Highly Active Antiretroviral Therapy (HAART) involves using a combination of at least three antiretroviral drugs to suppress the HIV virus and stop the progression of HIV disease. HAART decreases the viral load, improves immune function, and prevents opportunistic infections. The goals of HAART are to prolong life, improve quality of life, maximize viral suppression, and reconstitute the immune system. Current guidelines recommend starting HAART for all HIV patients regardless of CD4 count. Proper counseling, adherence, monitoring, and management of side effects are important for the success of HAART.

1. D R A B H I S H E K K G U P T A
Highly Active Antiretroviral
Therapy (HAART)

2. Introduction
 The use of multiple drugs that act on different viral
targets is known as highly active antiretroviral
therapy (HAART)
 HAART decreases the patient's total burden of HIV,
maintains function of the immune system, and
prevents opportunistic infections that often lead to
death

3. History
 The first effective therapy against HIV was the nucleoside
reverse transcriptase inhibitor (NRTI) zidovudine (AZT)
 To distinguish from this early anti-retroviral therapy (ART),
the term highly active anti-retroviral therapy (HAART) was
introduced
 Hammer and colleagues and Gulick and co-
investigators illustrating the substantial benefit of
combining 2 NRTIs with a new class of anti-
retrovirals, protease inhibitors, namely indinavir. This
concept of 3-drug therapy was quickly incorporated into
clinical practice and rapidly showed impressive benefit with
a 60% to 80% decline in rates of AIDS, death, and
hospitalization.

4. Goals of Antiretroviral Therapy
 The currently available ARV drugs cannot eradicate
the HIV infection from the human body
Clinical goals : Prolongation of life and improvement
in quality of life
Virological goals : Greatest possible reduction in
viral load for as long as possible
Immunological goals : Immune reconstitution that is
both quantitative and qualitative
Reduction of HIV transmission in individuals :
Reduction of HIV transmission by suppression of
viral load

5.  Therapeutic goals : Rational sequencing of drugs in a
fashion that achieves clinical, virological and
immunological goals while maintaining treatment
options, limiting drug toxicity and facilitating
adherence

6. Clinical Staging of HIV

9. Current guidelines: when to start ART
 Current US DHHS guidelines (published April 8,
2015) state:
Antiretroviral therapy (ART) is recommended for all
HIV-infected individuals to reduce the risk of disease
progression.
AIDS-defining condition
 Pregnancy
Symptomatic from HIV including any of the
following:
1. HIV-associated neurocognitive disorder (HAND)

10. 2. Severe thrombocytopenia
3. HIV-associated nephropathy
4. HIV-related malignancies
5. Chronic hepatitis B or C infection and,
6. Age 50 or older
Patients with seronegative partners should be
counselled
Decisions to initiate ART should be individualized,
particularly for long-term nonprogressors or and for
patients with potential barriers to adherence

11. Current World Health Organization guidelines
(dated June 30, 2013)
 Initiate ART if CD4 cell count ≤500 cells/ml
 • As a priority, initiate ART in all individuals with
severe/advanced HIV disease (WHO clinical stage 3 or 4)
or CD4 count ≤ 350 cells/mm
 Initiate ART regardless of WHO clinical stage or CD4 cell
count in
 • Active TB disease
 • HBV co-infection with severe chronic liver disease
 • Pregnant and breastfeeding women with HIV
 • HIV-positive individual in a serodiscordant partnership
(to reduce HIV transmission risk)

12. When to start ART in Adults and Adolescents
WHO Clinical Stage WHO Clinical Stage
HIV infected Adults & Adolescents (Including pregnant women)
Clinical Stage I and II Start ART if CD4 < 350 cells/mm3
Clinical Stage III and IV Start ART irrespective of CD4 count
For HIV and TB co-infected patients
Patients with HIV and TB co-infection
(Pulmonary/ Extra-Pulmonary)
Start ART irrespective of CD4 count
and type of tuberculosis (Start ATT
first, initiate ART as early as possible
between 2 weeks to 2 months when TB
treatment is tolerated)
For HIV and Hepatitis B and C co-infected patients
-Without any evidence of chronic
active Hepatitis
Start ART if CD4 < 350 cells/mm3
-With documented evidence of chronic
active Hepatitis
Start ART irrespective of CD4 count

13. Counseling and Education Before
Initiating ART
 RECOMMENDATIONS: Counselling and education
should include the following:
Basic education about HIV, CD4 cells, viral load, and
resistance
Available treatment options and potential risks and
benefits of therapy
The need for strict adherence to avoid the
development of viral drug resistance
Use of safer-sex practices and avoidance of needle-
sharing activity, regardless of viral load, to prevent
HIV transmission or super-infection

14. BENEFITS AND RISKS OF EARLY ART IN
ASYMPTOMATIC HIV-INFECTED PATIENTS
 Early therapy = initiation at CD4 counts >500
cells/mm3 )
 Benefits of early therapy
Earlier treatment reduces both HIV-related and non-
HIV-related morbidity and mortality
Delay or prevention of immune system compromise
Possible lower risk of antiretroviral resistance
Decreased risk of sexual transmission of HIV

15. Disadvantages of early therapy
Potential drug-related reduction in quality of life in
otherwise asymptomatic individuals
Possibility of greater cumulative side effects from
ART
Possibility for earlier development of drug resistance
and limitation in future antiretroviral options if
adherence and viral suppression are suboptimal
 Possibility for earlier onset of treatment fatigue
 Higher prescription drug costs for the individual

16. Potential barriers to adherence include:
Communication difficulties that arise when the
patient’s attitude about disease and therapy is
different from that of the provider’s. Without open
and nonjudgmental communication from the
healthcare team, patients may not trust or may
misunderstand the prescribed regimen
Language or literacy barriers
Unstable living situations (including limited or absent
social support)
Discomfort with disclosure of HIV status, which may
become known when medications are taken

17. Inability to set long-term goals
Inadequate knowledge about disease and
effectiveness of medications or healthy living,
including a patient’s lack of belief in his/her ability
to take medications regularly
Difficulty accessing adequate healthcare
Housing, food, lack of childcare, or other immediate
life needs, which are viewed as more pressing than
taking the medications regularly

18. Monitoring

19. VIROLOGIC AND IMMUNOLOGIC MONITORING FOR NON-PREGNANT PATIENTS
HIV RNA Levels
(copies/mL)
CD4 Lymphocyte Count
(cells/mm3 )
Baseline
All patients Yes Yes
Treatment Monitoring
Following: (1) initiation
of ART or (2) a change in
ART regimen after
virological failure with
new resistance to prior
ART
Within 4 weeks of
initiation of ART or
change in regimen.
At least every 8 weeks
until complete
suppression is
documented
Repeat at 12 weeks and
then every 4 months until
CD4 >200 cells/mm3 on
two measurements
obtained at least 4 months
apart, then monitor as
below once suppressed
Following a change in
ART to simplify
treatment regimen or
reduce toxicity for
patients with suppressed
virus
Within 4 weeks after
change in regimen
Monitor as below for
suppressed

20. Patients on ART who
achieve complete
suppression
At least every 4 months
after complete
suppression .
May extend intervals to
every 6 months in
selected stable patients
with CD4 counts >200
cells/mm3 after 1 year
of complete suppression
If CD4 300 to 500
cells/mm3 :At least
every 6 months .
If CD4 >300 to 500
cell/mm3:At least every
12 months.
If CD4 >500 cells/mm3
:further monitoring is
optional
Patients Not on ART:
all HIV-infected
patients should be
offered ART regardless
of CD4 count
If CD4 ≤500 cells/mm3:
At least every 4 months
If CD4 >500 cells/mm3:
At least every 6 months
If CD4 ≤500
cells/mm3: At least
every 4 month.
If CD4 >500 cells/mm3:
At least every 6 month

21. HIV Resistance Assays
 Clinicians should perform resistance testing under
the following circumstances:
 At baseline, regardless of whether ART is being
initiated (genotypic testing)
 In patients experiencing treatment failure or
incomplete viral suppression while receiving ART
(genotypic and/or phenotypic testing)
 Genotypic assays detect mutations in the genes of the
reverse transcriptase and protease enzymes, as well
as the gp41 domain for the currently available fusion
inhibitors

22.  Phenotypic assays directly measure susceptibility of
the patient’s HIV strain to specific individual drugs
compared to sensitive HIV

23. Classes of drugs
 There are five classes of drugs, which are usually used
in combination, to treat HIV infection
1. Nucleoside reverse transcriptase inhibitors
(NRTI) and nucleotide reverse transcriptase
inhibitors (NtRTI)- are nucleoside and nucleotide
analogues which inhibit reverse transcription. HIV is
an RNA virus and hence unable to become integrated
into the DNA in the nucleus of the human cell; it
must be "reverse" transcribed into DNA. Since the
conversion of RNA to DNA is not done in the
mammalian cell it is performed by a viral protein
which makes it a selective target for inhibition.

24.  NRTIs are chain terminators such that once
incorporated, work by preventing other nucleosides
from also being incorporated into the DNA chain
because of the absence of a 3’ OH group. Both act
as competitive substrate inhibitors. Examples of
currently used NRTIs includes Zidovudin, Abacavir,
Lamivudine, Emtricitabine and tenofavir.
2. Non-Nucleoside reverse transcriptase
inhibitors (NNRTI)- Inhibit reverse
transcriptase by binding to an allosteric site of the
enzyme; NNRTIs act as non-competitive
inhibitors of reverse transcriptase

25.  NNRTIs can be further classified into 1st generation and
2nd generation NNRTIs.
 1st generation NNRTIs include Nevirapine and
Efavirenz.
 2nd generation NNRTIs are Etravirine and Rilpivirine.
HIV-2 is naturally resistant to NNRTIs.
3. Protease inhibitors- block the viral protease enzyme
necessary to produce mature virions upon budding
from the host membrane. Particularly, these drugs
prevent the cleavage of gag and gag/pol precursor
proteins

26.  Examples of HIV protease inhibitors are Lopinavir,
Indianavir, Nelfinavir, Amprenavir and Ritonavir.
 Darunavir and Atazanavir are currently recommended
as first line therapy choices.
 Resistance to some protease inhibitors is high.
4. Integrase inhibitors (also known as integrase
nuclear strand transfer inhibitors or INSTIs)-
Raltegravir became the first to receive FDA
approval in October 2007. As of early 2014, two
other clinically approved integrase inhibitors
are elvitegravir and dolutegravir.

27.  Entry inhibitors- (or fusion inhibitors) interfere
with binding, fusion and entry of HIV-1 to the host
cell. Maraviroc and enfuvirtide are the two currently
available agents in this class.
 Maraviroc works by targeting CCR5, a co-receptor
located on human helper T-cells.
 Enfuvirtide is a peptide drug that must be injected
and acts by interacting with the N-terminal heptad
repeat of gp41 of HIV to form an inactive hetero six-
helix bundle, therefore preventing infection of host
cells.

28. Regimens
 Most current HAART regimens consist of three drugs:
2 NRTIs ("backbone")+ a PI/NNRTI/INSTI ("base").
Initial regimens use "first-line" drugs with a high efficacy
and low side-effect profile.
 The US DHHS preferred initial regimens for adults and
adolescents in the United States, as of April 2015, are:
 tenofovir/emtricitabine and raltegravir (an integrase
inhibitor)
 tenofovir/emtricitabine and dolutegravir (an integrase
inhibitor)
 abacavir/lamivudine (two NRTIs) and dolutegravir for
patients who have been tested negative for the HLA-
B*5701 gene allele

29. tenofovir/emtricitabine, elvitegravir (an integrase
inhibitor) and cobicistat (inhibiting metabolism of
the former) in patients with good kidney function
(gfr > 70)
tenofovir/emtricitabine, ritonavir,
and darunavir (both latter are protease inhibitors)
 The WHO preferred initial regimen for adults and
adolescents as of June 30, 2013 is:
tenofovir + lamivudine (or emtricitabine) + efavirenz

30. For Children
 The WHO & DHHS recommends for children less
than 3 years:
abacavir (or zidovudine) + lamivudine + lopinivir/
ritonivir
 For children 3 years to less than 10 years and
adolescents <35 kilograms:
abacavir + lamivudine + efavirenz

31. In India- by NACO
 Zidovudin + lamivudine + Nevirapine/efavirenz.
 Tenofovir + lamivudine + Nevirapine/efavirenz.
 Zidovudin + lamivudine + Atazanavir/Ritonavir
 Zidovudin + lamivudine + Lopinavir/Ritonavir

32. Adverse events

38. How to manage adverse events

43. Do not start ART in the presence of an active OI. In
general, OIs should be treated or stabilized before
commencing ART. Mycobacterium avium complex
(MAC) and progressive multifocal
leukoencephalopathy (PML) are exceptions, in
which commencing ART may be the preferred
treatment.
Manage OIs before Starting
ART

46. ART in Pregnant women

48. HIV and Hepatitis Co-infection
 HIV modified the natural history of HBV infection,
higher rate of progression to advance liver disease
among co infection.
 Choice of ART- ARV with anti HBV activity such as
3TC and TDF
 First line regime- TDF + 3TC +EFV
 Alternative – AZT+ 3TC+EEV
 No ARV drugs are active against HCV infection , but
they decline the progression

49. ART Treatment Failure and
when to switch

51. Second line regime
 A second-line regimen should be recommended only
by CoE/ ART plus Centre.
 When failure has been identified clinically or
immunologically, many patients can be expected to
have significant NRTI resistance at the time of
switching
 Cross resistance exists between d4T and AZT; thus
NRTI-component in the second-line regimens should
be either ddI/ABC or TDF/ABC.
 High level AZT/3TC resistance reduces susceptibility
to ABC.

52.  NNRTI (such as EFV and NVP): usually there is
complete cross-resistance

53. Management algorithm

56. Final words
 HIV care requires, as always, partnerships and open
communication. The provider can make
recommendations most likely to lead to positive
outcomes only if the patient's own point of view and
social context are well known.
 Guidelines are only a starting point for medical
decision making. They can identify some of the
boundaries of high-quality care but cannot substitute
for sound judgment.