structure of HIV, classification of ART drugs, newer ART drugs, MOA, Pharmacokinetics, adverse effects,

1. SEMINAR PRESENTATION
Moderator
Dr. Saroj Purohit

2. • HIV infection/AIDS is a global problem.
• At the end of 2009, an estimated 33.3 million
PLWHA according to UNAIDS.
• More than 95% of people living with
HIV/AIDS reside in low- and middle-income
countries;
– 50% are female, and
– 2.5 million are children <15 years.

3. • A significant proportion of people (25%) are
unaware that they are HIV-positive
• Racial and ethnic minorities continue to be
disproportionately affected by HIV
• Strongest risk factors for excess mortality is viral
load greater than 400 copies/mL, CD4+ count less
than 200 cells/mL and cytomegalovirus retinitis
• Availability of antiretroviral therapy has resulted
in decline in AIDS death rates

4. • HIV attacks and binds to specific cells of
immune system, including
– 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

5. 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

6. HIV life cycle and antiretroviral drug targets

8. Classification of 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)

9. Nucleo(t)side Reverse Transcriptase Inhibitors (NRTIs)
• First agents available for
HIV Infection.
• Less potent than NNRTIs)
and pIs.
• Have a central role in ART.
• Have activity against HIV-1
and HIV-2.
• Nucleoside and nucleotide an
alogues
• Differ from normal substrates
only by a minor modification in
sugar (ribose) molecule
Drugs
•Abacavir (ABC)
•Didanosine (ddI)
•Emtricitabine (FTC)
•Lamivudine (3TC)
•Stavudine (d4T)
•Tenofovir (TDF)
•Zidovudine (ZDV;
formerly azidothymidine
[AZT])

10. 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
RNA
DNA
• Acting as "false building blocks causes Chain termination,
Nucleus
• Once incorporated, work by preventing other nucleosides from
Host absence of a 3’ OH group.
also being incorporated b/c ofCell
10

11. MOA of NRTIs

12. 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.

13. Name
Dosage Form(s)
Adult Dose
Adverse Events
Abacavir
300-mg tablet;
20-mg/mL oral
solution
600 mg PO qd or
300 mg PO bid
Hypersensitivity reaction (may include fever,
rash, nausea, vomiting, diarrhea, malaise,
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,
250-mg, 400-mg
enteric-coated
capsule;
10-mg/mL
suspension
>60 kg: 400 mg PO qd
Peripheral neuropathy, pancreatitis, nausea,
< 60 kg: 250 mg PO qd lactic acidosis
Take 30 min ac or 2 hr pc
Oral solution: Divide
daily dose bid
Emtricitabine 200-mg capsule;
10-mg/mL oral
solution
200 mg PO qd or
240 mg (24 mL) oral
solution PO qd
Minimal toxicity, hyperpigmentation

14. Name
Dosage Form(s)
Adult Dose
Adverse Events
Lamivudine
150-mg, 300-mg tablet;
10-mg/mL solution
300 mg PO qd or
150 mg PO bid
Minimal toxicity, severe acute exacerbation of
hepatitis may occur with HBV-coinfection upon
discontinuation
Stavudine
15-mg, 20-mg, 30-mg,
40-mg capsule;
1-mg/mL oral solution
>60 kg: 40 mg PO
bid
< 60 kg: 30 mg PO
bid
Peripheral neuropathy, pancreatitis, lactic
acidosis, lipoatrophy, hyperlipidemia
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
capsule;10-mg/mL oral 200 mg PO tid
solution;10-mg/mL
intravenous solution
Nausea, vomiting, headache, asthenia,
Anemia, granulocytopenia, myopathy, lactic
acidosis, hepatomegaly with steatosis, nail
pigmentation, lipid abnormalities, lipoatrophy,
hyperglycemia

15. Nonnucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
• Were introduced in 1996 with
approval of nevirapine.
• Have potent activity against
HIV-1 and are part of
preferred initial regimens.
• Efavirenz, confers most
significant inhibition of viral
infectivity
• All exhibit same mechanism
of action
Drugs
First-generation
Delavirdine(DLV)
Efavirenz (EFV)
Nevirapine (NVP)
Second-generation
Etravirine (ETR)
Rilpivirine (RPV)

16. 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

17. MOA of NNRTIs

18. 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)

19. Name
Dosage Form(s)
Adult Dose
Adverse Events
Delavirdine 100-mg, 200-mg tab.
400 mg PO tid
Rash, headache
Efavirenz
600-mg tab.;
50-mg, 200-mg caps
600 mg PO qd
Take on empty stomach
to decrease Adrs
Rash, CNS (eg, somnolence, vivid
dreams, confusion, visual
hallucinations), hyperlipidemia
Etravirine
100-mg, 200-mg
tablets
200 mg PO bid
Rash, nausea
Nevirapine 200-mg tab; 400 mg
XR tab; 10-mg/mL
susp.
200 mg PO bid
XR: 400 mg PO qd
Rash, hepatitis
Rilpivirine
25 mg PO qd with meal
Depressive disorders, insomnia,
headache, rash
25-mg tablet

20. Protease Inhibitors (PIs)
• First introduced in 1995
• Are an integral part of
treatment
• Exhibit activity against
clinical isolates of both
HIV-1 and HIV-2.
Drugs
• Atazanavir sulfate, ATV
• Darunavir
• Fosamprenavir
Calcium, FOS-APV
• Indinavir, IDV,
• lopinavir /
ritonavir, LPV/RTV
• Nelfinavir mesylate, NFV
• Saquinavir mesylate, SQV
• Tipranavir, TPV

21. 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.

22. MOA of PIs

23. 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.

24. Name
Dosage Form(s)
Atazanavir
100-mg, 150-mg, 200- 400 mg PO qd or
mg, 300-mg capsules 300 mg + ritonavir 100 mg PO qd
Indirect hyperbilirubinemia,
prolonged PR interval,
hyperglycemia, skin rash (20%),
hyperlipidemia
Darunavir
75-mg, 150-mg, 300- 800 mg qd + ritonavir 100 mg PO
mg, 400-mg, 600-mg qd or 600 mg bid + ritonavir 100
tablets
mg PO bid
Rash, nausea, diarrhea,
hyperlipidemia, hyperglycemia
Fosamprenavir
700-mg tab;
50-mg/mL oral sus.
Indinavir
Adult Dose
Adverse Events
700 mg bid + ritonavir 100 mg PO Rash, nausea, vomiting,
bid or 1400 mg PO bid or 1400 mg diarrhea, hyperlipidemia,
+ ritonavir 100-200 mg PO qd
hyperglycemia
Sus.: Take without food
with RTV: Take with food
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;

25. Name
Dosage Form(s)
Adult Dose
Adverse Events
Lopinavir /
ritonavir
100-mg/25-mg, 200mg/50-mg tablets;
80-mg/20-mg per mL oral
solution
400 mg/100 mg PO bid or
800 mg/200 mg PO qd
Oral solution: Take with meals
Nausea, vomiting, diarrhea, asthenia,
hyperlipidemia, hyperglycemia
Nelfinavir
250-mg, 625-mg tablets,
50 mg/g oral powder
1250 mg PO bid or 750 mg PO tid
(cannot be boosted) Take with food
Diarrhea, hyperlipidemia,
hyperglycemia
Ritonavir
100-mg tablet; 100-mg
soft gelatin capsule;
80-mg/mL oral solution
Boosting dose for other PIs: 100-400 mg/d Nausea, vomiting, diarrhea, asthenia,
Nonboosting dose 600 mg bid
hyperlipidemia, oral paresthesias,
hyperglycemia
Saquinavir
500-mg tablet;
200-mg hard gelatin
capsule
1000 mg + ritonavir 100 mg PO bid
Unboosted not recommended
Take with food, or within 2 h pc
Nausea, diarrhea, headache,
hyperlipidemia, hyperglycemia, PR
and QT interval prolongation
Tipranavir
250-mg soft gelatin
capsule
100-mg/mL oral solution
500 mg + ritonavir 200 mg PO bid
Unboosted not recommended
Hepatotoxicity, rash, hyperlipidemia,
hyperglycemia, intracranial
hemorrhage

26. 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.

28. • 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

29. 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

31. 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, with approval
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/or elvitegravir.

32. 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

33. Name
Dosage Form(s)
Adult Dose
Adverse Events
Raltegravir
400-mg tablet
400 mg PO bid
Nausea, diarrhea,
headache,
CK
elevations,
myopathy/rhabdomy
olysis (rare)
With rifampin: 800
mg PO bid
Elvitegravir
Available in ‘quad’
pill, elvitegravir/cob
icistat/emtricitabine
/tenofovir (Stribild).
_
nausea, diarrhea,
fatigue, and
headache

34. 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 +
emtricitabine
Stribild

35. 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,

36. Drugs with Potential to Interact with
PIs or NNRTIs
• Statins (simvistatin &
lovastatin)
• Azole antifungals
• Anticonvulsants
• Anti-TB (Rifampicin)
• Warfarin
36
•
•
•
•
Midazolam, trizolam
Clarithromycin
Oral contraceptives
Amitriptyline

37. 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

38. 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).

39. Therapy options
Standard ART consists of 2 NRTIs in combination with an
NNRTI, PI, or integrase inhibitor.
• Preferred regimen
NNRTI – Based regimen
• EFV/TDF/FTC
PI – Based regimen
• ATV/r + TDF/FTC
• DRV/r (OD) + TDF/FTC
INSTI – Based regimen
• RAL + TDF/FTC
Alternative Regimens
NNRTI-Based Regimens
EFV + ABC/3TC
RPV/TDF/FTC
RPV + ABC/3TC
PI-Based Regimens
ATV/r + ABC/3TC
DRV/r + ABC/3TC
FPV/r (once or twice daily)
+ABC/3TC or TDF/FTC
LPV/r (once or twice daily)
+ABC/3TC or TDF/FTC
INSTI-Based Regimen
RAL + ABC/3TC

41. 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.

42. Dosing of Antiretroviral Agents in
Hepatic Failure

43. Dosing of Antiretroviral Agents in
Renal Failure

44. 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

45. 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
Reaction
Generalized urticaria, angioedema or anaphylaxis
Peripheral Severe discomfort, objective weakness, loss of 2-3
Neuropathy previously present reflexes or sensory dermatomes
45
Fatigue
Normal activity reduced > 50%

46. Lab Indications to Change ART Due to Toxicity
Parameter
Grade 3
Toxicity
Normal Reference
Values
Hemoglobin (Hgb)
< 7.0 g/dL
M: 13.8 – 17.2 g/dL
F: 12 – 15.6 g/dL
*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*=
3.9-9.75mg/dL
≤ 1.3 mg/dL
SCr
> 1.7-2.0 (adult)
≤ 1.2 mg/dL
AST / ALT
5-10 x ULN* =
210-420 U/L,
240-480 U/L
≤ 42 U/L , ≤ 48U/L
Amylase, Lipase
> 2-3 x ULN*
23-85 U/L, 0-160 U/L
Triglyceride (TG)
8.49- 13.56
mmol/L
< 200 mg/dL
1.6-2.0 X ULN
< 200 mg/dL
Hematology
Chemistries
LFTs
Pancreatic
Enzymes
Lipids
Cholesterol
46
* ULN = Upper Limit of Normal
*ANC= Absolute neutrophil count

47. Serious Adverse Effects of NRTIs
• All NRTIs**
– Lactic acidosis/fatty
liver*
– Lipoatrophy (loss of
subcutaneous fat)
*Potentially life-threatening
• Anemia
– Zidovudine (AZT, ZDV)
• Pancreatitis*
– didanosine (ddI)
• Neuropathy
– didanosine (ddI)
– stavudine (d4T)
**d4T > ddI, AZT > ABC, TDF, 3TC
47

48. Serious Adverse Effects of NNRTIs
• All NNRTIs
– Hepatitis*
– Skin rash
• CNS symptoms
– efavirenz
• Stevens-Johnson
syndrome*
– nevirapine
*Potentially life-threatening
48

49. Serious Adverse Effects of PIs
• All PIs
– Insulin resistance
hyperglycemia and diabetes
– Elevated serum lipids
– Abnormal fat accumulation
– Liver toxicity*
*Potentially life-threatening
49

50. 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

51. Lipodystrophy Syndrome:
NRTIs versus PIs
PIs
NRTIs
d4T>ZDV
Lactic acid
SC fat wasting
TG
Buffalo hump
Intra-abdominal fat
Cholesterol
TG
Insulin resistance
John M, et al. Antiviral Ther. 2001;6:9-20.

52. • 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

54. 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

55. • 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

56. • 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

57. 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

58. 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

59. 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

60. Rx of hyperlipidemia
Lipid problem
Preferred
alternative
comment
Isolated high LDL Statin
niacin
High cholesterol Statin or fibrate
and TG
Start one and
add other
Start low dose
and titrate
upward, watch
for myopathy
with PIs
Combination
may increase
risk of myopathy
Isolated high TG
statin
fibrate
Combination
may increase
risk of myopathy

61. 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

62. 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

63. • 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,

64. 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

65. • 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

66. 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

67. 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
67

68. 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
68

69. 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
69

70. THANK YOU