• HIV infection/AIDS adalah Masalah Global

saat ini.

• Setidaknya pada tahun 2009 terdapat sekitar

33.3 juta PLWHA menurut UNAIDS

• Lebih dari 95% PLWHA tinggal di negara

dengan income menengah sampai rendah;
– 50% adalah wanita, dan

– 2.5 juta anak-anak dibawah 15 tahun

• 25% orang dengan HIV tidak sadar bahwa
mereka HIV-positive
• Faktor resiko tertinggi pada tingkat kematian
adalah virus berjumlah lebih besar dari 400
copies/mL, CD4+ dibawah 200 cells/mL and
cytomegalovirus retinitis
• Keberadaan dari antiretroviral therapy dampak
menurunkan angka kematian dari AIDS
• HIV menyerang dan berikatan ke sel spesifik
immune system, termasuk
– monocytes, macrophages, & T-cell lymphocytes
• CD4 receptors (for binding)

• coreceptor proteins (CCR-5, CXCR-4)(for fusion)

• conformational changes to key HIV proteins (gp41 &
gp120)

• HIV fuses releases its contents

ss viral RNA is transcribed via RT into a ds proviral DNA that is subsequently incorporated
into host cell's genetic material via integrase enzyme. HIV then uses the infected cell's
machinery to translate, transcribe, and produce immature viral particles that bud and
break from infected cell. For these immature virions to become infectious, the HIV
protease enzyme must cleave large precursor polypeptides into functional proteins

5
HIV life cycle and antiretroviral drug targets
 Klasifikasi ART Drugs
• Nucleo(t)side Reverse Transcriptase Inhibitors
(NRTIs)
• Nonnucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
• Protease Inhibitors (PIs)
• Entry Inhibitors - Chemokine (CCR5) co-receptor
antagonist
• Fusion Inhibitors
• Integrase Inhibitors (HIV integrase strand transfer
inhibitors)
 Nucleo(t)side Reverse Transcriptase Inhibitors (NRTIs)

• First agents available for

HIV Infection. Drugs
• Less potent than NNRTIs) •Abacavir (ABC)
and pIs.
• Have a central role in ART.
•Didanosine (ddI)
• Have activity against HIV-1 •Emtricitabine (FTC)
and HIV-2. •Lamivudine (3TC)
• Nucleoside and nucleotide •Stavudine (d4T)
analogues •Tenofovir (TDF)
• Differ from normal substrates •Zidovudine (ZDV;
only by a minor modification in
sugar (ribose) molecule formerly azidothymidine
[AZT]
MOA

• Interrupt HIV replication cycle via competitive inhibition of

HIV reverse transcriptase and termination of the DNA chain
• Reverse transcriptase.
• An HIV-specific DNA polymerase
• Allows HIV RNA to be transcribed into ss and
ultimately ds proviral DNA and incorporated into host-
cell genome.
• Proviral DNA chain elongation is necessary before
genome incorporation can occur
• Acting as "false building blocks" causes Chain termination,
• Once incorporated, work by preventing other nucleosides from
also being incorporated b/c of absence of a 3’ OH group.

10
MOA of NRTIs
 Pharmacokinetics
• NRTIs are prodrugs and undergoes phosphorylation by
intracellular kinases to exert their activity.
• Oral bioavailability ranges from 25%-93%, with tenofovir and
didanosine on lower end of spectrum.
• Food does not significantly affect absorption
• Except didanosine, which must be taken on empty stomach
• Renal elimination
• Exception is abacavir, given at normal dose regardless of
creatinine clearance.
• Minimal drug-drug interactions occur.
• Clinically significant Interactions involve didanosine.
• With tenofovir, didanosine levels are higher than expected,
• Didanosine and ribavirin combination should be avoided.
Name Dosage Form(s) Adult Dose Adverse Events

Abacavir 300-mg tablet; 600 mg PO qd or Hypersensitivity reaction (may include fever,

20-mg/mL oral 300 mg PO bid rash, nausea, vomiting, diarrhea, malaise,
solution shortness of breath, cough, pharyngitis);
patients positive for HLA-B*5701 are at highest
risk for hypersensitivity (perform HLA
screening before initiating)

Didanosine 125-mg, 200-mg, >60 kg: 400 mg PO qd Peripheral neuropathy, pancreatitis, nausea,
250-mg, 400-mg < 60 kg: 250 mg PO qd lactic acidosis
enteric-coated Take 30 min ac or 2 hr pc
capsule; Oral solution: Divide
10-mg/mL daily dose bid
suspension

Emtricitabine 200-mg capsule; 200 mg PO qd or Minimal toxicity, hyperpigmentation

10-mg/mL oral 240 mg (24 mL) oral
solution solution PO qd
Name Dosage Form(s) Adult Dose Adverse Events
Lamivudine 150-mg, 300-mg tablet; 300 mg PO qd or Minimal toxicity, severe acute exacerbation of
10-mg/mL solution 150 mg PO bid hepatitis may occur with HBV-coinfection upon
discontinuation

Stavudine 15-mg, 20-mg, 30-mg, >60 kg: 40 mg PO Peripheral neuropathy, pancreatitis, lactic
40-mg capsule; bid acidosis, lipoatrophy, hyperlipidemia
1-mg/mL oral solution < 60 kg: 30 mg PO
bid

Tenofovir 300-mg tablet 300 mg PO qd Nausea, vomiting, diarrhea, headache,

asthenia, renal insufficiency

Zidovudine 300-mg tablet; 100-mg 300 mg PO bid or Nausea, vomiting, headache, asthenia,
capsule;10-mg/mL oral 200 mg PO tid Anemia, granulocytopenia, myopathy, lactic
solution;10-mg/mL acidosis, hepatomegaly with steatosis, nail
intravenous solution pigmentation, lipid abnormalities, lipoatrophy,
hyperglycemia
 Nonnucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• Were introduced in 1996 with Drugs

approval of nevirapine. First-generation
• Have potent activity against Delavirdine(DLV)
HIV-1 and are part of
preferred initial regimens. Efavirenz (EFV)
• Efavirenz, confers most Nevirapine (NVP)
significant inhibition of viral
infectivity Second-generation
• All exhibit same mechanism Etravirine (ETR)
of action Rilpivirine (RPV)
MOA
• HIV reverse transcriptase is a heterodimer composed
of 2 subunits (p66 and p51).
• NNRTIs bind p66 subunit at a hydrophobic pocket
distant from active site of enzyme (allosteric site)
• This noncompetitive binding induces a conformational
change in enzyme
• 1st generation NNRTIs are more rigid in structure
• Resistance can quickly be developed .
• 2nd generation NNRTIs have a more flexible structure,
• Adjust readily and resist mutation more effectively
MOA of NNRTIs
 Pharmacokinetics
• All utilize cyt P450 for metabolism and exert varying induction
and inhibition effects on specific isoenzymes
(eg, CYP3A4, CYP2C9).
• Results in a significant potential for drug-drug interactions
• Delavirdine primarily uses the 3A4 isoenzyme for metabolism.
• Nevirapine is metabolized mainly by 3A4 with some secondary
metabolism through 2B6.
• Efavirenz is primarily metabolized through 2B6 and secondarily
through 3A4.
• Etravirine is a substrate of 3A4, 2C9, and 2C19.
• Highly protein-bound (98-99%), primarily to albumin and
alpha1 acid glycoprotein except nevirapine
• Serum half-lives are fairly extended, ranging (25-55 hours),
• Except for delavirdine, (2-11 h)
Name Dosage Form(s) Adult Dose Adverse Events
Delavirdine 100-mg, 200-mg tab. 400 mg PO tid Rash, headache

Efavirenz 600-mg tab.; 600 mg PO qd Rash, CNS (eg, somnolence,

50-mg, 200-mg caps Take on empty vivid dreams, confusion, visual
stomach to decrease hallucinations), hyperlipidemia
Adrs

Etravirine 100-mg, 200- 200 mg PO bid Rash, nausea

mg tablets

Nevirapine 200-mg tab; 400 200 mg PO bid Rash, hepatitis

mg XR tab; 10- XR: 400 mg PO
mg/mL susp. qd

Rilpivirine 25-mg tablet 25 mg PO qd with meal Depressive disorders,

insomnia, headache, rash
 Protease Inhibitors (PIs)

• First introduced in 1995 Drugs

• Are an integral part of • Atazanavir sulfate, ATV
• Darunavir
treatment
• Fosamprenavir
• Exhibit activity against Calcium, FOS-APV
clinical isolates of both • Indinavir, IDV,
HIV-1 and HIV-2. • lopinavir /
ritonavir, LPV/RTV
• Nelfinavir mesylate, NFV
• Saquinavir mesylate, SQV
• Tipranavir, TPV
MOA
• HIV protease is a 99-amino-acid, aspartic acid protein
• Responsible for maturation of virus particles late in
viral life cycle.
• Systematically cleaves individual proteins from
gag and gag -pol polypeptide precursors into
functional subunits for viral capsid formation during
or shortly after viral budding from an infected cell.
• Competitive inhibitors
• Directly bind to HIV protease and prevent subsequent
cleavage of polypeptides.
MOA of PIs
 Pharmacokinetics
• Significant first-pass metabolism by cytochrome P450
(CYP) 3A4 and 3A5 and intestinal efflux by p-glycoprotein
is observed.
• Highly protein-bound (97-99%), primarily to albumin and
alpha1 acid glycoprotein except indinavir,
• Short serum half-lives, ranging from 1.5-2 hours for
indinavir and 7 hours for atazanavir.
• Significant Interactions with medications cleared through
CYP450 isoenzymes
• Low-dose ritonavir (100-200 mg) is frequently
coadministered with other protease inhibitors to block
intestinal and hepatic 3A metabolism.
Name Dosage Form(s) Adult Dose Adverse Events
Atazanavir Indirect hyperbilirubinemia,
100-mg, 150-mg, 200- 400 mg PO qd or
prolonged PR interval,
mg, 300-mg capsules 300 mg + ritonavir 100 mg PO qd
hyperglycemia, skin rash (20%),
hyperlipidemia

Darunavir 75-mg, 150-mg, 300- 800 mg qd + ritonavir 100 mg PO Rash, nausea, diarrhea,
mg, 400-mg, 600-mg qd or 600 mg bid + ritonavir 100 hyperlipidemia, hyperglycemia
tablets mg PO bid
Fosamprenavir 700-mg tab; 700 mg bid + ritonavir 100 mg PO Rash, nausea, vomiting,
bid or 1400 mg PO bid or 1400 mg diarrhea, hyperlipidemia,
50-mg/mL oral sus.
+ ritonavir 100-200 mg PO qd hyperglycemia
Sus.: Take without food
with RTV: Take with food

Indinavir 100-mg, 200-mg, 400- 800 mg PO q8h Nephrolithiasis, nausea, indirect

mg capsules 800 mg PO bid + ritonavir 100-200 hyperbilirubinemia,
mg PO bid hyperlipidemia, hyperglycemia
Take 1 h ac or 2 h pc;
Name Dosage Form(s) Adult Dose Adverse Events
Lopinavir / 100-mg/25-mg, 200- 400 mg/100 mg PO bid or Nausea, vomiting, diarrhea, asthenia,
ritonavir mg/50-mg tablets; 800 mg/200 mg PO qd hyperlipidemia, hyperglycemia
80-mg/20-mg per mL oral Oral solution: Take with meals
solution

Nelfinavir 250-mg, 625-mg tablets, 1250 mg PO bid or 750 mg PO tid Diarrhea, hyperlipidemia,
50 mg/g oral powder (cannot be boosted) Take with food hyperglycemia

Ritonavir 100-mg tablet; 100-mg Boosting dose for other PIs: 100-400 mg/d Nausea, vomiting, diarrhea, asthenia,
soft gelatin capsule; Nonboosting dose 600 mg bid hyperlipidemia, oral paresthesias,
80-mg/mL oral solution hyperglycemia

Saquinavir 500-mg tablet; 1000 mg + ritonavir 100 mg PO bid Nausea, diarrhea, headache,
200-mg hard gelatin Unboosted not recommended hyperlipidemia, hyperglycemia, PR
capsule Take with food, or within 2 h pc and QT interval prolongation

Tipranavir 250-mg soft gelatin 500 mg + ritonavir 200 mg PO bid Hepatotoxicity, rash, hyperlipidemia,
capsule Unboosted not recommended hyperglycemia, intracranial
100-mg/mL oral solution hemorrhage
 Entry Inhibitors - Chemokine
(CCR5) co-receptor antagonist
• Maraviroc
• Binding of gp120 HIV surface protein to CD4 receptor induces
a structural change that reveals V3 loop of the protein.
• V3 loop then binds with a chemokine coreceptor (principally
either CCR5 or CXCR4), allowing gp41 to insert itself into the
host cell and leading to fusion of the cell membranes.
• Maraviroc selectively and reversibly binds CCR5
coreceptor, blocking V3 loop interaction and inhibiting fusion
of cellular membranes.
– As some viral strains may use an alternate co-receptor CXCR4 for
entry,
– a tropism assay is necessary to confirm that patient’s virus only uses
CCR5 for entry.
• Pharmacokinetics
• 75% protein-bound, primarily to albumin and alpha1acid
glycoprotein.
• Terminal half-life is 15-30 hours.
• Metabolized through CYP3A4 and is a substrate for efflux
pump p-glycoprotein.
• Dosage adjustment is required when administered in
combination with potent inhibitors or inducers of CYP3A4300
mg PO bid
• Dose
150 mg PO bid (CYP3A4 inhibitors ± inducers)
600 mg PO bid (CYP3A4 inducers)
• ADRs
– Constipation, dizziness, cough, Pyrexia, Upper respiratory tract
infections, Rash, Musculoskeletal symptoms, Abdominal pain,
Hepatotoxicity, nasopharyngitis
 Fusion Inhibitors
• Enfuvirtide,
• Act extracellularly to prevent fusion of HIV to CD4 or other
target cell.
• Blocks second step in fusion pathway by binding to HR1 region
of gp41.
• Does not allow HR1 and HR2 to fold properly,
• Thus preventing conformational change of gp41 required to
complete final step in fusion process
• Dose 90 mg SC bid
• Dose adjustments are not required in patients with renal
insufficiency or mild-to-moderate hepatic insufficiency
• ADRs Injection-site reactions
(eg, pain, erythema, induration, nodules)
diarrhea, nausea, fatigue, hypersensitivity reactions, increased
rate of bacterial pneumonia
 Integrase Inhibitors (HIV integrase strand
transfer inhibitors)
• HIV integrase
• Responsible for transport and attachment of proviral DNA to host-cell
chromosomes, allowing transcription of viral proteins and subsequent
assembly of virus particles.
• Proviral integration involves 2 catalytic reactions:
• 3'-processing in host-cell cytoplasm to prepare proviral strands for attachment
• Strand transfer whereby proviral DNA is covalently linked to cellular DNA
• IIs Competitively inhibit strand transfer reaction by binding metallic ions in
active site.
• Raltegravir & Elvitegravir
• Dolutegravir
– Newest integrase inhibitor, is now in very advanced clinical trials, withapproval
expected towards the end of 2013.
– once-a-day medication, can be taken separately.
– doesn't require a booster
– appears to work against virus that is resistant to raltegravir and/orelvitegravir.
 Pharmacokinetics
Raltegravir
• Rapid absorption, taken with or without food. half-life of 10-12 hours
• Longer half-life in women,
• 83% bound to plasma proteins
• Metabolized by uridine diphosphate glucuronyl transferase
• Other antiretroviral agents may alter metabolism
• Antacids may decrease absorption by divalent cation binding,
Elvitegravir
• administered with low-dose ritonavir (100 mg) to reduce its first-pass
metabolism and systemic clearance.
• Coadministration results in a 20-fold increase in systemic exposure and a
terminal half-life of 10-13 hours.
• metabolized through CYP3A4 and UGT1A1/UGT1A3.
• Drug-drug interactions with other medications are likely because of
ritonavir
• Antacids may decrease absorption
Name Dosage Form(s) Adult Dose Adverse Events

Raltegravir 400-mg tablet 400 mg PO bid Nausea, diarrhea,

headache, CK
With rifampin: 800 elevations,
mg PO bid myopathy/rhabdom
y olysis (rare)

Elvitegravir Available in ‘quad’ nausea, diarrhea,

pill, elvitegravir/cob _ fatigue, and
icistat/emtricitabin headache
e
/tenofovir (Stribild).
 Commercial Fixed-dose combinations

Combination Name

Zidovudine + lamivudine Combivir

Zidovudine + abacavir Epzicom

Zidovudine + lamivudine + abacavir Trizivir (combivir +ABC)

Tenofovir + emtricitabine Truvada

Tenofovir + emtricitabine + efavirenz Atripla (Truvada +EFV)

Stavudine + lamivudine + nevirapine Triomunea

Lopinavir + ritonavir Kaletra

Rilpivirine + tenofovir/emtricitabine Complera

Elvitegravir+ cobicistat+ tenofovir + Stribild

emtricitabine
 Anti HIV agents under trials
• Nucleosides- DAPD, DOTC, GW-42086, D-D4FC
• Non-nucleosides- DPC 961, DPC
083, Capravirine, Calanolide A, TMC 120
• PI’s- BMS 232632, AG 1776, DMP 450, CGP61755, DPC
681, DPC 684, TMC 126
• Fusion Inhibitors - T- 1249
• Interleukin-2
• Vaccine development- vCP1452, gp-160
• Integrase Inhibitors- DCQA/DCTA, Zintevir
• Hydroxyurea-like Compounds- BCX-34,
 Drugs with Potential to Interact with
PIs or NNRTIs
• Statins (simvistatin & • Midazolam, trizolam
lovastatin) • Clarithromycin
• Azole antifungals • Oral contraceptives
• Anticonvulsants • Amitriptyline
• Anti-TB (Rifampicin)
• Warfarin

36
 Goals of Antiretroviral Therapy

Control of viral replication

Prevention or delay of progressive

immunodeficiency

Delayed progression to AIDS

Prolonged Survival

Decreased selection of
resistant virus
 DHHS ART Guidelines
Therapy should be initiated in following patient :
• ART should be initiated in all patients with a history of
an AIDS-defining illness or with a CD4 count <350
cells/mm3 (AI).
• ART should also be initiated, regardless of CD4 count,
in patients with the following conditions:
– Pregnancy (AI), to prevent perinatal transmission
– HIV- associated nephropathy (AII),
– Active TB
– Hepatitis B virus (HBV) coinfection when treatment of HBV
is indicated (AIII).
 Therapy options
Standard ART consists of 2 NRTIs in combination with an
NNRTI, PI, or integrase inhibitor.

• Preferred regimen Alternative Regimens

NNRTI-Based Regimens
NNRTI – Based regimen EFV + ABC/3TC
• EFV/TDF/FTC RPV/TDF/FTC
RPV + ABC/3TC
PI – Based regimen PI-Based Regimens
• ATV/r + TDF/FTC ATV/r + ABC/3TC
• DRV/r (OD) + TDF/FTC DRV/r + ABC/3TC
FPV/r (once or twice daily)
INSTI – Based regimen +ABC/3TC or TDF/FTC
• RAL + TDF/FTC LPV/r (once or twice daily)
+ABC/3TC or TDF/FTC
INSTI-Based Regimen
RAL + ABC/3TC
 Patient selection
• Patients initiating ART should be willing and
able to commit to lifelong treatment
• Should understand benefits and risks of
therapy and importance of adherence
• Patients may choose to postpone therapy, and
providers, on a case-by-case basis,
• May elect to defer therapy based on clinical
and/or psychosocial factors.
Dosing of Antiretroviral Agents in
Hepatic Failure
Dosing of Antiretroviral Agents in
Renal Failure
 Types of Treatment Failure:
• Virologic Failure: if viral load is not <400 copies/mL after 3mo

• Immunologic Failure:
– The CD4 cell count persistently falls below the baseline CD4 cell count
– The CD4 cell count fails to increase by more than 25-50 cells/μL after
one year of treatment

– There is a > 50% decline in CD4 cell count from its highest level on ART

• Clinical Failure:
– when the patient has a new AIDS-defining illness—i.e., a new WHO
stage 3 or 4 condition--after initiation of ART
 Clinical Indications to Change ART
Due to Toxicity
Symptom Clinical Indication
Nausea Severe discomfort or minimal intake for > 3 days
Vomiting Severe vomiting of all foods/fluids in 24 hrs, orthostatic
hypotension or need of IV fluids
Diarrhea Bloody diarrhea, orthostatic hypotension or need of IV
fluids
Fever Unexplained fever of > 39.6 C
Headache Severe or requires narcotics
Allergic Generalized urticaria, angioedema or anaphylaxis
Reaction
Peripheral Severe discomfort, objective weakness, loss of 2-3
Neuropathy previously present reflexes or sensory dermatomes
45
Fatigue Normal activity reduced > 50%
 Lab Indications to Change ART Due to Toxicity
Grade 3 Normal Reference
Parameter
Toxicity Values
Hemoglobin (Hgb) < 7.0 g/dL M: 13.8 – 17.2 g/dL
F: 12 – 15.6 g/dL
Hematology *ANC < 750/mm3 1500 to 7000/mm3
Platelet count < 49 x 103/µL 130-400 x 103/µL
Total Bilirubin > 3-7.5 x ULN*= ≤ 1.3 mg/dL
3.9-9.75mg/dL
Chemistries
SCr > 1.7-2.0 (adult) ≤ 1.2 mg/dL

AST / ALT 5-10 x ULN* = ≤ 42 U/L , ≤ 48U/L

LFTs 210-420 U/L,
240-480 U/L

Pancreatic Amylase, Lipase > 2-3 x ULN* 23-85 U/L, 0-160 U/L
Enzymes
Triglyceride (TG) 8.49- 13.56 < 200 mg/dL
Lipids mmol/L
Cholesterol 1.6-2.0 X ULN < 200 mg/dL
46
* ULN = Upper Limit of Normal *ANC= Absolute neutrophil count
 Serious Adverse Effects of NRTIs
• All NRTIs** • Anemia
– Zidovudine (AZT, ZDV)
– Lactic acidosis/fatty
• Pancreatitis*
liver*
– didanosine (ddI)
– Lipoatrophy (loss of
• Neuropathy
subcutaneous fat) – didanosine (ddI)
– stavudine (d4T)
*Potentially life-threatening
**d4T > ddI, AZT > ABC, TDF, 3TC

47
Serious Adverse Effects of NNRTIs

• All NNRTIs • CNS symptoms

– Hepatitis* – efavirenz
– Skin rash • Stevens-Johnson
syndrome*

– nevirapine

*Potentially life-threatening

48
 Serious Adverse Effects of PIs
• All PIs

– Insulin resistance hyperglycemia and diabetes

– Elevated serum lipids

– Abnormal fat accumulation

– Liver toxicity*

*Potentially life-threatening

49
 LIPODYSTROPHY SYNDROME
• Main clinical features are peripheral fat loss, central
fat accumulation, gyneacomastia, buffalo hump
and other peripheral lipomatosis.

• Incidence: 20-80% of pts in ARV drugs

• Presumed Mechanism: inhibition of DNA
polymerase gamma resulting in depletion of
mitochondrial DNA
 Lipodystrophy Syndrome:
NRTIs versus PIs

PIs
NRTIs
d4T>ZDV

Lactic acid SC fat wasting Intra-abdominal fat

TG Cholesterol
Buffalo hump TG
Insulin resistance
John M, et al. Antiviral Ther. 2001;6:9-20.
• Rx
– Low fat diet and aerobic exercise
– Testosterone replacement therapy (in hypogonadal
men) or anabolic steroids (eugonadal men)
– Growth hormone (6mg/kg) may reduce fat
accumulation

– Metformin (500mg bid)

• improves insulin sensitivity, results in weight loss and
decreased intra- abdominal fat

– Restorative surgery
– Regimen change: PIs to NNRTIs or ABC
 Lactic Acidosis/Hepatic Steatosis

• Hyperlactemia is defined as venous lactate

>2mmol/L

• Mortality rate: up to 55%

• Presumed Mechanism of toxicity: inhibition of
DNA polymerase gamma resulting in depletion
of mitochondrial DNA
• Dx
– Clinical: N & V, myalgia, abd. Pain &
distention, diarrhea, wt loss

– Lab.
• Elevated venous lactic acid
• Surrogate markers include elevated creatinine
phosphokinase (CPK), lactate dehydrogenase
(LDH), amylase or aspartate aminotransferase
(AST), increase anion gap (>16), CT, US, biopsy showing
liver steatosis
• Rx
– Lactic acid <5mmol/L may not require
– Therapeutic switch : D4T, ddl, or AZT to ABC,3TC or
TDF may be reasonable
– Supportive measures: hydration, mitochondrial
ventilation and dialysis

– Anecdotal case reports show possible benefit of

thiamine, L-carnitine, vit-C and antioxidants
– Riboflavin 50mg/kg - most extensive & favourable
 Insulin Resistance
• Incidence:
– 30-90% pts on PIs and overt DM occurs in 1-11% with
a mean of 7% in 5yr

• Screening:
– RBG, FBG and HbA1c after 2-3 mo of the start of PI
base regimen

• Risk:
– Risk of atherosclerosis
 Insulin Resistance
• Rx
– STD RX of type II DM and exercise
– The two major classes of agents are insulin secretagogues
(sulunylureas ) and insulin sensitizing agents ( metformin and
thiazolidinediones / glitazones)
– Metformin and glitazones have the potential advantage of
improving insulin resistance and decreasing visceral fat
accumulation

– Therapeutic switch to non PI base ARV agents

 Hyperlipidemia
• All PIs appears to have this effect with possible exception of
atazanavir;
• Observed within 2 to 3 month of initiating PI based regimen
• Risk:
– Possible risk of atherogenesis
• DX & Rx:
– ^LDL and TG--PI based ART esp.with retonavir
– ^TC and HDL—EFV & NVP
 Rx of hyperlipidemia
Lipid problem Preferred alternative comment
Isolated high LDL Statin niacin Start low dose
and titrate
upward, watch
for myopathy
with PIs
High cholesterol Statin or fibrate Start one and Combination
and TG add other may increase
risk of myopathy
Isolated high TG fibrate statin Combination
may increase
risk of myopathy
 Hepatotoxicity
• NRTIs can cause hepatic steatosis, generally after more than 6 months of
therapy, probably via mitochondrial toxicity.(D4T!)
• NNRTIs can cause hepatitis in first 2-3 months of therapy, sometimes as a
part of hypersensitivity reaction (NVP>EFV, DLV)-fluminant hepatic
necrosis (NVP)
• PIs can also cause hepatitis by an unknown mechanism, particularly in
patients co-infected with hepatitis B or C, raised hepatic
aminotransferase concentrations and alcoholism (RTV-the most
common, among PIs)
• Most hepatotoxic appears to be NVP followed by full dose RTV
 HYPERSENSITIVITY
• Is about 100 times more common in HIV Pts than in
general population.
• Erythematous maculopapular, pruritic and confluent
rash, most ly on body and arms and begins after 1-2
weeks of therapy.

• SJS or TEN develops in less than 0.3% of patients.

• All NNRTI (Nevirapine,Delavirdine,Efavirenz, Etravirine),
NRTI (Abacavir) and PI (Amprenavir) are common
• About 50% of ARV hypersensitivity resolves
spontaneously despite continuation of therapy.
• Therapy should be stopped if there is mucosal
involvement, blistering, exfoliation, clinically
significant hepatic dysfunction

• Glucocorticosteroids are ineffective for prevention of

nevirapine hypersensitivity.
• Rechallenge is possible for mild to moderate NNRTI
hypersensitivity but not for abacavir,
Laboratory monitoring of patients on ART:

– CD4 cell count %: 3 and 6 months post-initiation, then

every 6 months (all ages)
– Viral load: 3 and 6 months post-initiation, then as
follows: (Every 6 months for adults)

– FBC:
• AZT-based ART: at 4 and 12 weeks post-initiation, then
annually only, and as clinically indicated
• If not on AZT-based ART: annually only, and as clinically
indicated
• AST/ALT:
– NVP-based ART: 2, 4, and 12 weeks post-initiation, thereafter only as
clinically indicated
– EFV-based ART: 4 and 12 weeks post-initiation, thereafter only as
clinically indicated
– PI-based ART: only as clinically indicated
• Glucose and total cholesterol/triglycerides annually only if on PI-
based ART
• Creatinine and creatinine clearance : 3 and 6 months post-initiation
and then, if stable, every 6 months (TDF only)
• RPR (rapid plasma reagin )or VDRL test: after baseline, only as
indicated
 Principles of HIV Drug Resistance
• Results from changes (mutations) in genetic information in
virus
• These changes occur whenever HIV is replicating
• Partial HIV suppression promotes resistance
• Resistance can be delayed by suppressing virus completely
• RT and protease are flexible (highly mutable)
• Resistance may fade but not disappear when a drug is stopped
• Some mutations allow certain viruses to resist effects of one or
more antiretroviral drugs
• Drug resistant virus usually grows faster and better than drug
susceptible virus
• Drug resistant virus replaces drug susceptible virus in patient

66
 Resistance Testing
• Two types:
– Genotyping
Detects drug resistance mutations on virus genome
that may make it resistant to certain antiretrovirals
• Less expensive
• Can usually be completed in 1-2 weeks
– Phenotyping
Measure ability of viruses to grow in presence of
various concentrations of antiretroviral drugs
• More expensive
• Generally takes 2-3 weeks to complete

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Resistance Mutations
• For some drugs (NNRTIs and 3TC), a single mutation
causes high-level resistance.
– Resistance to these drugs occurs very quickly
• For other drugs (most NRTIs and PIs), many mutations
must occur before high-level resistance is observed.
– Resistance to these drugs occurs more slowly
Cross-Resistance
• Resistance to one drug can cause resistance to others
of the same class
– NNRTI: complete cross-class resistance
– NRTI: partial cross-class resistance
– PI: partial cross-class resistance
• Partly overcome by ritonavir boosting

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Minimize Emergence of Viral Resistance

• Never prescribe ARVs in absence of adherence

counseling and support
• Never prescribe monotherapy or dual therapy
• Ensure optimal serum drug concentrations
– Avoid drug interactions
– Diagnose and manage malabsorption
• If ARV medications are to be discontinued, stop
all drugs at same time
– Possible exception: NNRTI-based regimen

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THANK YOU