1. Anti-Retroviral Therapy-considerations and resistance management

2. Outline ART Drugs available Mechanism of action and side effects
Mechanism of resistance
cART NACO guidelines
Special circumstances while prescribing cART
Drug Resistance
Switching and substitution in drug resistant cases

3. References NACO Guidelines 2013 and 2015 update
Harrisons Principle of Internal Medicine;19th Edition
aidsetc.org,

4. Current ARV Medications
NRTI & NtRTI
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir (TDF)
Zidovudine (AZT, ZDV)
NNRTI
Delavirdine (DLV)
Efavirenz (EFV)
Etravirine (ETR)
Nevirapine (NVP)
Rilpivirine (RPV) PI
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir (LPV)
Nelfinavir (NFV)
Saquinavir (SQV)
Tipranavir* (TPV)
Integrase Inhibitor (INSTI)
Dolutegravir* (DTG)
Elvitegravir* (EVG)
Raltegravir (RA)
Fusion Inhibitor
Enfuvirtide(ENF, T-20)
CCR5 Antagonist
Maraviroc (MVC)
Pharmacokinetic (PK) booster
Ritonavir (RTV)
Cobicistat (COBI)
July 2015

7. Reverse Transcriptase Inhibitors
NRTI & NtRTI
TDF Tenofovir
300mg OD. Only nucleotide approved in cART. CAUTION- Renal, Osteomalacia, flare of HBV
3TC Lamivudine
300mgOD. One of the safest ARV. CAUTION-HBV flare.
AZT Zidovudine
300mgBD.CAUTION-BM suppression, lactic acidosis, steatosis, lipodystrophy, myopathy
ABC Abacavir
300mgBD.CAUTION-HLA-B5701+ individual, poor GI tolerance.
ddI Didanosine
250mgOD.CAUTION-Diarrhea, peripheral neuropathy, pancreatitis, severe nausea. 
FTC Emtricitabine 
200mgOD. Well tolerated. CAUTION-HBV flare, skin discolouration
d4T Stavudine
 30-40mgBD. CAUTION-BM suppression, lactic acidosis, steatosis, lipodystrophy, renal clearance, peripheral neuropathy
NNRTI
Nevirapine
200mgBD/400mgOD. CAUTION-Skin rash, hepato- toxicity.
Efavirenz
600mgHS. CAUTION- CNS effects(4D’s), Transaminitis, teratogenic?, dyslipidemia

8. M184V , K70R , K65R/E/N
Y181C, K103N
Y181C,M230L,K101P

9. Thymidine analogue mutations- primer rescue

10. Protease inhibitors LPV Lopinavir/Ritonavir ATV Atazanavir
( ) mg BD. CAUTION-Diarrhea, dyslipidemia, SJS-TEN, nausea.
ATV Atazanavir 
400mgOD. Caution- Jaundice, PR prolongation, GI side effects, lipoatrophy
DRV Darunavir/cobicistat 
( ) mg OD. CAUTION- Increased triglycerides, Jaundice, GI side-effects.
IDV Indinavir 
800mgTDS. CAUTION-Jaundice, Nephrolithiasis, GI side effects
NFV Nelfinavir
750mgTDS. CAUTION-Diarrhea, QTc prolongation, allergic reactions
SQV Saquinavir 
1000mgBD. CAUTION- Rash, Poor GI tolerance, mucosal ulceration.
FPV Fosamprenavir 
1400mgBD. CAUTION-Nausea, diarrhea, fatigue, rash

12. Integrase Inhibitors(INSTI)
Raltegravir
400mgBD. CAUTION-Nausea, headache, rhabdomyolysis.
Elvitegravir
FDC with cobi+teno+emtri. CAUTION- Nausea, headache, URTIs
Dolutegravir
50mgBD. CAUTION- Insomnia, hypersensitivity, hepatotoxicity.

14. Entry Inhibitors- Enfuviritide Maraviroc(CCR5 antagonist)
90mg sc BD. CAUTION- local reactions, pneumonia, hypersensitivity
Maraviroc(CCR5 antagonist)
300mg BD. CAUTION-hepatotoxicity, coryza-like illness, dizziness, fatigue

16. Treatment Guidelines Outline
Overview
Initiation of Therapy
Management of the Treatment-Experienced Patient
Special Issues

17. What the Guidelines Address
Baseline evaluation
When to initiate therapy
When to change therapy
Therapeutic options
Adherence
ART-associated adverse effects
Special considerations
Preventing secondary transmission

18. Goals of Treatment
Reduce HIV-related morbidity; prolong duration and quality of survival
Restore and/or preserve immunologic function
Maximally and durably suppress HIV viral load
Prevent HIV transmission

19. Use of CD4 Cell Levels to Guide Therapy Decisions
Most recent CD4 count is best predictor of disease progression
A key factor in determining urgency of ART or need for OI prophylaxis
Important in determining response to ART
Adequate response: CD4 increase cells/µL per year

21. Use of HIV RNA Levels to Guide Therapy Decisions
Check at baseline
Every 6 months for stable pts
Patients with VL suppression >2 years
Isolated “blips”
(transient low-level RNA, typically <400 copies/mL)
Goal of ART:
HIV RNA below limit of detection (ie, < copies/mL, depending on assay)

22. Rationale for Early ART
improves and preserves immune function.
better immunologic responses and clinical outcomes.
Reduction in morbidity and mortality.
Reduction in HIV-associated inflammation and complications
reduce risk of HIV transmission.

23. Potential Benefits of Early Therapy
Decrease in complications
HIV-associated nephropathy
Liver disease progression from hepatitis B or C
Cardiovascular disease
Malignancies (AIDS defining and non-AIDS defining)
Neurocognitive decline
Blunted immunological response owing to ART initiation at older age
Persistent T-cell activation and inflammation

24. WHO Recommendations for Initiating ART
ART is recommended for treatment:
“ART is recommended for all HIV-infected individuals to reduce the risk of disease progression.”
ART is recommended for prevention:
“ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.”
Current recommendation: ART is strongly recommended for all

25. Potential Concerns about Early Therapy
ARV-related toxicities
Nonadherence to ART
Drug resistance
Cost

26. Conditions when to Consider More-Rapid Initiation of ART
Pregnancy
AIDS-defining condition
Acute opportunistic infection
Lower CD4 count (eg, <200 cells/µL)
Acute/recent infection
Rapid decline in CD4
Higher viral load (eg, >100,000 copies/mL)
HIVAN
HBV coinfection
HCV coinfection

27. Consider Deferral of ART
CD4 count is low (<500 / cumm)
deferral should be considered only in unusual situations, and with close follow-up
When there are significant barriers to adherence
If co-morbidities complicate or prohibit ART

28. Principles for selecting the first-line regimen
1. Choose 3TC (Lamivudine) in all regimens
2. Choose one NRTI to combine with 3TC (AZT or TDF)
3. Choose one NNRTI (NVP or EFV)

37. Four pronged strategy between NACP and RNTCP
Prevention
Isoniazid Preventive Therapy (IPT)
Air-borne Infection Control (AIC)
Awareness generation
Early Detection of TB-HIV
100% coverage of PITC in TB patients
PITC in Presumptive TB cases
Rapid diagnostics for detecting TB and DR-TB in PLHIV
ICF activities at all HIV settings: ICTC, ART Centre, LAC and TI settings
Prompt Treatment of TB-HIV
Prompt initiation of TB Treatment
Early Initiation of ART
Management of special TB-HIV cases
TB-HIV patients on PI-based ART
TB-HIV in children
TB-HIV in pregnant women
Drug Resistant TB-HIV
TB / HIV co-ordination to reduce Mortality
Trainer Notes:
Trainer has to emphasise that the central dogma of TB-HIV coordination is to reduce Mortality and is the central theme of the four strategies
The strategies are based on the public health principles of disease prevention and interventions
Prong-1: Deals with strategies to prevent acquiring TB in PLHIV (reduce the risk) by INH prophylaxis, AIC, Awareness generation
Prong-2: Deals with early detection of TB or HIV by: 100% coverage of Provider Initiated Counselling and Testing (PITC), PITC in all presumptive TB cases, Rapid diagnostics for detection of TB and DR-TB in PLHIV and Intensive case finding (ICF)
Prong-3: Deals with management of TB-HIV TB Co-infected Patients- Prompt initiation of TB treatment and Early initiation of ART
Prong -4: Deals with management of special TB-HIV cases 10

38. 3 ‘I’ strategy
Intensified case finding and Operational guidelines for single window delivery services

39. Three “I”s to reduce burden of TB among PLHIV
ICF: Intensified (TB) case finding (ICF) at ICTC, ART centres and LAC
IC-AIC: Air-borne infection control measures for prevention of TB transmission at HIV care settings
IPT: Implementation of Isoniazid preventive treatment (IPT) for all PLHIV (On ART + Pre-ART)
Trainer Notes:
Briefly Describe the 3 I’s. Detailed description is provided in the following slides

42. Selecting Initial ART Regimen: Selected Clinical Scenarios
Chronic kidney disease (eGFR <60 mL/min)
Consider avoiding TDF
If eGFR <70 mL/min, do not use:
EVG/c/TDF/FTC
ATV/c + TDF
DRV/c + TDF
Options:
ABC/3TC if HLA-B*5701 negative (if HIV RNA >100,000, do not use with EFV or ATV/r; if CrCl <50 mL/min, must dose adjust 3TC)
DRV/r + RAL
LPV/r + 3TC
Modify TDF dose

43. Selecting Initial ART Regimen: Selected Clinical Scenarios
Osteoporosis
Consider avoiding TDF: associated with greater decrease in BMD, osteomalacia, urine phosphate wasting
Use ABC/3TC if HLA-B*5701 negative
(if HIV RNA >100,000 copies/mL, do not use with EFV or ATV/r)
Psychiatric illness
Consider avoiding EFV: can exacerbate psychiatric symptoms; may be associated with suicidality
High cardiac risk
Consider avoiding ABC and LPV/r: increased CV risk in some studies

44. Selecting Initial ART Regimen: Selected Clinical Scenarios
Hyperlipidemia
Adverse effects on lipids:
PI/r
ABC
EFV
EVG/c
Beneficial lipid effects:
TDF give TLN

45. Selecting Initial ART Regimen: Selected Clinical Scenarios
HBV
Use TDF/FTC (or TDF + 3TC) if possible: use 2 NRTIs with activity against both HIV and HBV
If TDF contraindicated: co-treat HBV with FTC or 3TC + entecavir or another HBV-active drug
Continue TLE

46. HIV DRUG RESISTANCE

47. OUTLINE OF PRESENTATION
Definition and types of resistance
Factors contributing to drug resistance
Resistance testing methods
Limitations of drug resistance testing
Global action plan for HIV DR

48. Drug resistance
Ability of HIV to replicate in the presence of ARV HIV infection is characterized by – high level of virus turnover heterogeneous viral population –quasispecies Reverse transcription of viral RNA into DNA , introduces on an average one mutation for each transcription

49. Emergence of drug resistance

50. Emergence of drug resistance

51. Genetic barriers to resistance
Low genetic barrier to resistance
- Single mutation causing high level of resistance
- NRTIs-Lamivudine
- NNRTIs-Effavirenz and Nevirapine
High genetic barrier to resistance
- Requires accumulation of multiple mutations
- Protease inhibitors

52. Time to development of resistance
Months to years
PI, RTV++
Weeks to month
NRTI(ddl, TDF, AZT, ABC, d4T)
Entry Inh (ENF), PI
Days to weeks
NRTI(3TC,FTC), NNRTI

53. HIV Drug Resistance - Evolution

54. Primary resistance
Primary infection with HIV strains that exhibit resistance to single of multiple ARV drugs.
Mostly due to transmission of ARV drug resistant strains.
HIV-2 – resistant to
NNRTIs
Non subtype B strains

55. Acquired resistance
Acquired HIVDR occurs when resistance mutations occur individuals receiving ART

56. How common is resistance ?
On average, it is estimated that 20-38% of people on ARVs will develop resistance during therapy with in 2 years
About 5 to 20% of virus that is transmitted has resistance to at least one antiretroviral drug

57. Cross resistance
Resistance to drugs to which a virus has never been exposed.

58. Predictors of virologic suppression
Low baseline viral load
H/o prior viral suppression
No. of new medication administered
No. of new drug classes used.
Tolerance & convenience of new regimen.
Use of ritonavir boosted PI have better rates of viral suppression compared with NNRTI.
Rhee SY, Fessel WJ, Liu TF, et al. Predictive value of HIV-1 genotypic resistance test interpretation algorithms. J Infect Dis 2009; 200:453

59. What factors contribute to resistance ?
Resistance occurs when drug levels in the body are not adequate to stop replication of the virus.
Medication adherence
Medication absorption
Drug-drug interactions
Transmitted resistance

60. HIV genetic sequence identified
Genotypic Testing
Genotype Testing-
This test determines the genetic sequence of the HIV virus in the patient’s blood which is then compared to a database to identify if mutations are present.
Blood sample taken from patient
HIV genetic sequence identified
Patient’s HIV sequence is compared to HIV database (Stanford, IAS-USA) then report made which tells which resistance mutations are present

62. Phenotypic Testing
Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs
RT, PR gene sequences and integrase derived from patient plasma HIV RNA are inserted into the backbone of a laboratory clone of HIV
Replication of these viruses at different drug concentrations are monitored

63. Phenotypic testing Phenotypic Testing
Phenotypic resistance is reported as “fold” resistance. If the test sample grows twenty times as much as normal, it has “20-fold resistance”
Automated phenotypic assays that can produce results in 2 to 3 weeks are commercially available, but they cost more

64. Limitation of drug resistance testing
Resistant assay only measures the dominant species
Sample should have sufficient viral load (> 1000 copies/ml)
Testing should be done in presence of ARV drug in question
Interpretation of results in patients who have multiple regimen changes is difficult
Limitations of both genotypic and phenotypic assay
lack of uniform quality assurance testing for all available assays
relatively high cost
Drug-resistant viruses that constitute less than 10% to 20% of the circulating virus population will probably not be detected by commercially available assays

65. PHENOTYPIC VS GENOTYPIC ASSAYS

66. Choice of assays Genotypic testing
Preferred when virologic failure occurs while on HAART.
Both genotypic and phenotypic testing
Preferred when complex drug resistance mutation pattern is suspected involving more than one class of drugs.
Esp in suspects of multiple PI mutations
(Accessed on January 25, 2011).

67. Drug Resistance testing Recommendations
RECOMMENDED
COMMENT
Acute HIV infection, regardless of whether treatment is to be started
To determine if resistant virus was transmitted; guide treatment decisions.
If treatment is deferred, consider repeat testing at time of ART initiation.
Genotype preferred.
Chronic HIV infection, at entry into care
Transmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection.
If treatment is deferred, consider repeat testing at time of ART initiation. Genotype preferred to phenotype.
Consider integrase genotypic resistance assay if integrase inhibitor resistance is a concern.

68. Drug Resistance Testing: Rcommendations (2)
Drug Resistance testing Recommendations
Drug Resistance Testing: Rcommendations (2)
RECOMMENDED
COMMENT
Virologic failure during ART
To assist in selecting active drugs for a new regimen.
Genotype preferred if patient on 1st or 2nd regimen; add phenotype if known or suspected complex drug resistance pattern.
If virologic failure on integrase inhibitor or fusion inhibitor, consider specific genotypic testing for resistance to these to determine whether to continue them.
(Coreceptor tropism assay if considering use of CCR5 antagonist; consider if virologic failure on CCR5 antagonist.)
Suboptimal suppression of viral load after starting ART
To assist in selecting active drugs for a new regimen.

69. Drug Resistance Testing: Recommendations (3)
RECOMMENDED
COMMENT
Pregnancy
Recommended before initiation of ART or prophylaxis.
Recommended for all on ART with detectable HIV RNA levels.
Genotype usually preferred; add phenotype if complex drug resistance mutation pattern.

70. Drug Resistance Testing: Recommendations (4)
NOT USUALLY RECOMMENDED
COMMENT
After discontinuation (>4 weeks) of ARVs
Resistance mutations may become minor species in the absence of selective drug pressure.
Plasma HIV RNA <500 copies/mL
Resistance assays cannot be performed consistently if HIV RNA is low.

71. Definitions of Virologic Response
Virological response
Definitions of Virologic Response
Virologic suppression:
Confirmed HIV RNA below LLOD (eg, <50 copies/mL)
Virologic failure:
Inability to achieve or maintain HIV RNA <200 copies/mL
Incomplete virologic response:
Confirmed HIV RNA ≥200 copies/mL after 24 weeks on ART
Virologic rebound:
Confirmed HIV RNA ≥200 copies/mL after virologic suppression
Virologic blip:
An isolated detectable HIV RNA level that is followed by a return to virologic suppression

72. Def of treatment failure
Clinical failure
New or recurrent WHO stage 4 condition, after at least 6 months of ART
Immunological Failure
Fall of CD4 count to pre-therapy baseline (or below)
50% fall from the on-treatment peak value (if known)
Persistent CD4 levels below 100 cells/mm
Virological failure
Plasma viral load > 10,000 copies/mL
WHO Guidelines on Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a public health approach Revision

73. Clinical Correlation with CD4 counts
Infection
Non infectious
>500/cumm
Cd. vaginitis
PGL, GBS, polymyositis
Ba pneumonia
Pul Tb
H zoster
Oral candida
Hairy leucoplakia
Cervical cancer
Myopathy
Anaemia
ITP
<200
PCP,HSV
cd. Esophagitis
Toxoplasmosis
PML
Miliary & extrapulm TB
Wasting
Bcell lymphoma
Cardiomyopathy
PER neuro
CNS lymphoma
<50
CMV
MAC

74. Virologic Failure: Management
Drug failure- management
Virologic Failure: Management
General principles of selecting new ART:
New regimen should contain at least 2 (preferably 3) fully active agents
In general, 1 active drug should not be added to a failing regimen (drug resistance is likely to develop quickly)
Consult with experts

75. Drug failure- Management
Clinical scenario
Reccommendation
LLOD-<200 copies/mL
Transient blips- no change required
Persistent RNA between LLOD and 200: low risk of new resistance; monitor at least every 3 months
Persistent HIV RNA >200 to <1,000 copies/mL
Resistance is likely to develop; do resistance test if possible, consider ART change according to results
HIV RNA >1,000 copies/mL and no resistance identified
assess for drug-drug and drug-food interactions
Restart same regimen or start new ART
HIV RNA >1,000 copies/mL and drug resistance
Change regimen early to prevent further resistance

76. Clinical failure- Management
Clinical scenario
Recommendation
Failure of NNRTI + NRTIs
Often resistance to NNRTI +/– 3TC and FTC
Boosted PI + NRTIs or RAL often effective
Failure of boosted PI + NNRTIs
No resistance or resistance only to 3TC/FTC
Assess adherence and drug interactions, may continue same ART
Failure of INSTI + NRTIs
May have resistance to 3TC/FTC +/- INSTI resistance
Consider boosted PI + NRTIs or an INSTI
Consider regimen with boosted PI + DTG if testing predicts susceptibilty to DTG

77. Virological failure- Management
Second line failure
Drug resistance with treatment options that allow full virologic suppression
If fully active boosted PI is available:
Boosted PI + NRTIs or INSTI (if susceptible to INSTI)
If no fully active boosted PI:
Regimen should include at least 2 (preferably 3) fully active agents, if possible
Select ARVs that are likely to be active based on ART history, past and present resistance tests, tropism testing (if CCR5 antagonist is considered)

78. Take home message

79. Thank you