3. Antiretroviral Therapy (ART)
AIDS ( Acquired immuno-deficiency syndrome) is a fatal
disease, caused by human immuno-deficiency virus (HIV),
which breaks down the body’s immune system, leaving the
patient vulnerable to a host of life-threatening opportunistic
infections, neurological disorders or malignancies.
If a person infected once, he will remain infected for life.
AIDS is called Modern Pandemic, as it affecting both developed
and developing countries.
4. At present there is no vaccine or cure for HIV infection/AIDS.
So, HIV can be control by either prevention i.e. by education
and prevention of blood-borne viral transmission or by
antiretroviral treatment (ART).
Antiretroviral therapy (ART) are the combination of drugs
which suppress the HIV infection, but not cure it, and proved
to be useful in prolonging the life of severely ill AIDS patients
and it also improves the quality of life of HIV infected patients.
But adequate suppression requires strict adherence to
antiretroviral therapy.
5. Goals of Antiretroviral Therapy
1) To achieve maximal and durable virological suppression
(ideally a viral load < 50 copies/ml).
2) To reconstitute and preserve immunologic function.
3) To reduce morbidity and mortality, associated with both HIV
infection and use of antiretroviral drugs (ARVs).
4) To improve quality of life.
5) To prevent sexual transmission of HIV.
7. Why Initiate ART Early ?
Better survival.
Potent, durable and convenient regimens are readily available.
Decrease risk of non-AIDS defining complications.
Prevent neurocognitive decline.
Reduce immune activation, inflammation.
Greater likelihood of CD4 normalization.
Lesser risk of development of IRIS.
Lesser likelihood of developing ARV resistance.
Lesser risk of development of toxicities.
Prevention of transmission.
Cost-effective.
8. When should ART be Initiated in the setting of
an Acute Opportunistic Infections (OI) ?
Most Opportunistic Infections: as soon as possible.
Cryptococcal meningitis: 4-6 weeks after initiation of anti-
fungal treatment.
Tuberculosis (TB)
CD4<50/mm3: Around 2 weeks of initiation of anti-TB
treatment.
CD4>50/mm3: Around 8 weeks of initiation of anti-TB
treatment.
CNS Opportunistic Infections
May be delayed until clinical stabilization.
Careful monitoring for Immune Reconstitution Inflammatory
Syndrome (IRIS).
9. Assessing Patient Readiness Prior to Initiating ART
Before starting the ART to a patients, the following issues should
be discussed :
Availability of treatment in the free ART program,
Affordability (referral to free ART program if long term
affordability suspect),
Conceptual understanding of treatment and it’s benefits,
The importance of high level lifelong adherence to drugs and
the consequences of sub-optimal adherence (more expensive
second-line regimens, progression of clinical disease) and
The need to address alcohol abuse
Treatment should be initiated only after ensuring that patient has
understood the consequences of initiating and being on lifelong
treatment.
10. Baseline Evaluation
History and physical examination
The patient’s comorbid conditions (e.g., cardiovascular disease
[CVD], chemical dependency, liver or renal disease, psychiatric
illnesses, or tuberculosis [TB])
Routine chemistry and hematology
HIV antibody testing (if prior documentation is not available or if
HIV RNA is below the assay’s limit of detection)
Liver function test
Lipid profile and blood glucose
CD4+ T-lymphocyte count
Plasma HIV RNA level (viral load)
HIV resistant testing
HLA-B5701 screening
RPR or VDRL testing
11. Anti-toxoplasma antibody titer
PPD skin testing
Serology for hepatitis A, hepatitis B and hepatitis C
Immunization with pneumococcal polysaccharide; influenza as
indicated.
Immunization with hepatitis A and hepatitis B if seronegative.
Counseling regarding natural history and transmission.
Help contacting others who might be infected.
13. Choice of First Line Regimen
Preferred :
Efavirenz/Tenofovir /Emtricitabine or Nevirapine
(EFV/TDF/FTC or NVP)
Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV)
Acceptable :
Zidovudine/Lamivudine/Efavirenz or Nevirapine
(AZT/3TC/EFV or NVP)
Consider (only in special situations) :
Abacavir/Lamivudine/Efavirenz (ABC/3TC/EFV)
Didanosine/Lamivudine/Efavirenz (ddl/3TC/EFV)
14. Doses of commonly used ARVs
DRUG
DOSE
Zidovudine (AZT)
300 mg bd
Lamivudine (3TC)
150 mg bd OR 300 mg od
Didanosine (ddl)
200 mg bd (BW>60 kg), 125 mg bd
(BW<60 kg)
Abacavir (ABC)
300 mg bd OR 600 mg od
Emtricitabine (FTC)
200 mg od
Efavirenz (EFV)
600 mg od
Nevirapine (NVP)
200 mg od, increase later to 200 mg bd
Tenofovir (TDF)
300 mg od
Ritonavir (r)
600 mg bd; as boosted dose 100 mg
15. Efavirenz is preferred over NVP when concomitant use of
rifampicin is indicated, patients preference for once daily
(lower pill burden) regimen and if pre-therapy CD4 count is
>250/mm3 and >400/mm3 in women and men respectively.
Nevirapine is preferred over EFV in women planning pregnancy
and those with underlying severe psychiatric illness.
16. TDF/FTC is the preferred backbone because it has similar
virological response as compared to AZT/3TC but has been
associated with lower toxicity particularly in women, low pill
burden (one pill once a day when combined with EFV), better
sequencing options after failure of first-line
regimen, concomitant treatment of underlying undiagnosed
HBV infection and has been proven to be cost effective in an
analysis in India.
AZT/3TC is a powerful backbone and preferred in women who
plan pregnancy/or are pregnant but has been associated with
higher short term hematological and long term morphologic
and metabolic toxicities.
Stavudine should be avoided because of long term toxicity
concerns that are often irreversible.
17. Clinical situations for use of Protease Inhibitors in first-line
regimens :
HIV-2 or HIV-1/HIV-2 infection.
Pregnancy with CD4>250/mm3.
Sub-optimal NRTI use in the past (e.g. 2NRTIs)
Exposure to NVP in pregnancy (especially within 1 year of
receipt).
Dual toxicity to NVP and EFV.
21. The utility of virological monitoring has been debated. Few
recent studies have documented better outcomes amongst
programs offering routine viral load monitoring versus not
offering the same.
22. Complications in the use of ART
1. Immune Reconstitution Inflammatory Syndrome (IRIS)
:
It is a paradoxical worsening of pre-existing, untreated or
partially treated opportunistic infections or exacerbations of
pre-existing or development of new autoimmune
conditions, after initiation of ART.
It occurs due to inflammatory response to pre-existing clinical
or sub-clinical pathogens or nonpathogenic antigens.
It occurs in 10 – 30% of patients, especially in when CD4+ T cell
count is <50 cells/µl and initiating ART closer to starting of OI
treatment.
23. It is of two types : First, paradoxical IRIS is the worsening of
well controlled underlying infection; Second, unmasking IRIS
is the occurrence of new manifestations in a patient apparently
well prior to initiation of ART
Signs and symptoms appears within 2 weeks to 2 years after
initiation of ART, which includes localised lymphadenitis,
prolonged fever, pulmonary infiltrates, increased intracranial
pressure, uveitis, sarcoidosis and grave’s disease.
No clear strategies exist for management of IRIS, however 4
weeks of steroids (1.5 mg/kg/day for 2 weeks followed by 0.75
mg/kg/day for 2 weeks) has been found to be effective, while
specific antimicrobial therapy is more effective.
29. 3. ART-Related Drug Interactions :
Anticonvulsants : Avoid prescribing carbamazepine,
phenobarbital, and phenytoin for patients receiving nonnucleoside reverse transcriptase inhibitors (NNRTIs) or PIs.
Levetiracetam may be considered.
Antifungal Drugs : Avoid or use caution when combining
voriconazole with the NNRTIs or unboosted PIs.
Fluconazole decrease Nevirapine clearance by 2 folds.
Monitor LFT closely when co-administered.
Antimycobacterial Drugs : Not to use rifampin with any PIs.
Give rifabutin with proper dose adjustment.
30. Antihypertensive drugs : Calcium channel blockers level
increases with protease inhibitors, careful monitoring is
advised when co-administered.
Lipid-Lowering Agents :
Lovastatin and simvastatin are contraindicated with all PIs and
delavirdine (DLV).
Pravastatin is the safest drug for treating hyperlipidemia
during concurrent PI therapy.
Atorvastatin can be used cautiously at lower doses (5 to 10 mg)
with careful titration.
Rosuvastatin can be used at lower doses (5 mg) with careful
titration.
Fibric acid derivatives can be used in recommended dosage.
31. Oral Contraceptives : Use caution when prescribing oral
contraceptives for patients receiving ART because of the
variations in effect on ethinyl estradiol levels.
Women who are taking efavirenz, nevirapine,
lopinavir/ritonavir, nelfinavir, ritonavir, tipranavir/ritonavir,
darunavir/ritonavir, or saquinavir to use alternate or
additional forms of birth control.
Sedative/Hypnotics : Not to prescribe midazolam or triazolam
for patients receiving PIs.
Lorazepam or oxazepam may be considered.
Herbal Therapy : All herbal products should be used with
caution.
32. When to change ART?
Substitution (Only after confirmed virological suppression) :
Toxicity (e.g. TDF for AZT anemia)
Simplification (e.g. bid to qd regimens)
Cost (e.g. from EFV to NVP)
Drug-Drug interaction (e.g. from NVP to EFV when initiating
rifampicin)
Pregnancy (e.g. from EFV to NVP)
Proactive (e.g. from d4T to TDF)
Switching : For ART failure.
33. ART failure
Virological failure :
Rebounders: Confirmed re-emergence of virus (defined as viral
load>1000 copies/ml) after virological suppression.
Non-responders: Inability to achieve virological suppression
after initiation of ART (defined as VL<400 copies at 6 months
and <50 copies/ml at 12 months).
Immunologic failure (patients not monitored on viral
load) :
Confirmed >30% drop in CD4 count from peak value.
Non-improvement in CD4 count>100 cells in the first year of
initiating or changing ART.
34. Clinical failure (patients not monitored on viral load ):
Development of new AIDS defining condition 3 months after
initiation or change in ART regimen.
Virological monitoring is critical to identify failure early.
The disadvantage of immunologic/clinical monitoring is late
identification of failure causing increased accumulation of
drug resistant mutations that can compromise efficacy of
future regimens.
35. Choice of second-line regimens : Genotypic resistance testing has to
be performed when the patient is on or within 2 weeks of
discontinuation of a failing regimen as its better predictor of resistance
than expert opinion alone.
36. ART in Special Situations
1. HIV and pregnancy :
Goal : Treat the mother’s HIV infection.
Prevent mother-to-child transmission of HIV.
Pregnancy is an indication to initiate ART irrespective of
mothers CD4/VL status.
Nevirapine is contraindicated amongst women with pretherapy CD4 count > 250 mm3.
Discontinuation of ART after delivery when the mother does
not need ART for her own health may be associated with
higher risk of clinical progression and development of
resistance.
Therapy may be continued after delivery and simplified to
NNRTI based first-line regimens if the mother is virologically
suppressed.
38. 2. HIV and Tuberculosis (TB) :
Antiretroviral therapy is indicated for all TB patients irrespective of
CD4/PVL status.
For patients with CD4<50/mm3 ART should be initiated around 2
weeks of starting anti-TB treatment.
For patients with CD4>50/mm3, ART may be delayed until 8 weeks of
anti-TB treatment.
For CNS TB ART initiation may be deferred until 4-8 weeks after
starting ATT.
A rifampicin (RMP)/rifabutin (RBT) based regimen is necessary
throughout the duration of anti-TB treatment as it has better
outcomes (failure and relapse) apart from shortening the duration of
TB treatment.
Ethambutol should be included in the maintenance phase as the
prevalence of primary INH resistance is high in India.
Daily treatment (rather than intermittent) throughout the course of
TB treatment is more effective in preventing treatment failure and
relapse rates.
40. 3. HIV and Hepatitis Co-infection :
HIV with HBV co-infection
Antiretroviral therapy is indicated for all HIV-infected
patients who need HBV treatment irrespective of CD4 counts
or HBV DNA/ALT levels.
Choice of ARVs
First-Line : Tenofovir/Emtricitabine or
Tenofovir/lamivudine
(Adefovir can be added if needed)
Second-line : maintain Tenofovir in the regimen, e.g.
Tenofovir/Zidovudine/Protease Inhibitors.
41.
HIV and HCV co-infection :
Chronic HCV infection is an indication to initiate ART
irrespective of the CD4/VL status.
Choice of ARV
Preferred : Telaprevir or Boceprevir
• Avoid :
Zidovudine : Additive Bone marrow toxicity (with Interferon
and ribavirin).
Stavudine : higher incidence of lactic acidosis.
Didanosine : interaction with ribavirin and hepatic
decompensation.
Abacavir : Lower response, probably related to antagonism
with ribavirin (both are guanosine analogs).
42. Post-exposure Prophylaxis of HIV
Comprehensive management given to minimize the risk of
infection following potential exposure to blood-borne
pathogens e.g. HIV.
This includes:
1. First aid
2. Counseling
3. Risk assessment
4. Relevant laboratory investigations based on informed
consent of the source and exposed person.
5. Depending on the risk assessment, the provision of short
term (4 weeks) of antiretroviral drugs.
6. Follow up and support
44. Post-exposure prophylaxis (PEP) has its greatest effect if begun
within 2 hours of exposure, it is essential to act immediately.
There is little benefit if >72 hours later.
The prophylaxis needs to be continued for 4 weeks (28 days).
Preferred PEP regimen : Tenofovir 300 mg PO qd +
Emtricitabine 200 mg PO qd + Raltegravir 400 mg PO bid.
(Lamivudine 300 mg PO qd may be substituted for
Emtricitabine)
Alternative regimen : Zidovudine 300mb bd + Lamivudine
150mg bd OR Stavudine 30mg bd + Lamivudine 300mg bd.
45. Follow-up of an exposed person :
Clinical follow-up : the exposed person must be monitored
for the eventual appearance of signs indicating an HIV
seroconversion: acute fever, generalized lymphadenopathy,
cutaneous eruption, pharyngitis, non-specific flu symptoms
and ulcers of the mouth or genital area. These symptoms
almost always appears within 3 to 6 weeks after
exposure.
Laboratory follow-up : after exposure testing at 3 months
and 6 months is recommended.
46. References
1. Antiretroviral Therapy – Evidence based Treatment
Options in 2012, HIV Medicine Association of India.
(www.hivmai.org)
2. Guidelines for the Use of Antiretroviral Agents in
HIV Infected Adults and Adolescents,2013.
(http://aidsinfo.nih.gov/guidelines)