 Patient Self-report may overestimate adherence
 Suboptimal self-report indicates suboptimal therapeutic
response

32. Factors Associated with Adherence Failure
 Mental illness (depression)
 Active drug use/alcoholism
 Lack of patient education
 Adverse effects of medications
 Treatment fatigue
 High cost
medications/insurance
 Nondisclosure of HIV status
 Low literacy
 Regimen complexity
 Younger age
 Stigma
 Psycho-social stressors
 Polypharmacy, cognitive
impairment

33. Factors Associated with Adherence
Success
 Regimen simplicity
 Low pill burden
 Older Age
 Good tolerability
 Directly observed therapy
 Trusting patient-provider
relationship
 Using motivational strategies
 Multi-disciplinary care
 Case managers, social
workers, psychiatric care,
pharmacists, nurses, etc.

34. Methods Improving Adherence
 Establish readiness to start therapy
 Strengthen early linkage to care and retention of care
 Provide education on HIV disease, treatment, and prevention
 Provide education on importance of adherence and consequences
of poor adherence
 Individualize treatment with patient involvement
 Continuum of support services is needed
 Team including providers from many disciplines

35. Specific Methods to Improve Adherence
 Simplify regimen and food
requirements
 Review, anticipate and treat
side effects
 Identify all possible barriers to
adherence before starting
therapy
 Use positive reinforcement
 Systemically monitor treatment
efficiency and retention in care
 Use educational aids (pictures,
pillboxes, and calendars)
 Engage a support system
 Utilize a team approach
 Assess adherence at each visit
 Identify type and reasons for
nonadherence

36. Opportunistic Infections and Treatment

37. Oropharyngeal Candidiasis
 Oropharyngeal candidiasis is characterized by painless, creamy
white, plaque-like lesions that can occur on the buccal surface, hard
or soft palate, oropharyngeal mucosa, or tongue surface.
 Drug of Choice: Oral fluconazole is as effective as and, in certain
studies, superior to topical therapy for oropharyngeal
 Mild-to-moderate episodes of oropharyngeal candidiasis can be
adequately treated with topical therapy, including once-daily
miconazole in 50-mg mucoadhesive buccal tablets (BI)or
clotrimazole troches 5 times daily

38. Disseminated Mycobacterium
Avium complex (MAC)
• Caused by bacteria commonly found in soil, food, and
water
• Symptoms: high fever, night sweats, abdominal pain,
diarrhea, weight loss, fatigue, swollen glands, anemia
• CD4 count <50 cells/µL
• Prophylaxis
• Azithromycin 1200 mg PO once weekly (AI), or
• Clarithromycin 500 mg PO BID (AI), or
• Azithromycin 600 mg PO twice weekly (BIII)

39. Cytomegalovirus Disease (CMV)
Caused by common Herpes virus HHV-5
Symptoms: blind spots or moving black spots, blurred vision, blindness,
diarrhea or abdominal pain, difficult swallowing, pain, weakness, or numbness
at the base of your spine, causing trouble with walking
Preferred Systemic Induction Therapy: Valganciclovir 900mg PO BID for 14-21
days
Chronic Maintenance: Valganciclovir 900mg PO daily
CMV Retinitis Induction Therapy: For Immediate Sight-Threatening Lesions
(Adjacent to the Optic Nerve or Fovea):
 Intravitreal injections of ganciclovir (2mg) or foscarnet (2.4mg) for 1-4 doses
over a period of 7-10 days

40. Pneumocystis Pneumonia
PCP or PJP
 Caused by fungus called Pneumocystis jiroveci (PJP)
 Still major cause of death in AIDS population
 CD4<200
 Symptoms: fever, dry cough, wheezing, SOB, rapid breathing,
fatigue, major weight loss, chest pain when you breath
 Prophylaxis
 Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended prophylactic
agent (AI).39,41-43 One double-strength tablet daily is the preferred regimen (AI),
 but one single-strength tablet daily43 also is effective and may be better tolerated
than the double-strength tablet (AI).

41. Clinical Question: �
An HIV patient comes to the pharmacy
counter for treatment for skin lesions.
What would you tell him?
A. Use hydrocortisone cream
B. Start an antibiotic
C. Bathe in oatmeal soap
D. Contact physician
immediately

42. Kaposi Sarcoma
HHV-8 Diseases (Kaposi Sarcoma [KS])
Initiate or optimize ART (AII)
Symptoms: mucocutaneous lesions, lower extremities, face, trunk,
orophyaryngeal mucosa, pulmonary involvement (males with HIV)
Treatment: Chemotherapy (per oncology consult) + ART Primary ,
immunotherapy (interferon alpha, interlueki-12), and/or anti-HHV8
therapy

43. ART long term effects
 Cardiovascular disease
 Lipid abnormalities
 Diabetes
 MI
 Malignancies
 HCC
 Cervical Cancer
 Neurological complications
 Insomnia
 Depression
 Peripheral neuropathy
 Persistant Inflammation and immunodeficiency
 HIV related nephropathy
 Kidney damage

45. Facial Lipoatrophy

46. Key Points
 Antiretroviral Therapy improves QOL, reduces HIV transmission, and
reduces HIV related co-morbidities if taken consistently
 The backbone of ART in treatment naïve patients is 2 NRTIs +1 PI or 1
INSTI or 1 NNRTI
 There are currently 5 drug targets for HIV
 Pis have the most drug interactions (CYP450)
 Abacavir can cause hypersensitivity syndrome and requires patients get
tested HLA B*5701
 Efavirenz is teratogenic
 Adherence rates 90-95% are needed to reduce virologic failure and drug
resistance
 Some long term ART side effects include increased cholesterol, increased
cervical cancer, lipodystrophy, and diabetes
 Some Opportunistic infections that may occur in patients with AIDS include
Kaposi sarcoma, PJP, and CMV

47. References
 http://aidsinfo.nih.gov/contentfiles/perinatal_fs_en.pdf
 http://www.cdc.gov/hiv/risk/gender/pregnantwomen/emct.html
 http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/
 http://hab.hrsa.gov/deliverhivaidscare/clinicalguidelines.html
 http://aidsetc.org/resource/guidelines-use-antiretroviral-agents-adults-and-
adolescents-training-slide-sets
 http://www.cdc.gov/hiv/prevention/research/tap/
 www.Micromedex.com
 www.ucsfhealth.org

48. AETC Contact Information
 Pennsylvania/MidAtlantic AETC
 Website: www.pamaaetc.org
 Phone: 412-624-1895
 Consultation: 888-664-AETC
 National Clinician Consultation Service
 800-933-3413
 PEP Line
 888-448-4911
 Linda Frank, PhD, MSN, FAAN
 412-624-9118
 frankie@pitt.edu