The document discusses the history and management of HIV/AIDS. It describes the early treatments for HIV/AIDS and the development of highly active antiretroviral therapy (HAART). It then discusses the symptoms of HIV/AIDS and how the virus destroys CD4+ T cells. It provides details on diagnosing HIV and the replication cycle of the virus. The remainder of the document outlines the different classes of antiretroviral drugs used to treat HIV, including entry inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. It also discusses initiating antiretroviral therapy and considerations for special populations such as children,

1. Management of HIV/AIDS
Asim Raza Rph

2. History of HIV/AIDS
 The first effective therapy against HIV was the
nucleoside reverse transcriptase inhibitor (NRTI)
zidovudine (AZT). It was approved by US FDA in
1987.subsequently several more NRTIs were
developed but even in combination were unable to
suppress the virus for long periods of time and
patients still inevitably died. To distinguish from this
early anti-retroviral therapy (ART), the term highly
active anti-retroviral therapy (HAART) was
introduced.

3. HIV/AIDS Symptoms
 Many people do not develop symptoms after getting
infected with HIV. Others have a flu-like illness within
several days to weeks after exposure to the virus. They
complain of fever, headache, tiredness, and enlarged lymph
glands in the neck. These symptoms usually disappear on
their own within a few weeks. During this period, the virus
continues to multiply actively and infects and kills the cells
of the immune system. The immune system allows us to
fight against the bacteria, viruses, and other infectious
causes.
 The virus destroys the cells that are the primary infection
fighters, called CD4+ or T4 cells

4. Once the immune system weakens, a person
infected with HIV can develop the following
symptoms:
 Lack of energy
 Weight loss
 Frequent fevers and sweats
 Persistent or frequent yeast infections
 Persistent skin rashes or flaky skin
 Short-term memory loss
 Mouth, genital, or anal sores from herpes
infections.

5.  Cough and shortness of breath
 Seizures and lack of coordination
 Difficult or painful swallowing
 Mental symptoms such as confusion and forgetfulness
 Severe and persistent diarrhea
 Fever
 Vision loss
 Nausea, abdominal cramps, and vomiting
 Weight loss and extreme fatigue
 Severe headaches with neck stiffness
 Coma

6. Diagnosis
 Many HIV-positive people are unaware that they areHIV-1
testing is initially by an enzyme-linked immunosorbent assay
(ELISA) to detect antibodies to HIV-1. Specimens with a
nonreactive result from the initial ELISA are considered HIV-
negative unless new exposure to an infected partner or partner
of unknown HIV status has occurred. Specimens with a reactive
ELISA result are retested in duplicate. If the result of either
duplicate test is reactive, the specimen is reported as
repeatedly reactive and undergoes confirmatory testing with a
more specific supplemental test (e.g., Western blot or, less
commonly, an immunofluorescence assay (IFA)) infected with
the virus.

7.  Only specimens that are repeatedly reactive by
ELISA and positive by IFA or reactive by Western
blot are considered HIV-positive and indicative of
HIV infection. Specimens that are repeatedly
ELISA-reactive occasionally provide an
indeterminate Western blot result, which may be
either an incomplete antibody response to HIV in
an infected person or nonspecific reactions in an
uninfected person

8. HIV Replication Cycle

9. Entry to the Cell
 HIV enters macrophages and CD4+ T cells by the
adsorption of glycoproteins on its surface to receptors on
the target cell followed by fusion of the viral envelope with
the cell membrane and the release of the HIV capsid into
the cell.
 Entry to the cell begins through interaction of the trimeric
envelope complex (gp160 spike) and both CD4 and a
chemokine receptor (generally either CCR5 or CXCR4, but
others are known to interact) on the cell surface. gp120
binds to integrin α4β7 activating LFA-1 the central integrin
involved in the establishment of virological synapses, which
facilitate efficient cell-to-cell spreading of HIV-

10. Classes of Drugs
 There are five classes of drugs, which are usually used
in combination, to treat HIV infection. Use of these
drugs in combination can be termed anti-retroviral
therapy (ART), combination anti-retroviral therapy
(cART) or highly active anti-retroviral therapy
(HAART). Anti-retroviral (ARV) drugs are broadly
classified by the phase of the retrovirus life-cycle that
the drug inhibits. Typical combinations include 2
NRTIs as a "backbone" along with 1 NNRTI, PI or
INSTI as a "base.

11. 1.Entry Inhibitors
 Entry inhibitors (or fusion inhibitors) interfere with
binding, fusion and entry of HIV-1 to the host cell by
blocking one of several targets. Maraviroc and
enfuvirtide are the two currently available agents in t.
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
cellshis class. Maraviroc works by targeting CCR5, a
co-receptor located on human helper T-cells

12. 2.Nucleoside reverse transcriptase
inhibitors (NRTI) and nucleotide reverse
transcriptase inhibitors (NtRTI)
 These 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. NRTIs are chain terminators such that once
incorporated, work bypreventing 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 include
zidovudine, abacavir, lamivudine, emtricitabine, and
tenofovir

13. 3 Non-Nucleoside reverse
transcriptase inhibitors (NNRTI)
 These inhibit reverse transcriptase by binding to an
allosteric site of the enzyme; NNRTIs act as non-
competitive inhibitors of reverse transcriptase.
NNRTIs affect the handling of substrate (nucleotides)
by reverse transcriptase by binding near the active
site. 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.[11] HIV-2 is naturally resistant to NNRTIs

14. 4 Integrase inhibitors
 These are also known as integrase nuclear strand transfer
inhibitors or INSTIs) inhibit the viral enzyme integrase,
which is responsible for integration of viral DNA into the
DNA of the infected cell. There are several integrase
inhibitors currently under clinical trial, and raltegravir
became the first to receive FDA approval in October 2007.
Raltegravir has two metal binding groups that compete for
substrate with two Mg2+ ions at the metal binding site of
integrase. As of early 2014, two other clinically approved
integrase inhibitors are elvitegravir and dolutegravir.[13]

15. 5 Protease inhibitors
 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. Examples
of HIV protease inhibitors are Lopinavir,
Indinavir, Nelfinavir, Amprenavir and Ritonavir.
Darunavir and atazanavir are currently
recommended as first line therapy choices.

16. Fixed-dose combinations
 Brand Name Drug Names (INN) Date of FDA Approval
Company
 Combivir lamivudine + zidovudine September 26, 1997
GlaxoSmithKline
 Kaletra lopinavir + ritonavir September 15, 2000 Abbott
Laboratories
 Trizivir abacavir + lamivudine + zidovudine November 15, 2000
GlaxoSmithKline
 Epzicom (in USA)
 Kivexa (in Europe and Russia) abacavir + lamivudineAugust 2, 2004
GlaxoSmithkline

17.  Truvada tenofovir + emtricitabine August 2, 2004 Gilead Sciences
 Atripla emtricitabine + tenofovir + efavirenz July 12, 2006 Gilead
Sciences and
 Bristol-Myers Squibb
 Complera (in USA)
 Eviplera (in Europe and Russia) emtricitabine + rilpivirine + tenofovir
August 10, 2011Gilead Sciences and
 Janssen Therapeutics (formerly Tibotec)
 Stribild elvitegravir + cobicistat + emtricitabine + tenofovir August 27,
2012Gilead Sciences

18. Triumeq abacavir + dolutegravir +
lamivudine August 22, 2014 ViiV Healthcare
Evotaz atazanavir + cobicistat January 29,
2015 Bristol-Myers Squibb
Prezcobix darunavir + cobicistat January 29,
2015 Janssen Therapeutics
Dutrebis lamivudine + raltegravir February
6, 2015 Merck & Co.

19. Generic and Trade Names of Drugs for
Treatment of AIDS/HIV
Abacavir
Abacavir is an antiretroviral agent, prescribed for HIV-1/AIDS along with other medications.
Trade Names
Abamune | Abavir | Abcavir | Abec | Abmune | Virol |
Abacavir Sulfate and Lamivudine
Abacavir Sulfate and Lamivudine contains antiretroviral agents, prescribed for HIV-1 infection. It blocks
HIV reproduction.
Abacavir Sulfate, Lamivudine and Zidovudine
Abacavir Sulfate, Lamivudine and Zidovudine contains a nucleoside reverse transcriptase inhibitor
(NRTI), prescribed for HIV-1 infection. It works by preventing human immunodeficiency virus (HIV) cells
multiplication in your body.

20. Amantadine
 Amantadine is a synthetic (man-made) anti-viral and antiparkinson agent, prescribed for Parkinson's disease
also for treating certain types of flu.
 Trade Names
 Amantral | Amantrel | Comantrel | Neaman |
 Ampenavir
 Ampenavir is a protease inhibitor, prescribed for HIV/AIDS in combination with at least two other antiviral
medications. It inhibits the growth and multiplication of human immunodeficiency virus.
 Atazanavir
 Atazanavir is an antiretroviral drug, prescribed for HIV/AIDS. It inhibits HIV protease and blocks the formation of
new virus cells.
 Trade Names
 Atazor | Atazor (150mg) | Atazor (200mg) | Atazor (300mg) | Virataz (300 mg) |

21. Lamivudine
 Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor (nRTI), prescribed for
HIV/AIDS, and hepatitis B either alone or with other medication.
 Trade Names
 Emduo 30 | Emduo 40 | Emduo E 30 | Emduo E 40 | Emduo Junior DT | Emduo Susp |
Haptavir(100mg) | Hepavud | Hepitec | Hepravir | Heptavir | Heptavir (150 mg) | Hivir | Hivir (150
mg) | Ladiwin | Lamda | Lami | Lami (150 mg) | Lamidac | Lamidac -100 |
 More...
 Lamivudine- Zidovudine
 Lamivudine- Zidovudine contains antivirals, prescribed for HIV infection.
 Lopinavir and Ritonavir
 Lopinavir and Ritonavir contains antiretroviral agents, prescribed for HIV-1 infection.

22. Initiation of antiretroviral therapy
 Antiretroviral drug treatment guidelines have changed over
time. Before 1987, no antiretroviral drugs were available and
treatment consisted of treating complications from
opportunistic infections and malignancies. After antiretroviral
medications were introduced, most clinicians agreed that HIV
positive patients with low CD4 counts should be treatedThe
timing of when to initiate therapy has continued to be a core
controversy within the medical community. Most recently, the
NA-ACCORD study observed patients who started
antiretroviral therapy either at a CD4 count of less than 500
versus less than 350 and showed that patients who started
ART at lower CD4 counts had a 69% increase in the risk of
death

23. Special population
(Acute infections)
 In the first 6 months after infection HIV viral loads tend to be
elevated and people are more often symptomatic than in later
latent phases of HIV disease. There may be special benefits to
starting antiretroviral therapy early during this acute phase,
including lowering the viral "set-point" or baseline viral load,
reduce the mutation rate of the virus, and reduce the size of the
viral reservoir (See section below on viral reservoirs).[4] The
SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no
treatment in acute HIV infection and found that 48 weeks of
treatment delayed the time to decline in CD4 count below 350
cells per ml by 65 weeks and kept viral loads significantly lower
even after treatment was stopped

24. Children
 HIV can be especially harmful to infants and children, with one study in Africa
showing that 52% of untreated children born with HIV had died by age 2.[54]
By five years old, the risk of disease and death from HIV starts to approach
that of young adults. The WHO recommends treating all children less than 5
years old, and starting all children older than 5 with stage 3 or 4 disease or
CD4 <500 cells/ml.[39] DHHS guidelines are more complicated but
recommend starting all children less than 12 months old aThe WHO
recommends for children less than 3 years:[39]
 abacavir (or zidovudine) + lamivudine + lopinivir + ritonivir
 and for children 3 years to less than 10 years and adolescents <35 kilograms:
 abacavir + lamivudine + efavirenznd children of any age who have
symptoms

25. Pregnant Women
 The goals of treatment for pregnant women include the same
benefits to the mother as in other infected adults as well as
prevention of transmission to her child. The risk of transmission from
mother to child is proportional to the plasma viral load of the
mother. Untreated mothers with a viral load >100,000 copies/ml
have a transmission risk of over 50%.The risk when viral loads are <
1000 copies/ml are less than 1%. ART for mothers both before and
during delivery and to mothers and infants after delivery are
recommended to substantially reduce the risk of transmission] The
WHO balances the low risk of transmission through breast feeding
from women who are on ART with the benefits of breastfeeding
against diarrhea, prneumonia and malnutrition

26. Older Adults
 With improvements in HIV therapy, several studies now estimate
that patients on treatment in high-income countries can expect a
normal life expectancy. This means that a higher proportion of
people living with HIV are now older and research is ongoing into
the unique aspects , but it is important to take into account that
older patients are more likely to be on multiple non-HIV
medications and consider drug interactions with any potential HIV
medications. There are also increased rates of HIV associated non-
AIDS conditions (HANA) such as heart disease, liver disease and
dementia that are multifactorial complications from HIV, associated
behaviors.

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